Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(O)CO>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: OCCO
Product: CCOC(=O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21

Procedure:
A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. The material crystallized upon cooling. A small portion of the solid was collected by filtration, washed with water, and dried under high vacuum. The solid was recrystallized from ethanol with refrigeration, collected by filtration, washed with ethanol/water mixture, and dried under high vacuum at 70° C. over 2 days to give 2.0 g, mp 141°-42° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([NH:5][CH2:6][CH2:7][OH:8])[CH3:4].C(N(C(C)C)CC)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>ClCCl>[Si:20]([O:8][CH2:7][CH2:6][NH:5][CH:3]([CH3:4])[C:2]([F:10])([F:9])[F:1])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(NCCO)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(NCCO[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred solution of 2-(1,1,1-trifluoropropan-2-ylamino)ethanol (40) (5.50 g, 35.0 mmol, Eq: 1.00) in dichloromethane (100 ml) were added diisopropylethylamine (6.33 g, 8.56 ml, 49.0 mmol, Eq: 1.4) followed by tert-butyldimethylsilyl chloride (5.8 g, 38.5 mmol, Eq: 1.1) at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 hrs and then it was poured into water (100 ml) and the organic layer was separated, washed with brine, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 0 to 10% ethyl acetate-hexane) to obtain N-(2-(tert-butyldimethylsilyloxy)ethyl)-1,1,1-trifluoropropan-2-amine (41) (oil, 3.52 g, 13.0 mmol, 37.1% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH:12]([OH:15])[CH2:13][Cl:14])=[N:7][C:6]=2[CH:16]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[ClH:14].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH:12]([OH:15])[CH2:13][NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:6]=2[CH:16]=1
Reactant: CC(C)(C)N
Reactant: Cc1ccc2sc(SCC(O)CCl)nc2c1
Product: Cc1ccc2sc(SCC(O)CNC(C)(C)C)nc2c1
Product: Cl

Procedure:
A mixture of 10 g. of 5-methyl-2-(3'-chloro-2'-hydroxypropylthio)benzothiazole and 20 ml. of t-butylamine was heated at 100°C. in a sealed tube for 4 hours, and dried in vacuo to give a yellow oil, which was purified by column chromatography on basic alumina and converted to its hydrochloride by a usual method. This hydrochloride was recrystallized from acetone-methanol to give needles of 5-methyl-2-(3'-t-butylamino-2'-hydroxypropylthio)benzothiazole hydrochloride, mp 152° - 155°C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][O:8][C@@H:7]([CH2:11][NH:12][C:13]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[CH:16]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:6]1)(=[O:4])=[O:3].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+]>C(Cl)Cl>[CH3:39][N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C@@H:7]4[O:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]4)[C:22]4[C:17](=[N:18][CH:19]=[CH:20][N:21]=4)[CH:16]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CS(=O)(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCNCC4)cc3)cc3nccnc23)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cc4nccnc4c(NC[C@H]4CN(S(C)(=O)=O)CCO4)n3)cc2)CC1

