Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:31])[C@@H:4]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:5][CH2:6][NH:7][C:8](=O)[CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[CH:11]1.B#B>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[NH:20][C@H:4]1[CH2:5][CH2:6][N:7]([CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)[C:3]1=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H](CCNC(=O)Cn1ccc2cnccc21)NC(=O)OCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCN(CCn2ccc3cnccc32)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyric acid methyl ester (0.51 g, 1.20 mmol) in THF (5 mL) is added diborane (5 mL, 0.500 mmol, 1 M solution in THF). The resulting mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is suspended in EtOAc (10 mL), treated with 10 drops of H2O, 5 drops of 1 N NaOH and further quenched with saturated NH4Cl solution. The mixture is concentrated in vacuo to about 1/2 volume, partitioned between EtOAc and 10% Na2CO3 solution and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic phases are washed with saturated NaCl, dried over MgSO4, filtered and concentrated in in vacuo. The crude product obtained is partially purified by column chromatography in a gradient of 2% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to afford [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester. FAB MS, [M+H]+=379. To a solution of this crude [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is added a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is stirred at room temperature under a balloon of H2 for 18 hours. The reaction mixture is filtered through a pad of Celite and washed with MeOH (3x). The crude product is concentrated in vacuo and then azeotroped with toluene to give 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate as a residue (wet with excess HOAc). FAB MS, [M+H]+=245. The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using the above 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1. Part J. The crude product is partially purified by column chromatography eluting in a gradient of 3% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2. The residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[CH2:16]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:10][C:11]1[CH:12]=[C:13]([CH2:33][CH:34]2[CH2:35][CH2:36][N:37]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:38][CH2:39]2)[CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=1)[CH2:16]2
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CC2CCN(Cc3ccccn3)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a mixture of 2-chloromethylpyridine hydrochloride salt (16.9 mg, 0.103 mmol), 7-methyl-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.120 mmol) and potassium carbonate (71.2 mg, 0.515 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a yellow oil (34.1 mg, 65%). 1H NMR (300 MHz, CDCl3): δ 8.56 (d, 1H), 7.65 (t, 1H), 7.34 (m, 3H), 7.18 (m, 3H), 6.98 (d, 2H), 4.76 (s, 2H), 4.20 (s, 2H), 3.64 (s, 2H), 2.90 (d, 2H), 2.73 (s, 3H), 2.57 (d, 2H), 2.03 (t, 2H), 1.62 (m, 2H), 1.35 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25](=[O:30])N(OC)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:30])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)c3ccc(F)cc3)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A solution of 200 mg (0.456 mmol) (2R,4R)-4-(4-Methoxy-benzylsulfanyl)-2-[2-(methoxy-methyl-carbamoyl)-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in 3 ml THF was treated at 0° C. with 1.14 ml (1.14 mmol, 1M THF solution) of a 4-fluorophenyl-magnesium bromide solution and after 10 min warmed up to room temperature. The reaction was partitioned between aqueous aqueous 10% KHSO4/t-butyl methyl ether (3×). The organic phases were washed with aqueous 10% NaHCO3 and saturated NaCl solution, dried over MgSO4 and evaporated to give 144 mg (68%) of (2R,4R)-2-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 474 (MH+).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2>C1COCC1>[O:1]1[CH2:6][CH:5]=[N:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cccnc2N1
Solvent: C1CCOC1
Product: C1=Nc2ncccc2OC1

Procedure:
