Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([C:13]2[N:18]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[N:16]=[C:15]([N:22]3[CH2:25][CH:24]([OH:26])[CH2:23]3)[C:14]=2[CH3:27])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[N:6]1([C:13]2[N:18]=[C:17]([CH:19]3[CH2:20][CH2:21]3)[N:16]=[C:15]([N:22]3[CH2:23][CH:24]([O:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:25]3)[C:14]=2[CH3:27])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
A solution of methanesulfonyl chloride (0.63 ml, 7.6 mmol) in dichloromethane (10 ml) is added dropwise to a solution of 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyrimidin-4-yl)-azetidin-3-ol 189 (1.90 g, 6.3 mmol) and triethylamine (1.74 ml, 13 mmol) in dichloromethane (90 ml) at 0° C. The mixture is stirred 1 hour at 0° C. and 1 hour at room temperature. Water (40 ml) is added and the mixture is extracted three times with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford pure methanesulfonic acid 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyrimidin-4-yl)-azetidin-3-yl ester 190 (2.66 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10](OC)=[O:11])=[N:4][CH:3]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][N:16]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccnc(-c2ncc(C)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(-c2cc(CO)ccn2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-(5-methylthiazol-2-yl)isonicotinate (2.390 g; 10.20 mmol) in anh. MeOH (50 ml) was treated with NaBH4 (772 mg; 20.40 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 24 h. After concentration to dryness under reduced pressure, the resulting residue was treated with water, and extracted with DCM. The organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (2-(5-methylthiazol-2-yl)pyridin-4-yl)methanol as an off-white solid. LC-MS (conditions A): tR=0.48 min.; [M+H]+: 207.05 g/mol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8]2.O.[OH-].[Na+]>Br>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2ccc(C(F)(F)F)nc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc2ccc(C(F)(F)F)nc12
Yield: 99.1 %

Procedure:
A solution of 8-methoxy-2-trifluoromethylquinoline (10.0 g) in 48% hydrobromic acid (40 ml) was stirred at reflux overnight. The reaction mixture was poured into water (200 ml) and the pH adjusted to 12.5 using 46-48% sodium hydroxide solution. After extraction with dichloromethane (2×25 ml) the aqueous layer was acidified to pH5.3 by the addition of 37% hydrochloric acid solution. The mixture was then extracted using dichloromethane (2×100 ml) and the combined organic extracts washed with water, dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (9.3 g) as a white solid.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH2:18]>C(O)C>[O:14]=[C:5]1[NH:4][C:3]([NH:18][C:17]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:16]=2[CH3:15])=[N:8][CH:7]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Cc1ccc(C)c(N)c1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cc(C)ccc2C)[nH]c1=O
Reaction time: 17 h
Yield: 45.5 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5pyrimidinecarboxylate (10 g) and 2,5-dimethylaniline (8.5 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-6-oxo-2-(2,5-dimethylanilino)-5-pyrimidinecarboxylate (6.1 g). M.p. 252°-254° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:22]=[C:23]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:17]=2)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (64 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 441 (M+1). Mp: 130.0-131.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17](OCC)=[O:18])=[N:15][N:16]=2)[N:13]=1.[CH2:29]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[CH2:29]([CH:36]1[CH2:41][CH2:40][N:39]([C:17]([C:14]2[N:12]3[N:13]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[CH:10][C:11]3=[N:16][N:15]=2)=[O:18])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CCOC(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Solvent: CO
Product: O=C(c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.4 %

Procedure:
A solution of ethyl 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (21 mg, 0.05 mmol) and 4-benzylpiperidine (0.175 mL, 1.0 mmol) in methanol (0.5 mL) was heated in a microwave oven at 160° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, then the crude product was purified using reverse phase preparative HPLC (Conditions: Water SunFire Prep C18, OBD 19×100 m, 5 □m; Fluted with 0% to 100% B, 10 min gradient, 100% B hold for 5 min, (A 90% H2O, 10% MeOH, 0.1% of TEA and B 10% H2O, 90% MeOH, 0.1% of TFA); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 18 mg (66%) of the title compound as a white powder. HPLC/MS (method A): retention time=4.12 min, (M+H)+=542.1.