Procedure:
A solution of (S)—N-((4-(methylsulfonyl)morpholin-2-yl)methyl)-7-(4-(piperazin-1-yl)phenyl)pyrido[4,3-b]pyrazin-5-amine (60 mg, 0.12 mmol), Formalin (48 mg, 0.48 mmol) and NaBH(AcO)3 in 5 mL of DCM, was stirred at room temperature for 2 hours. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:10˜10:1) to give 46 mg of title compound. MS (m/z)=498 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:9]C(=O)C(C)[O:5][C:3]1=[O:4].[CH2:11]1[O:18]C(=O)C[O:14][C:12]1=[O:13].C(Cl)(Cl)Cl.CCCCCCCC/C=C\CCCCCCCC(OCC(OC(CCCCCCC/C=C\CCCCCCCC)=O)C[N+](C)(C)C)=O.O>C(Cl)Cl>[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9].[C:12]([OH:14])(=[O:13])[CH2:11][OH:18]
Reactant: O=C1COC(=O)CO1
Reactant: CC1OC(=O)C(C)OC1=O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)C(=O)O
Product: O=C(O)CO
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Cationic poly(lactic acid, glycolic acid) microcarriers (cPLGA) were prepared as follows. 0.875 g of poly (D,L-lactide-co-glycolide) 50:50 polymer (Boehringer Mannheim, Indianapolis, Ind.) with an intrinsic viscosity of 0.41 dl/g (0.1%, chloroform, 25° C.) was dissolved in 7.875 g of methylene chloride at 10% w/w concentration, along with 0.3 g of DOTAP. The clear organic phase was then emulsified into 500 ml of PVA aqueous solution (0.35% w/v) by homogenization at 4000 rpm for 30 minutes at room temperature using a laboratory mixer (Silverson L4R, Silverson Instruments). System temperature was then raised to 40° C. by circulating hot water through the jacket of the mixing vessel. Simultaneously, the stirring rate was reduced to 1500 rpm, and these conditions were maintained for 2 hours to extract and evaporate methylene chloride. The microsphere suspension was allowed to cool down to room temperature with the help of circulating cold water.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:22])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (840 mg, 1.8 mmol) produced in Synthesis Example 27 in DMF (7 mL) was added hydrazine monohydrate (purity of 80%, 285 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (770 mg, yield 92%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)[CH3:7].CN(C)[CH:21]=[O:22]>>[CH2:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:21]=[O:22])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)[CH3:7]
Reactant: CN(C)C=O
Reactant: CCc1cc2cc(OC)ccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1[nH]c2ccc(OC)cc2c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Dimethylformamide (1 mL) was cooled to 0° C. Phosphorus oxychloride (0.25 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 2-ethyl-5-methoxyindole (226 mg, 1.7 mmol) in dimethylformamide (2 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (25 mL) and stirred for 10 minutes. The precipitate was collected, washed with cold water and dried overnight in a vacuum desiccator set at 40° C. equipped to an oil driven vacuum pump yielding a white solid (213 mg, 62%): TLC Rf 0.55 in 4:1 ethyl acetate/hexanes. Melting point=211-212° C. 1H NMR (600 MHz, CDCl3) δ 11.84 (s, 1H), 10.04 (s, 1H), 7.58 (d, 1H, J=2.4 Hz), 7.30-7.28 (d, 1H, J=9 Hz), 6.81-6.79 (dd, 1H, J1=9 Hz, J2=2.4 Hz), 3.77 (s, 3H), 3.08-3.04 (q, 2H, J=7.8 Hz), 1.33-1.28 (t, 3H, J=7.8 Hz). 13C NMR (150 MHz, CDCl3) δ 183.86, 155.48, 153.86, 130.09, 126.33, 112.68, 112.20, 111.95, 102.41, 55.25, 18.92, 14.54. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.92; H, 6.97; N, 6.34.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([OH:41])=[C:36]([CH3:42])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:43]=[CH:44][CH:45]=[CH:46][C:4]=2[NH:3]1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:41][C:47](=[O:49])[CH3:48])=[C:36]([CH3:42])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:43]=[CH:44][CH:45]=[CH:46][C:4]=2[NH:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Product: CC(=O)Oc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C

Procedure:
A solution of 42 mg (0.07 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 7i) in 5 mL acetic anhydride was heated to 50° C. for 2 h. The mixture was evaporated down i.vac. and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:20])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])C.[OH-].[Na+]>CCO.O>[C:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:6]1([CH3:20])[C:4]([OH:5])=[O:3])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(C)CCCCN1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C(=O)O)CCCCN1C(=O)c1ccccc1
Temperature: 40 °C
Yield: 12.9 %