2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g, 6.66 mmol) was refluxed with boron hydride methyl sulfide complex (2 mL) in THF (10 mL) for 30 min to give 2H-pyrido[3,2-b]-1,4-oxazine. In a manner analogous to the preparation of 5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine, 2H-pyrido[3,2-b]-1,4-oxazine was nitrated, reduced and reacted with 2,4-dichloro-5-fluoropyrimidine (400 mg) and 3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give 5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-2,4-pyrimidinediamine as a gray solid. 1H NMR (CDCl3): δ 2.91 (d, J=4.8 Hz, 3H), 3.55 (t, J=4.2 Hz, 2H), 4.24 (t, J=4.5 Hz, 2H), 4.49 (s, 2H), 4.90 (br, 1H), 6.51 (dd, J=2.7 and 8.1 Hz, 1H), 6.64 (s, 1H), 6.90 (dd, J=2.1 and 8.1 Hz, 1H), 7.08 (s, 1H), 7.14 (br, 1H), 7.18 (t, J=8.1 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.51 (t, J=2.1 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H); LCMS: ret. time: 11.91 min.; purity: 100%; MS (m/e): 426.12 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.CS[C:40]1[NH:41][CH2:42][CH2:43][N:44]=1>C(O)C>[ClH:30].[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([NH:2][N:44]4[CH2:43][CH2:42][N:41]=[CH:40]4)[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: CSC1=NCCN1
Reactant: N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C([C@H]1CC[C@H](NN2C=NCC2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
To a solution of 1-(trans-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg) and triethylamine (120 mg) in ethanol (10 ml) was added 2-methylthioimidazoline (116 mg), and the mixture was heated for 48 hours under reflux. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (dichloromethane/methanol containing 10% ammonia=10/1) and transformed into hydrochloride with 4 N hydrochloric acid in ethyl acetate to give a colorless solid of the title compound (30 mg).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=O.C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>O.O1CCCC1>[OH:4][CH2:5][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Reaction time: 0.17 h
Yield: 105.3 %

Procedure:
A solution of 1.63 g of sodium borohydride in 25 ml of water is added dropwise to a well stirred solution of 3.0 g of cis-(±)-4-(methoxycarbonyl)-3-[((phenylmethoxy)carbonyl)amino]-2-azetidinone in 190 ml of tetrahydrofuran. The addition is made over a period of 10 minutes while stirring in an ice bath. The reaction is stirred for 3 hours. Methylene dichloride (250 ml) is added followed by anhydrous sodium sulfate. A clear solution is obtained by filtration. The solvent is removed and the residue is dissolved in acetone. The solution is clarified by filtration and concentrated to give 2.84 g of the title compound. Physical characteristics are as follows: 13C NMR (δ, CH3OH-d6): 55.9, 60.2, 61.6 67.9, 128.7-129.3, 137.6, 158, 170.7.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH:11][CH2:12][C@@H:13]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22](S(CCC)(=O)=O)[N:21]=2)=[C:18]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:17]=[CH:16]1)[CH3:14]>C1COCC1>[OH:11][CH2:12][C@@H:13]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[N:21]=2)=[C:18]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:17]=[CH:16]1)[CH3:14]
Reactant: CCCS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@@H](C)CO)n1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](CO)n1cnc(-c2ccc(F)cc2)c1-c1ccnc(Oc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (95%) (252 mg, 10 mmol) was added in small portions to absolution of 4-fluorophenol (2.21 g, 19.8 mmol) in dry THF (50 mL). After the vigorous reaction had subsided, this solution was added to a solution of the product of example 1 (g) (2 g, 4.95 mmol) dissolved in dry THF (200 mL). The reaction mixture was stirred at rt under argon for 1 h. The reaction mixture was concentrated, and the residue partitioned between EtOAc and H2O. The organic phase was washed with 1N NaOH, brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (silica gel, 0–4% MeOH/CH2Cl2) to give the title compound as a light yellow solid. ES (+) MS m/e=409 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][NH2:12])[CH2:9][NH2:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([O:23][C:24](=O)[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O)(C)(C)C.II>CC(O)(C)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][N:12]3[C:24](=[O:23])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]3=[N:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NCC(CN)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 39 %

