Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9](Cl)=[O:10])=[CH:8][C:4]=2[CH:3]=1.[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:20]1[CH:21]=[N:22][C:23]([NH2:29])=[C:24]([O:26][CH2:27][CH3:28])[CH:25]=1)([OH:19])[CH3:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:20]1[CH:21]=[N:22][C:23]([NH:29][C:9]([C:7]2[NH:6][C:5]3[S:12][C:2]([Cl:1])=[CH:3][C:4]=3[CH:8]=2)=[O:10])=[C:24]([O:26][CH2:27][CH3:28])[CH:25]=1)([OH:19])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)(O)c1cnc(N)c(OCC)c1
Reactant: O=C(Cl)c1cc2cc(Cl)sc2[nH]1
Product: CCOC(=O)C(C)(O)c1cnc(NC(=O)c2cc3cc(Cl)sc3[nH]2)c(OCC)c1

Procedure:
The title compound was prepared from 2-chloro-6H-thieno[2,3-b]pyrrole-5-carbonyl chloride and 2-(6-amino-5-ethoxy-pyridin-3-yl)-2-hydroxy-propionic acid ethyl ester in a manner analogous to that described hereinabove in Example 2 using appropriate starting materials. LC/MS+=438.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[NH:40])[NH2:39])=[CH:34][CH:33]=1)=[O:5])C.[OH-].[Na+]>>[OH:5][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:18])=[O:19])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH2:40])=[CH:36][CH:37]=1)=[O:3]
Reactant: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(OCc2nc3cc(NS(=O)(=O)c4cccc5cccnc45)ccc3n2CC(=O)O)cc1

Procedure:
Prepared analogously to Example 3 from 1-ethoxycarbonylmethyl-2-[(4-amidinophenyl)-oxymethyl]-5-(quinoline-8-sulphonylamino)-benzimidazole and sodium hydroxide solution.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C.O>O1CCCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)c2ccc(F)cc2)CCNCC1
Temperature: 60 °C
Yield: 0 %

Procedure:
N-boc-4-methyl-4-piperidinecarboxylic acid (4 g, 16 mol), 4-Fluorobenzeneboronic acid (2.7 g, 20 mol), Pivalic anhydride (4.6 g, 25 mmol), Pd(OAc)2(0.111 g, 0.4 mol), 1,1′-Bis(diphenylphosphino)ferrocene (0.319 g, 0.1 mol) and (0.7 mL, 41 mmol) of water are mixed together in 20 mL of tetrahydrofuran and the mixture heated at 60° C. overnight. The reaction mixture was filtrated and the solvent was removed under vacuum. The residue was purified with column chromatography on silica using n-heptane-EtOAc (4:1) to yield 0.216 g (5%) of the title compound. MS (m/e): 322.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19].[Cl:20][C:21]([Cl:25])([F:24])[S:22]Cl>ClCCl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:14]([CH3:19])=[CH:15][C:16]([S:22][C:21]([Cl:25])([Cl:20])[F:24])=[C:17]1[CH3:18]
Reactant: Cc1ccc(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: FC(Cl)(Cl)SCl
Solvent: ClCCl
Product: Cc1cc(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 89.6 %

