Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:73][C:74]([CH3:86])([CH3:85])[CH2:75][CH2:76][C:77]1[CH:84]=[CH:83][C:80]([CH2:81][NH2:82])=[CH:79][CH:78]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:82][CH2:81][C:80]1[CH:83]=[CH:84][C:77]([CH2:76][CH2:75][C:74]([CH3:86])([CH3:85])[CH3:73])=[CH:78][CH:79]=1
Reactant: CC(C)(C)CCc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 100 °C
Yield: 91.2 %

Procedure:
Use a method similar to the General Procedure 5-1 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (623 mg, 1.46 mmol), palladium(II) acetate (33 mg, 0.146 mmol), BINAP (182 mg, 0.292 mmol), 4-(3,3-dimethyl-butyl)-benzylamine (560 mg, 2.93 mmol) and cesium carbonate (666 mg, 2.04 mmol) in degassed toluene (40 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 16 h. Cool the mixture to room temperature, dilute with EtOAc and wash with water. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and then hexane/EtOAc (19:1, 9:1) to obtain 7-chloro-6-[4-(3,3-dimethyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (622 mg, 91%). MS (ES+) m/z: 467 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([Cl:30])[CH:32]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NC(=O)c3cccc(Cl)c3)CN2Cc2ccccc2)CC1
Yield: 6.4 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3-chloro-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (4.3 mg, 6.4%) as light yellow oil. MS m/e=528.3 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].C([O:10][C:11](=O)[CH2:12][C:13]([CH3:15])=O)C.CN>O.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:11]([OH:10])=[CH:12][C:13]([CH3:15])=[C:4]([C:5]#[N:6])[C:3]1=[O:7]
Reactant: CNC(=O)CC#N
Reactant: CCOC(=O)CC(C)=O
Agent: CN
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)n(C)c(=O)c1C#N
Temperature: 90 °C
Yield: 95 %

Procedure:
250 parts of water, 98 parts of N-methylcyanoacetamide and 169 parts of acetoacetic acid ethyl ester are initially placed in an autoclave, 40 parts of gaseous monomethylamine are injected, while stirring, and the reaction mixture is then heated at 90° C. for 3 hours, a pressure of 2.9 bars being generated. The batch is diluted with 400 parts of water, 80 parts of 61% strength sulphuric acid are added at 30°-35° C., the batch is cooled to 20° C. and the precipitate which has been formed is filtered off. 155.8 parts (95% of theory) of 1,4-dimethyl-3-cyano-6-hydroxypyrid-2-one with a melting point of 285° C. are obtained.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([N:12]([C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]=[C:8]([C:10]#[N:11])[CH:9]=1)=[O:4].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:22][C:20]([C:19]1[C:18](=[O:25])[N:12]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:6]2[CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:5]2[C:3]=1[OH:4])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)N(CCC(C)C)n1cc(C#N)cc1C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cc(C#N)cn2n(CCC(C)C)c1=O
Temperature: 40 °C

Procedure:
To a solution of crude 4-cyano-1-[(2-ethoxycarbonyl-acetyl)-(3-methyl-butyl)-amino]-1H-pyrrole-2-carboxylic acid methyl ester (Example 15d, 2.552 mmol) in ethanol (30 mL) was added a 21% solution of sodium ethoxide in ethanol (2.07 g, 6.380 mmol) and the mixture was heated at 40° C. for 16 h. Upon cooling, the mixture was quenched with 1.0 M aqueous hydrochloric acid solution and brine. The aqueous mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester as a yellow solid, which was used in the next step without further purification. LC-MS (ESI) calcd for C16H19N3O4 317.14, found 318.3 [M+H+]. FT-IR (ATR) νmax (neat): 2231, 1642, 1610 cm−1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].II.Cl[CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].Cl>C1COCC1.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: O=C1CCCC1Cl
Reactant: COc1ccc(Br)c(OC)c1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2CCCC2=O)c(OC)c1
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of 1-bromo-2,4-dimethoxybenzene (345 μL, 1.2 eq.) in dry THF (0.5 mL) was added dropwise, under N2, to a suspension of Mg turnings (64 mg, 1.3 eq.) in dry THF (0.7 mL) and in presence of a catalitic amount of I2. The reaction mixture was stirred at reflux for 1 hr and then cooled down to 0° C. To this mixture was added dropwise a solution of 2-chlorocyclopentanone (0.2 mL, 2 mmol) in anh. THF (0.5 mL) and the reaction mixture was heated to reflux for 2 hr. The mixture was allowed to cool at r.t., it was diluted with Et2O and slowly mixed with ice and 1M HCl. The organic layer was then separated, washed twice with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude red oil was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give the title compound (297 mg, 67%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Li].[CH:12]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([CH:17]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:9][CH3:10])=[N:5][C:6]=2[Cl:8])[OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: O=CC1CCCC1
Agent: [Li]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(O)C2CCCC2)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine (8.0 g, 41.01 mmol) was dissolved in 500 mL dry THF and cooled to −78° C. Lithium diusopropylamine (36.9 mL of 2.0 M solution in hexanes) was added dropwise, and the reaction mixture was stirred for 20 minutes at −78° C. Cyclopentane-carboxaldehyde (8.05 g, 82.02 mmol was added, and the reaction mixture was stirred for 45 minutes at −78° C. The reaction was quenched by addition of saturated aqueous ammonium chloride. The aqueous mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 40% EtOAc in hexanes) to yield 9.76 g of cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanol. Mass Spec. M+H=294.
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](F)(F)[CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].O.S(=O)(=O)(O)[OH:18]>>[F:7][C:6]([F:9])([F:8])[CH:5]([C:10]([F:13])([F:12])[F:11])[C:4]([O:3][CH2:2][Cl:1])=[O:18]
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)OCCl
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Reaction time: 20 h
Yield: 101.1 %