Procedure:
A mixture of 2-(4-aminophenyl)propane-1,3-diamine.3HCl (632 mg, 2.30 mmol) and powdered K2CO3 (3.18 g, 23.0 mmol) in 30 mL t-BuOH was heated at 83° C. for 45 min, then tert-butyl(2-formylphenyl)carbamate (560 mg, 2.53 mmol) was added. At 6.5 hours the reaction was allowed to partially cool, approximately 25 mg tert-butyl(2-formylphenyl)carbamate was added, then iodine (48 mg, 0.188 mmol) added, stirred 5 min at rt, and the heating resumed at 83° C. After 1.5 hours the temperature was lowered to 75° C. and the reaction continued an additional 15 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution plus Na2S2O3, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The resulting solid was chromatographed eluting with CHCl3/MeOH to give the title compound as a yellow-tan solid (262 mg, 39%). 1H NMR (DMSO-d6) δ: 10.65 (br. s, 1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.39-7.45 (m, 1H), 6.98-7.08 (m, 2H), 6.93-6.98 (m, 2H), 6.51-6.57 (m, 2H), 4.96 (br. s, 2H), 4.12-4.20 (m, 1H), 3.61-3.70 (m, 1H), 3.36-3.53 (m, 2H), 2.73-2.85 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.[C:13](OC(C)=C)(=[O:15])[CH3:14]>C(OCC)(=O)C>[C:13]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([NH2:1])[C:3]([Cl:12])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:15])[CH3:14]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1c(Cl)ccc2c1CNCC2
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(Cl)c(N)c2C1

Procedure:
8-Amino-7-chloro-1,2,3,4-tetrahydroisoquinoline, prepared as in Example 12, is treated with one molar equivalent of isopropenyl acetate in refluxing ethyl acetate for 16 hours. The solvent is evaporated and the residue crystallized from benzene to yield 2-acetyl-8-amino-7-chloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[C:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:39][C:38]=1[C:51]1[N:60]=[CH:59][C:58]2[CH2:57][CH2:56][C:55]3[N:61]=[C:62]([NH:64][C:65](=[O:67])[CH3:66])[S:63][C:54]=3[C:53]=2[N:52]=1>ClCCl>[C:1]([N:48]1[CH2:47][CH2:46][CH:45]([C:44]#[C:43][C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[C:38]([C:51]3[N:60]=[CH:59][C:58]4[CH2:57][CH2:56][C:55]5[N:61]=[C:62]([NH:64][C:65](=[O:67])[CH3:66])[S:63][C:54]=5[C:53]=4[N:52]=3)[CH:39]=2)[CH2:50][CH2:49]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(C(C)=O)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7 μl acetic acid and 50 mg (0.16 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) are placed in 5 mL dichloromethane, combined with 32 μl diisopropylethylamine and stirred for 0.5 hours at ambient temperature. 60 mg (0.13 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide (Example 155) are added, then the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is extracted with potassium carbonate solution and dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24]([O:32][CH2:33]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[K+].[Br-]>>[C:24]([O:32][CH2:33][O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: O=C(OCCl)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: CN1C(C(=O)Nc2ccccn2)=C(OCOC(=O)c2ccccc2)c2ccccc2S1(=O)=O

Procedure:
By the procedure of Example 6, piroxicam (3.33 g, 10.1 mmol) and chloromethyl benzoate (4.29 g, 25.0 mmol) were converted to chromatographed title product, 2.3 g (4.9 mmol), 48.9%) white foam which gave white crystals from isopropyl alcohol: mp 149°-150° C.; IR (KBr) 1745, 1687 cm-1 ; 1H NMR (CDCl3) delta 3.07 (s, 3H), 5.89 (s, 2H), 6.97-7.08 (m, 1H), 7.19-7.35 (m, 2H), 7.35-7.63 (m, 2H), 7.63-7.99 (m, 6H), 8.22-8.35 (m, 2H), 9.22 (br s, 1H); precise mass calcd for C23H19N3O6S m/e 465.1001, found 465.1051
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[O:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]2)[CH2:20][CH2:19]1>COCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:29][C:27]4[CH:26]=[N:25][N:24]([CH:21]5[CH2:22][CH2:23][O:18][CH2:19][CH2:20]5)[CH:28]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: Nc1cnn(C2CCOCC2)c1