Procedure:
To a cooled (0° C.) solution of 3.00 g (9.74 mmoles) of the 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethylpyrrole prepared above in 60 mL of dichloromethane was added dropwise 1.03 mL (1.67 g, 9.86 mmoles) of dichlorofluoromethanesulfenyl chloride in 5 mL of dichloromethane solution. The mixture was maintained at 0° C. for 3 hours and then washed with a saturated aqueous solution of NaHCO3. Removal of solvent under reduced pressure afforded a black off which was chromatographed on silica gel with a 1% EtOAc in hexane eluent to give 3.85 g (90%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole as a yellow off: 1H NMR (CDCl3): δ2.00 (s, 3H), 2.10 (s, 3H), 6.27 (s, 1H), 7.80 (s, 2H).
Reaction SMILES: C([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:30]/[O:31][CH2:32][F:33])/[C:27]([OH:29])=[O:28])[N:22]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:30]/[O:31][CH2:32][F:33])/[C:27]([OH:29])=[O:28])[N:22]=1
Reactant: O=C(O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
Added to trifluoroacetic acid (100 ml) was 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid (13 g). The resulting mixture was stirred at room temperature for 24 hours. Trifluoroacetic acid was distilled off under reduced pressure. Water (100 ml) was added to the residue and an insoluble matter was filtered off. The solvent was distilled off from the filtrate under reduced pressure. The residue was crystallized from a 1:3 mixture of acetone and isopropyl ether, thereby obtaining the target product (2.18 g) as white crystals.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[O:24][CH3:25])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:14]1[CH:13]=[C:12]2[C:17](=[N:16][CH:15]=1)[NH:8][CH2:9][CH2:10][CH2:11]2
Reactant: COc1ccncc1-c1cnc2c(c1)CCCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccncc1-c1cnc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
6-(4-Methoxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (420 mg, 1.2 mmol) is dissolved in 20% trifluoroacetic acid in DCM (20 mL). The solution is stirred at room temperature for 16 hrs and then the solvent is removed. The residue is dissolved in DCM and saturated aqueous NaHCO3 solution is used to adjust the pH to 9˜10. The organic layer is separated, dried over Na2SO4, filtered and concentrated to give 290 mg of 6-(4-methoxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (290 mg crude) which is converted to 38 mg of the titled product according to the procedure of Urea Formation Method I.
Reaction SMILES: [CH3:1][C:2]1([OH:18])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([CH3:1])([OH:18])[CH2:3][CH2:4]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1ncc(N)c1N1CCCC(C)(O)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (212 mg, 0.83 mmol) in MeOH (15 mL) was added ammonium formate (386 mg, 5.63 mmol) and 10% palladium on carbon (88 mg, 0.83 mmol) and the mixture was heated at 80° C. for 18 hr. The mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was partitioned between DCM (20 mL) and water (20 mL) and the aqueous layer was re-extracted with DCM (3×20 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure to give 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-ol as a red oil. To a solution of this oil (140 mg, 0.623 mmol) in DCM (25 mL) was added 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (241 mg, 0.75 mmol), PyBOP (454 mg, 1.94 mmol) and DIPEA (0.17 mL, 1.0 mmol) and the mixture was stirred at room temperature for 16 hr. Water (20 ml) was added and the mixture was diluted with DCM (100 mL). The organic layer was washed with water (20 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-bromo-4-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (280 mg, 63% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 9.41 (s, 1H), 7.95 (s, 1H), 3.71 (s, 3H), 3.41-3.30 (m, 1H), 3.24-3.11 (m, 3H), 2.39 (br s, 1H), 2.07-1.75 (m, 5H), 1.84-1.78 (m, 1H), 1.52 (s, 9H), 1.43 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([OH:9])=O)([O-])=O.C(Cl)(=O)C(Cl)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[CH:26][CH:27]=1)=[O:9]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Product: Nc1cc(C(=O)Nc2ccc(F)cc2)ccc1OC(F)(F)F
Yield: 88.5 %