Reaction SMILES: [CH3:1][C:2]1([CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:7][CH2:6][C:5]([CH2:14]OC(=O)CC)([CH2:8][O:9]C(=O)CC)[CH2:4][O:3]1.[C:26]([O:30][CH2:31][C:32](=[O:34])[CH3:33])(=[O:29])[CH2:27][CH3:28]>>[CH3:1][C:2]1([CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:7][CH2:6][C:5]2([CH2:8][O:9][C:32]([CH3:33])([CH2:31][O:30][C:26](=[O:29])[CH2:27][CH3:28])[O:34][CH2:14]2)[CH2:4][O:3]1
Reactant: CCC(=O)OCC1(COC(=O)CC)COC(C)(COC(=O)CC)OC1
Reactant: CCC(=O)OCC(C)=O
Product: CCC(=O)OCC1(C)OCC2(CO1)COC(C)(COC(=O)CC)OC2
Yield: 53 %

Procedure:
A solution of propionyloxyacetone (10 g, 76.8 mmol), pentaerythritol (5.22 g, 38.4 mmol), and pyridinium p-toluenesulfonate (1.0 g, 4 mmol) in toluene (200 ml) was stirred under reflux for 6 hours, while water was removed using a Dean-Stark water separator. After cooling to room temperature, the reaction liquid was poured into ethyl acetate (300 ml)/an aqueous sodium hydrogencarbonate solution (350 ml). After phase separation, the organic layer was washed twice with water (200 ml), and once with saturated brine (200 ml), and then dried over sodium sulfate. After the sodium sulfate was filtered out, the solvent was distilled off under reduced pressure, to obtain 11.0 g of a concentrate residue. As a result of measurement of NMR spectra of the concentrate residue, it was found that the by-product of Comparative Example 1 (2-methyl-2,5,5-tris(propionyloxymethyl)-[1,3]dioxane) was hardly detected, while other by-products were formed, and that the starting material propionyloxyacetone remained at a similar level to that in Comparative Example 1. The concentrate residue was purified by column chromatography (eluent: ethyl acetate/hexane=1/2), to give 3,9-dimethyl-3,9-bis(propionyloxymethyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (7.3 g, 20.3 mmol, yield 53%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+:28].CO>>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([O-:24])=[O:23])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1.[Na+:28]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCC[C@H]1C(=O)[O-]

Procedure:
10 m Mol of cis-2-[(3,5-bistrifluoromethyl phenyl)-aminocarbonyl]-cyclohexane carboxylic acid was dissolved in 100 ml of 0.1N NaOH/methanol solution. The solvent was evaporated off to dryness to give sodium cis-2-[(3,5-bistrifluoromethyl phenyl)-aminocarbonyl]-cyclohexane carboxylate [melting point: 259°-260° C. (decomposition)].