Procedure:
Ethyl-1-benzoyl-2-methyl-piperidine-2-carboxylate (6.49 g, 23.51 mmol) was dissolved in EtOH (54 mL) and H2O (16 mL). NaOH (2.75 g, 68.6 mmol) was added and the reaction was heated to 40° C. for 1 h. An additional portion of NaOH (2.75 g, 68.6 mmol) was added and the reaction was heated to 65° C. for 1 h. The ethanol was removed and the residue was diluted with 50 mL of H2O. The pH was adjusted to ~2 with HCl (c). The aqueous layer was extracted 3× with ether and ethyl acetate. Removal of solvent provided 0.75 g, 22% yield of 1-benzoyl-2-methyl-piperidine-2-carboxylic acid. 1H NMR (200 MHz, DMSO) δ1.4 (s, 3H), 1.5-1.9 (comp m, 4H), 3.0 (m, 2H), 3.4 (m, 2H), 7.4 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:25])=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(Cl)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (R)-tert-butyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (1.17 g, 3.22 mmol) in 50 mL of dichloromethane was added 10 mL of trifluoroacetic acid in portions. The reaction was stirred at RT for 1 hour. The solvent was evaporated, and the residue was dissolved in 20 mL of dichloromethane, cooled to 0° C., and quenched with 1M NaOH until basic. After partitioning between CH2Cl2 and H2O, the mixture was separated and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (800 mg, 94% yield). LC/MS: m/z 262.9 (M+H)+ at 0.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH3:15][NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>O>[CH3:15][NH:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCCCCCCCCCCCCN
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A mixture of 1,12-diaminododecane (3 g) and N-methyl-1-(methylthio)-2-nitroethenamine (1.48 g) in water (50 ml) was stirred at room temperature for 20 hours. The solution was evaporated in vacuo and the residue chromatographed (silica/methanol). The appropriate eluate was evaporated to yield the title compound (1.8 g), mp. 123°-125°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][NH:9][CH2:10][CH2:11][NH2:12].ClCCCl.CCO>C(O)(C)C.[Cu].[Cu]Cl>[Br:7][C:4]1[S:3][C:2]([N:9]([CH3:8])[CH2:10][CH2:11][NH2:12])=[N:6][CH:5]=1
Reactant: CNCCN
Reactant: Brc1cnc(Br)s1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: ClCCCl
Solvent: CC(C)O
Solvent: CCO
Product: CN(CCN)c1ncc(Br)s1
Temperature: 70 °C
Yield: 36.6 %

Procedure:
15 mg (0.24 mmol) of copper and 68 mg (0.69 mmol) of copper(I) chloride were added to a solution of 1.0 g (4.1 mmol) of 2,5-dibromothiazole and 2.2 ml (24.7 mmol) of N-methylethylenediamine in isopropanol (2.3 ml). The mixture was then heated to 70° C. for 1 h. After cooling to RT, filtration through silica gel was carried out and the filtrate was evaporated under a vacuum. 348 mg (1.5 mmol, 36%) of N1-(5-bromothiazol-2-yl)-N1-methylethane-1,2-diamine were obtained by CC (DCE/EtOH/conc. aq. NH4—OH soln. 5:1:0.06) with the residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1>[F:11][C:9]1[CH:10]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2
Reactant: Fc1cc(Br)cc2cc[nH]c12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c2[nH]ccc2c1
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THF at −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at −60° C. for 4 h and was then poured onto an excess of freshly crushed dry ice. Water was added and the mixture was acidified to pH=4. The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 70h.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (89.7 mg, 67%)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C@@H:8]2[O:12][CH2:11][C@@H:10]([S:13]C(=O)C)[CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[O:12][CH2:11][CH:10]([SH:13])[CH2:9]2)=[CH:17][CH:18]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COc2ccc(F)cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(OCC2CC(S)CO2)cc1

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.943 gof product from Example 35, 0.86 ml of 25% sodium methoxide/methyl alcohol and 12 ml of tetrahydrofuran to give 0.417 g of the desired product.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1>>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][N:32]([C:3]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:22])[F:23])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:2])[CH2:33][CH2:34]1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1)N1CCS(=O)(=O)CC1
Yield: 77.3 %