Reactant: Fc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Solvent: COCCO
Product: Fc1ccc(-n2nnc3cnc(Nc4cnn(C5CCOCC5)c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 74.9 mg (0.30 mmol) 5-chloro-3-(4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 60.2 mg (0.36 mmol) 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-ylamine in 0.5 ml 2-methoxy-ethanol is stirred for 4 hours at 90° C. The reaction mixture is cooled to room temperature. The solvent is partially removed under vacuum and the residue is purified by preparative HPLC yielding “A20” as brown amorphous solid; HPLC/MS (B): 2.1 min, [M+H] 381;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]([OH:27])[CH2:25][CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)[C@H](CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)[C@H](CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)acetic acid (0.038 g, 0.077 mmol; Example 158, Step B) in a mixture of THF and methanol (4:1, 5 mL) was added sodium borohydride (9 mg, 0.24 mmol) at 0° C. Then the reaction was allowed to warm to room temperature. After being stirred at room temperature for 1.5 h, another 2 eq. of sodium borohydride were added and stirred for another 0.5 h. The reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (MgSO4), and concentrated under reduced pressure. The crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound as the first eluting fraction as a white solid after lyophilization.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:6][CH:7]([F:9])[F:8])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:6][CH:7]([F:9])[F:8])[CH3:10])#[N:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CC(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-4,4-difluoro-2-methylbutanonitrile hydrochloride product from Example 74A was initially charged in 109 ml of tetrahydrofuran/water (1:1), and 18.94 g (137.06 mmol) of potassium carbonate and 6.27 g (36.77 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.14 g (6.69 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 7.68 g of the target compound were obtained (61% of theory over two stages, 71% purity).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[C:11]([C:16](OC)=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[C:11]([CH2:16][OH:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Cl)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(OCc2ccccc2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg of methyl 4-(benzyloxy)-6-chloropyridine-2-carboxylate (WO2006/046734, page 123, Example 116(5)) in 3 ml of tetrahydrofuran was added 78 mg of lithium aluminum hydride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride solution, water and brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[CH2:8]([CH:10]([C:13]1[N:18]2[N:19]=[C:20]([CH3:23])[C:21](I)=[C:17]2[N:16]=[C:15]([CH3:24])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>C1COCC1.[Zn]>[Cl:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:21]1[C:20]([CH3:23])=[N:19][N:18]2[C:13]([CH:10]([CH2:8][CH3:9])[CH2:11][CH3:12])=[CH:14][C:15]([CH3:24])=[N:16][C:17]=12
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Reactant: Clc1ccsc1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sccc3Cl)c(C)nn12
Temperature: 85 °C
Yield: 80.9 %

Procedure:
Suspend Reike® zinc (5 g/100 mL THF, 20 mL, 15.0 mmol) in anhydrous THF (10 mL) and add 2-bromo-3-chlorothiophene (1.98 g, 10.0 mmol). Reflux the mixture under an inert atmosphere in an oil bath (85° C.) for 3 h. Cool the reaction to room temperature and centrifuge the remaining zinc metal. Canulate off the reagent solution into a new vessel under positive argon pressure and add 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.72 g, 5.0 mmol). Degas the solution by positive argon pressure for 10-15 min and add dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium (II) dichloromethane (0.225 g, 0.275 mmol). Stir at reflux temperature overnight under an inert atmosphere. Cool the reaction to room temperature, quench with saturated ammonium chloride, and dilute with ethyl acetate (75 mL). Separate and extract the aqueous portion with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments to give a yellow solid (1.35 g, 40%). ES/MS m/z (35Cl) 334.4 (M+1)+.