Procedure:
Prepared according to the procedure described for Example 1 using 3-nitro-4-trifluoromethoxybenzoic acid from Step A (5.1 g, 20.5 mmol), oxalyl chloride (2.1 mL, 20.5 mmol), and 4-fluoroaniline (Aldrich, Milwaukee, Wis.) (4.6 g, 41.1 mmol) to afford the product (5.7 g); m.p. 139-140° C.
Reaction SMILES: [NH2:1][NH2:2].Cl.[F:4][C:5]1[C:6]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[C:7]([C:11]([F:14])=[CH:12][CH:13]=1)[C:8](O)=[O:9]>C(O)C>[F:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:7]2[C:6]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[N:1][N:2]=[C:8]2[OH:9]
Reactant: NN
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccccn1
Agent: Cl
Solvent: CCO
Product: Oc1nnc(-c2ccccn2)c2c(F)ccc(F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3M-solution of hydrazine (60 mmol) in ethanol is added to a solution of crude 3,6-difluoro-2-(2-pyridylcarbonyl)benzoic acid hydrochloride (20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation yields 5,8-difluoro-4-(2-pyridyl)-1-phthalazinol.
Reaction SMILES: [CH:1]1C=CC2N(O)N=NC=2[CH:6]=1.CCN(CC)CC.[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(N)CC1.C(Cl)CCl>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:27]([OH:31])[C:28]([O:30][CH2:1][CH3:6])=[O:29])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)O
Agent: NC1CC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
74.2 Tert-butyl 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamate EDC (8.3 g, 43.3 mmol), HOBT (6.6 g, 43.1 mmol) and Et3N (7 ml, 50.2 mmol) were added to a mixture of 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (10.6 g, 35.9 mmol) and cyclopropylamine (3.3 ml, 47.6 mmol) in DCM (300 mL) at 5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After cooling to 5° C. more cyclopropylamine (2 ml, 28.5 mmol), EDC (5 g, 26.1 mmol), HOBT (4 g, 26.1 mmol) and Et3N (3.5 ml, 25.1 mmol) were added, the mixture was allowed to warm to room temperature and the stirring was continued overnight. DCM (300 mL) was added, followed by washing with 0.5 M aqueous HCl solution, brine and drying with MgSO4. The crude product was recrystallized from methyl-tert-butylether, the crystals obtained were washed with n-pentane and dried providing the title compound (10.2 g, 85%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[CH:11]=1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[CH:23]1[C:24]2[C:19](=[C:18]([NH:17][CH2:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH2:8])[CH:11]=3)[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2cccc3cnccc23)c1
Agent: Cl
Solvent: CO
Product: NCc1cccc(CNc2cccc3cnccc23)c1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 44 (364 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (316 mg) as light yellow powdery solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:29]=[C:28]([N:30]2[C:34]([NH:35][CH2:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH:39]=[CH:40][NH:41]4)=[N:33][N:32]=[N:31]2)[CH:27]=[C:26]([CH3:46])[C:22]=1[C:23]([OH:25])=O.ClN1C(=O)CCC1=O.[CH3:55][O:56][C:57](=[O:66])[CH:58]([P:60]([O:64][CH3:65])([O:62][CH3:63])=[O:61])[NH2:59].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O>ClCCl>[CH3:55][O:56][C:57](=[O:66])[CH:58]([P:60]([O:62][CH3:63])([O:64][CH3:65])=[O:61])[NH:59][C:23](=[O:25])[C:22]1[C:26]([CH3:46])=[CH:27][C:28]([N:30]2[C:34]([NH:35][CH2:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH:39]=[CH:40][NH:41]4)=[N:33][N:32]=[N:31]2)=[CH:29][C:21]=1[CH3:20]
Reactant: Cc1cc(-n2nnnc2NCc2cccc3[nH]ccc23)cc(C)c1C(=O)O
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1c(C)cc(-n2nnnc2NCc2cccc3[nH]ccc23)cc1C)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (1.31 g, 5 mmol) is added to a suspension of give 2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoic acid (Example 329; 1.81 g, 5 mmol) in dichloromethane (25 mL) at 25° C. The mixture is cooled to 0° C. and N-chlorosuccinimide (0.668 g, 5 mmol) is added. After stirring 15 min at 0° C., the mixture is stirred for an additional 15 min at 25° C. and then a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (3.01 g, 10 mmol) in dichloromethane (5 mL) is added in one portion. The reaction is stirred for 5 h, then the precipitated amine hydrochloride is filtered off, washed with dichloromethane and discarded. The filtrate is washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then is dried (MgSO4) and concentrated under reduced pressure. The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) and the appropriate fractions are combined and evaporated to yield rac.-N-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.O>C1COCC1>[N:26]([CH:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc2c1CCC2O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cccc2c1CCC2N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.34 g (29.28 mmol) 4-methyl-indan-1-ol and 7.8 ml (35.14 mmol) diphenylphosphoryl azide are dissolved in dry THF at room temperature under argon. To this mixture is added slowly 5.0 ml (35.14 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is stirred for 6 h at room temperature (TLC monitoring). Then the mixture is poured into water and extracted three times with toluene. The organic layers are combined, dried over MgSO4 and concentrated in vacuo. Purification using silica gel chromatography (hexane/EtOAc 9:1) affords pure 1-azido-4-methyl-indane as light orange liquid.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[CH:30]=[CH:29][C:13]([CH2:14][S:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].CCOC(OC(OCC)=O)=O.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C>[CH3:26][N:25]1[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:28])[N:17]=[C:16]1[S:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1]([N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[O:2])=[CH:32][CH:31]=2)=[CH:30][CH:29]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)O)cc4)cc3)n(C)c(=O)c12
Reactant: CN1CCNCC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)N5CCN(C)CC5)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (0.320 g, 0.720 mmol) in DMF (5.0 ml) were added DEPC (0.37 g, 2.27 mmol) and 1-methylpiperazine (0.200 ml, 1.80 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol: ammonia=20:1:0.1). The resulting solid was recrystallized from ethanol to provide colorless needles.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][C:29]2[CH:30]=[N:31][C:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:27][CH:28]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCOCC3)nc2)=C(c2ccccc2)S1(=O)=O
Yield: 17.2 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol), 6-morpholin-4-ylpyridin-3-amine (0.108 g, 0.60 mmol) and TEA (0.06 mL, 0.60 mmol) in MeCN (2 mL) was heated at 140° C. for 1 h in a microwave reactor. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 3:1 mixture of EtOAc and petroleum ether as eluant, to give the title compound (0.038 g, 17%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.81 (d, 1H), 7.24-7.1.5 (m, 1H), 7.14-7.10 (m, 4H), 6.94 (s, 1H), 6.72 (dd, 1H), 6.12 (d, 1H), 3.75 (t, 4H), 3.33 (t, 4H), 1.77 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.9, 157.5, 142.9, 131.6, 131.9, 130.0, 129.1, 128.3, 124.7, 124.2, 110.2, 105.9, 66.7, 62.1, 46.1, 27.9; Mass Spectrum: M+H+ 443.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25]O>CO>[CH3:25][O:15][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH:10]1[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16]
Reactant: CO
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 76 °C