Reaction SMILES: [C:1]([C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5])([OH:3])=O.C(Cl)CCl.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:40]=1[NH2:41]>CN(C=O)C.Cl>[Cl:17][C:10]1[CH:11]=[N+:12]([O-:16])[CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:26])[F:27])=[C:20]([O:28][CH2:29][CH:30]2[CH2:31][CH2:32]2)[CH:19]=1)[O:6][C:4](=[O:5])[C:1]([NH:41][C:40]1[CH:42]=[CH:43][C:44]([N+:46]([O-:48])=[O:47])=[CH:45][C:39]=1[O:38][CH3:37])=[O:3]
Reactant: O=C(O)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
(S)-4-(2-(carboxycarbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.10 mmol) was dissolved in DMF (5 ml), then EDC (29.2 mg, 0.15 mmol) was added. 2-methoxy-4-nitroaniline (34.2 mg, 0.2 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 2 hours. The reaction was diluted with HCl 1M and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 21 mg of the title product. (Yield: 32%).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>>[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH2:33][S:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:36])=[O:35])[CH:29]=1
Reactant: Cc1cc(CS(=O)(=O)Cl)no1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: Cc1cc(CS(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)no1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and (5-Methyl-isoxazol-3-yl)-methanesulfonyl chloride. Light yellow solid. MS (ESI): 474.13 (MH+)
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C:16]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:17]=1[C:18]([OH:20])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[Cl:50][C:51]1[CH:69]=[CH:68][C:54]([CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([CH2:62][NH:63][C:64](=[O:67])[CH2:65][NH2:66])[CH2:58][CH2:57]2)=[CH:53][CH:52]=1.[OH-].[Na+]>ClCCl>[C:8]([O:12][C:13]([NH:15][C:16]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:17]=1[C:18]([NH:66][CH2:65][C:64]([NH:63][CH2:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][C:54]2[CH:68]=[CH:69][C:51]([Cl:50])=[CH:52][CH:53]=2)[CH2:57][CH2:58]1)=[O:67])=[O:20])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triethylamine (1.1 mL, 8 mmol), 2-(tert-butoxycarbonylamino)-4,5-difluorobenzoic acid (607 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol) and HOBt (337 mg, 2.2 mmol) were added to a dichloromethane (20 mL) solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine dihydrochloride (738 mg, 2 mmol), and the resulting mixture was stirred at room temperature for 14 hours. A 0.6 M aqueous solution of NaOH (50 mL) was then added to the mixture, and the obtained mixture was extracted with dichloromethane (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to thereby provide 4-[[(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl) glycyl)amino]methyl]-1-(4-chlorobenzyl)piperidine (1.01 g, 92%). ESI/MS m/e 551.3 (M++H, C27H33ClF2N4O4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:31]([NH:35][S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][S:36]([C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:44]=1)(=[O:38])=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-3-{4-[6-(3-ethoxy-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-6-(3-ethoxy-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.108) (0.185 g, 0.41 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.13 g, 0.50 mmol) according to the general procedure VI. Obtained as an off-white solid (0.24 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([C@H:5]1[NH:10][C:9](=O)[CH2:8][NH:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C@@H:5]1[CH2:6][NH:7][CH2:8][CH2:9][NH:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1NC(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[C@@H]1CNCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled to −78° C. solution of (3R)-3-butyl-2,5-piperazinedione from step (b) above (600 mg, 2.52 mmol) in THF (10 mL) was added dropwise lithium aluminum hydride (21 mL, 21.1 mmol, 1 M in THF, Aldrich). The mixture was stirred at room temperature for 1 h, and then heated at reflux for 16 h. The mixture was cooled to 0° C. and quenched with sodium sulfate decahydrate until the gas evolution ceased. The mixture was stirred at room temperature for 3 h, filtered and the filter cake was washed with THF (2×10 mL). The filtrate was concentrated in vacuo to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 143 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][CH2:24][C:25]#[N:26])=[O:12])=[CH:5]2.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].CCOC(C)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]1[NH:23][CH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)=[O:12])=[CH:5]2