Procedure:
As described for Example 32, 4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (100 mg, 0.23 mmol) was converted, using thiomorpholine 1,1-dioxide (125.4 mg, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (95 mg, 77%) which was obtained as a white solid. MS: m/e=534.8 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:27]5[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35][CH2:36][CH2:37][NH2:38].[Cl:39]CCl>>[ClH:39].[ClH:39].[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:27]5[O:31][C:30]([CH2:32][NH:38][CH2:37][CH2:36][S:35][CH3:34])=[CH:29][CH:28]=5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: CSCCN
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cn2)o1
Product: CSCCNCc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cn2)o1
Product: Cl

Procedure:
5-(4-((4-Benzenesulphonyl-phenyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (250 mg) and (methylthio)ethylamine (185 mg)) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge, gave a yellow solid (245 mg), 70 mg of which was converted to the hydrochloride salt, (yellow solid, 68 mg); m/z 532 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C4C(=CC=CC=4)N=C(C)C=3)=[CH:17][CH:16]=2)[CH2:11]1)=[O:4]>C(OCC)(=O)C.CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11]1)=[O:4]
Reactant: COC(=O)C1=C(C2CC(c3ccc(OCc4cc(C)nc5ccccc45)cc3)=NO2)CCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1C1CC(c2ccc(O)cc2)=NO1
Reaction time: 3 h
Yield: 100 %

Procedure:
2-{3-[4-(2-Methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-cyclopent-1-enecarboxylic acid methyl ester intermediate from Example 27, was dissolved in ethyl acetate:methanol (1:1) (20 mL), degassed with nitrogen, and charged with 10% palladium on carbon and 50 PSI hydrogen. The reaction was shaken for 3 h, filtered, and concentrated to give cis-2-[3-(4-hydroxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-cyclopentanecarboxylic acid methyl ester (0.127 g, 100%) as an oil. MS found: (M+H)+=290.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]([N:26]2[CH2:31][C@H:30]([CH3:32])[N:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][C@H:27]2[CH3:41])=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C.ClCCl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH2:23][C:24]([N:26]2[CH2:31][C@H:30]([CH3:32])[N:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][C@H:27]2[CH3:41])=[O:25])=[C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:42])[CH:20]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of (2R, 5S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (0.110 g, 0.182 mmol) in dichloroethane (10 ml) was added trifluoroacetic acid (5 ml). The reaction was stirred for two hours at ambient temperature. The reaction was then diluted with dichloromethane and washed with 1N aqueous sodium hydroxide. The organics were dried over magnesium sulfate, filtered and concentrated to give the title compound (0.080 g, 87% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
1 g (4.62 mmol) of 5-bromoanthranilic acid (Fluka Buchs, Switzerland) and 6.94 ml 1M K2CO3 are stirred in 10 ml DMF. Argon gas is bubbled through the solution. 50 mg tetrakis-triphenylphosphin-palladium (Fluka) and 846 mg (6.94 mmol) phenylboronic acid (Fluka, Buchs, Switzerland) are added. The reaction mixture is stirred for 15 h at 80° C. (tlc-control). The solvent is evaporated, and 50 ml 4N NaOH are added to the residue. The aqueous phase is washed three times with ethyl acetate. Hydrochloric acid is added to the water phase until pH=7 is reached and the aqueous phase is extracted four times with ethyl acetate. After drying the organic phase with MgSO4, the solvent is evaporated and the residue crystallized from CH2Cl2-methanol-hexane. mp: 245° C. (dec.); MS: 214 (M++1); HPLC: tret=9.74 min (Grad 1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[NH:14][CH:13]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[NH:14][CH:13]=1)=[S:31]
Reactant: O=C(Nc1cccc(F)c1F)c1c[nH]c2ncc(Br)cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(NC(=S)c2c[nH]c3ncc(Br)cc23)c1F

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2,3-difluoro-phenyl)-amide (300 mg, 0.85 mmol) in toluene (6 mL) was added Lawesson's reagent (210 mg, 0.52 mmol). The suspension was heated under reflux for 14 h. The solvent was removed by evaporation and the residue was dried on the pump for the next reaction. MS (ES+): m/e=368 (M+H); LC: 3.6 min.