Procedure:
In a 500 ml round bottom flask with a magnetic stirring bar 3 g (9 mmol) (3RS, 4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid (SM050/4A) were suspended in 100 ml methanol. 50 mL 1.25 N HCl/MeOH was added and the mixture was stirred over night at reflux (76° C.). Another 50 mL 1.25 N HCl/MeOH was added and the reaction mixture was continued to reflux for 24 h. The solvent was removed by evaporation and the brown residue was diluted with 200 mL Na2CO3 aq. sat. and 5 mL 4 N NaOH aq. The mixture was extracted with 3 portions of 200 mL ethyl acetate. The combined organic layers were washed with 150 mL brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with ethyl acetate/heptane to yield after evaporation of the product containing fractions 2.74 g (88%) of the title compound as light yellow viscous oil. MS (m/e): 344.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11](O)[CH2:10][CH:9]=[CH:8]2.P(Cl)(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:19])[CH:9]=[CH:8]2
Reactant: COC(=O)Cc1ccc2c(c1)C=CCN2O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc2nc(Cl)ccc2c1
Yield: 20 %

Procedure:
(1-Hydroxy-quinolin-6-yl)-acetic acid methyl ester (1.0 g, 4.61 mmol) was refluxed for 25 minutes in phosphorous oxychloride (30 mL). The excess phosphorous oxychloride was evaporated, saturated sodium bicarbonate was added and the crude mixture was extracted several times with ethyl acetate. The product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.219 g (20%) of (2-chloro-quinolin-6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.8 Hz), 7.63 (m, 1H), 7.60 (dd, 1H, J=2.0, 8.4 Hz), 7.30 (d, 1H, J=8.8 Hz), 3.73 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][CH2:59][NH2:60]>CN(C=O)C>[CH3:56][O:57][CH2:58][CH2:59][NH:60][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: COCCN
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-methoxy-ethylamine (35 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 8 days, the reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and purified on a silica gel column to give the titled compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:19][C@H:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH3:18])[CH:7]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: Clc1cc(Cl)nc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: C[C@H](Nc1cc(Cl)cc(Cl)n1)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 42 h
Yield: 45.8 %

Procedure:
7.2 g of 2,4,6-trichloropyridine and 2.74 g of (S)-(−)-1-(4-fluorophenyl)ethylamine were dissolved in 25 ml of 1-butanol, and 13.7 ml of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 120° C. for 42 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.57 g of the objective compound as yellow oil.