Reactant: N#CCNC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NCc1nnn[nH]1)c1cc2cc(Cl)ccc2[nH]1
Yield: 17.2 %

Procedure:
5-Chloro-N-{1-[(cyanomethyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Example 25; 182 mg, 0.5 mmol), sodium azide (195 mg, 3.0 mmol) and ammonium chloride (163 mg, 3.05 mmol) in DMA (5 mL) were heated in a microwave at 180° C. for 1 min. EtOAc (50 mL) was added and the mixture washed with water (6×10 mL), brine (25 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The desired component was isolated by preparative HPLC (CH3CN:water) to give the title compound (35 mg, 14%) as a pale orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH2:17]([O:19]CC)C.[Li]CCCC.CN(C=O)C>CCCCCC.O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[C:4]=1[CH:17]=[O:19]
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc2c(c1C=O)Nc1ccccc1S2
Temperature: 20 °C
Yield: 30 %

Procedure:
4.6 g (20 mmol) of 2-methoxy-10H-phenothiazine are dissolved, under an argon atmosphere, in a three-necked flask, containing 140 ml anhydrous ethyl ether. 20 ml (50 mmol) of a solution of nBuLi (2.5 M) in hexane is then added dropwise, at 20° C. The reaction mixture is agitated for 3 hours at 20° C. before the dropwise addition of 6.2 ml (80 mmol) of anhydrous DMF. Agitation is maintained for another 15 hours at 20° C. The whole is then poured into 150 ml ice-cooled water and the product is extracted twice using 200 ml of ethyl acetate. The organic solution is washed with 100 ml of salt water, dried over MgSO4, filtered and concentrated under vacuum. The evaporation residue is taken up in diisopropyl ether, filtered and dried to produce a red solid with a yield of 30%. Melting point: 155–160° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:31](=[O:32])[CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH2:4][CH2:5]3)=[CH:13]1
Reactant: Cc1ccccc1CC(=O)O
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1CC(=O)N1CCc2cc(-c3cn(C)c4ncnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine-2HCl (70.6 mg, 0.209 mmol), (2-methylphenyl)acetic acid (31.4 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base (0.146 mL, 0.836 mmol). The mixture was stirred at room temperature overnight. LCMS showed reaction was completed. The reaction was poured into water (100 mL), white solid formed. EtOAc (100 mL) was used to extract the product. The Organic phase was separated from the water phase, dried by MgSO4, rotavaped to dryness, to give white solid. The solid was sonacated in water (10 mL), then filtered and dried to afford 7-methyl-5-{1-[(2-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (48 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02-8.24 (m, 2H) 7.32 (s, 1H) 7.25 (s, 1H) 7.12-7.24 (m, 5H) 6.07 (br. s., 2H) 4.26 (t, J=8.5 Hz, 2H) 3.87 (s, 2H) 3.73 (s, 3H) 3.24 (t, J=8.5 Hz, 2H) 2.24 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[CH3:29][NH:30][C:31](=[S:34])[NH:32][NH2:33].O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:33][NH:32][C:31]([NH:30][CH3:29])=[S:34])=[O:23]
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Reactant: CNC(=S)NN
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=S)NNC(=O)c1ccccc1-c1nc2ccc(F)cn2c1Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3.1 200 mg (0.533 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 56 mg (0.533 mmol) of 4-methyl-3-thiosemicarbazide and 125 mg (0.650 mmol) of DAPECI are dissolved in 1 ml of DMF and stirred at RT for 2 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 117 mg (47%) of 1-{2-[3-(2,6-dimethylphenylamino)-6-fluoro-imidazo[1,2-a]pyridin-2-yl]benzoyl}-4-methyl-3-thiosemicarbazide as solid; MS-FAB (M+H+)=463.7; Rf (HPLC, polar method): 1.69 min. This is employed in the next step without further purification.
Reaction SMILES: [C:1]([C:3]([CH:9]1[CH2:11][CH2:10]1)([CH3:8])[CH2:4][C:5]([OH:7])=O)#[N:2].Cl.[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26](C(OC4CCNCC4)=O)[CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)[N:15]=1>>[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:5](=[O:7])[CH2:4][C:3]([CH:9]4[CH2:11][CH2:10]4)([CH3:8])[C:1]#[N:2])[CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)[N:15]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: CC(C#N)(CC(=O)O)C1CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC(C)(C#N)C3CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 4 starting from 3-cyano-3-cyclopropylbutanoic acid and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=460.1.