Procedure:
In a four necked 1 liter flask equipped with a thermometer, a condenser and a stirrer, 1-chloromethoxy-1,1-difluoro-2-trifluoromethyl-3,3,3-trifluoropropane (276.6 g, 1.04 mol) and water (18.7 g, 1.04 mol) were charged, and concentrated sulfuric acid (74.8 g, 0.76 mol) was dropwise added thereto while stirring The reaction was continued at 110° C. for 20 hours. Then, the reaction mixture was distilled to give monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (187.8 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:32][OH:33])[C@@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH:32]=[O:33])[C@@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#C[Si](C)(C)C)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#C[Si](C)(C)C)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h

Procedure:
A RBF containing a solution of tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate (2.04 g, 4.15 mmol) in DCM (30 mL) was placed in an ice-bath for 10 min. Sodium bicarbonate (1.05 g, 12.4 mmol) and Dess-Martin Periodinane (2.29 g, 5.39 mmol) were added in sequence, the ice-bath was removed, and the reaction was stirred for 2 h. The reaction mixture was diluted with a 1:1 mixture of saturated sodium thiosulfate solution and brine (60 mL), and the resulting biphasic mixture was stirred vigorously for 2 min. The mixture was then extracted with DCM (3×30 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 120-g Redi-Sep column, eluting with 5-30% EtOAc/Hexanes to give tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-4-oxo-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate as a pale yellow oil.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[N:28]=[CH:27][C:26]([NH:29][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(N)cn1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cn1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 6-isopropoxypyridine-3-amine as the starting materials.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1>[Pd].CO.C(O)C>[ClH:1].[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:21]=[C:22]([O:26][C:27]([O:29][CH3:30])=[O:28])[C:23]([CH3:25])=[CH:24][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])c(OC)cc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)Oc1cc(Nc2ncnc3cc(N)c(OC)cc23)c(F)cc1C
Reaction time: 7 h
Yield: 9.1 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-nitroquinazoline hydrochloride (1.1 g, 25 mmol) and 10% palladium-on-charcoal catalyst (220 mg) in methanol (200 ml) and ethanol (10 ml) was stirred under hydrogen at 2.7 atmospheres for 7 hours. The catalyst was removed by filtration through diatomaceous earth, the solvent removed from the filtrate by evaporation and the solid residue washed with ether, collected by filtration and dried under vacuum to give 7-amino4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (930 mg, 91%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 67.5 %

Procedure:
A solution of Example 40H (2.89 g, 6.07 mmol), mesyl chloride (1.88 mL, 24.3 mmol), and pyridine (3.93 mL, 48.6 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.12 g, 68%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1H) 0.74 (m, 7H) 1.34 (m, 1H) 1.57 (m, 3H) 2.15 (m, 2H) 3.08 (m, 3H) 7.56 (m, 3H) 7.75 (m, 3H) 8.16 (m, 1H) 10.26 (m, 1H) 13.76 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(Oc3ccc(C#N)cn3)cccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Oc2cccc3c(CBr)cccc23)nc1
Temperature: 70 °C

Procedure:
To a solution of 6-(5-methylnaphthalen-1-yloxy)nicotinonitrile (Preparation 22) (530 mg, 2.04 mmol) in carbon tetrachloride (30 mL) under argon was added N-bromosuccinimide (435 mg, 2.44 mmol) followed by benzoyl peroxide (25 mg, 0.1 mmol). The mixture was heated to 70° C. for 16 h. The reaction mixture was cooled, filtered through celite, and washed with DCM (70 mL). The organic phase was washed with NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=3.93 min; m/z (ES+)=341.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=[C:40]([NH:42][C@H:43]4[CH2:48]CCN[CH2:44]4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.N(CCC)=C=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:40]([NH:42][CH:43]([CH3:48])[CH3:44])=[O:61])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CCCN=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) followed by isocyanatopropane (0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 439.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:23][CH:12]([CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[CH:13]=[O:14]
Reactant: O=CCCc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@H]1CCCN1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=CC(Cl)Cc1ccc2nccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a cooled (0° C.) solution of 3-quinoxalin-6-ylpropanal (0.195 g, 0.00105 mol) in chloroform (3 mL) was added D-proline (24 mg, 0.00021 mol) followed by N-chlorosuccinimide (147 mg, 0.00110 mol). The mixture was stirred at 0° C. for 2 h, and then at RT overnight. The mixture was diluted with methylene chloride. The solution was washed with water, brine, dried over Na2SO4, filtered, and concentrated to yield the desired product (220 mg, 95%). LCMS: (M+H)=221.3.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccccc2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a suspension of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (8.00 g, 34.9 mmol, 1.00 equiv) in CH2Cl2/DMF (7/1, 350 ml) at room temperature, 1-[2-(trifluoromethyl)phenyl]methanamine (4.90 mL, 34.9 mmol, 1.00 equiv), EDCI (8.03 g, 41.9 mmol, 1.20 equiv), HOBT (5.66 g, 41.9 mmol, 1.20 equiv), and diisopropylethylamine (DIEA, 18.3 ml, 105 mmol, 3.00 equiv) were added. Stirring was continued overnight at room temperature. The reaction mixture was partitioned between water and ethyl acetate (1:1, 600 ml). The product was extracted three times with ethyl acetate (100 ml). The organic extracts were combined and washed successively with saturated ammonium chloride (200 ml), water (200 ml), and saturated sodium chloride (200 ml). The ethyl acetate solution was dried with Na2SO4, filtered, and concentrated under reduced pressure to afford 11.67 g (87%) of the title compound. MS (ES+): m/e 408.9 [M+Na]+.
Reaction SMILES: Cl[C:2]1C=CC(C2C=CN3C(=O)NN=C3C=2C2C=CN=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([S:47]([CH2:50][CH3:2])(=[O:48])=[O:49])=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:53]=[CH:54][N:55]=[CH:56][CH:57]=2)=[CH:27][CH:26]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Product: CCS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1

Procedure:
The title compound was prepared by coupling 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one with the requisite benzyl halide in a manner analogous to that in which 7-(4-chlorophenyl)-2-(4-(methylsufonyl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=2.428 min, [M+H]+=505.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2[nH]ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cccc2[nH]ccc12
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a suspension of 4-aminoindole (1.0 g, 7.57 mmol), triethylamine (1.07 mL, 7.57 mmol) in methylene chloride (50 mL) at 0° C., was added dropwise a solution of chloroacetyl chloride (0.615 mL, 7.57 mmol) in methylene chloride (5 mL). After 30 minutes, the solution was washed with water (2×100 mL) and dried over anhydrous magnesium sulfate. Purification by chromatography over silica gel (60 g, 40% ethyl acetate-hexane) and crystallization form hexane-ethyl acetate afforded the title compound as a white solid (1.17 g, 74.1%), mp 114-116° C.; MS EI m/e 208/210 (M+).
Reaction SMILES: [NH2:1][OH:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5]>CO>[C:3]([CH2:4][CH2:5][N:1]([OH:2])[CH2:5][CH2:4][C:3]([OH:7])=[O:6])([OH:7])=[O:6]
Reactant: C=CC(=O)O
Reactant: NO
Solvent: CO
Product: O=C(O)CCN(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Methanol (200 ml) was added to a mechanically stirred aqueous solution of hydroxylamine (13.24 g of 50% solution, 0.2 moles). Acrylic acid (27.4 ml, 0.4 moles) was added dropwise to the solution at 25° C. over thirty minutes. After a few hours of reaction, a white precipitate began to form. The reaction mixture was stirred overnight at room temperature, and the resulting white solid was filtered out, washed with cold water, and dried in vacuum overnight to give 30.4 g (85%) of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4].C([O-])(=[O:23])C.[K+].N1C(=O)C2NC=NC=2NC1=O.[I-].[K+]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:23])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4]
Reactant: CC(=O)[O-]
Reactant: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(ncn2CCCCCCO)n(C)c1=O

Procedure:
1,3-dimethyl-7-(6-bromohexyl)-xanthine is refluxed overnight with a sixfold molar excess of potassium acetate with the addition of catalytic quantities, such as 2 mol percent, referred to the xanthine, of potassium iodide in a mixture of 5 ml of acetic anhydride and 200 ml of glacial acetic acid. The solvent is evaporated in vacuo. The residue is dissolved in water and the pH of the solution is adjusted to a value of 7 with 4N sodium hydroxide. The solution is then extracted with chloroform. The isolated 1,3-dimethyl-7-(acetoxyhexyl)-xanthine is subsequently hydrolysed to the corresponding hydroxyalkyl compound by boiling with 5% sulfuric acid.