Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:20][C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][C:22]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:29]2[CH2:30][CH2:31][N:26]([C:24]3[S:25][C:21]([CH3:20])=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)[CH2:27][CH2:28]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)c(C)s3)CC2)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (277 mg, 0.848 mmol), 1-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.148 ml, 0.848 mmol) in dimethylsulfoxide (2.6 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 161 mg (47.8%) of the desired product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[N:54]([C@@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:58])=[C:55]=[O:56]>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:55](=[O:56])[NH:54][C@@H:57]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH3:58])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-2-({(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (35 mg) was dissolved in 2 mL DCM and ((R)-1-isocyanato-ethyl)-benzene (5 equiv) added and reaction stirred at room temperature for 2 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+2% MeOH). The resulting compound was hydrolyzed according to General Procedures B to give the title compound (28 mg). LCMS (m/z): 886.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH:10]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH:10]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (2RS,3RS)-2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoate (26.5 g, 70.7 mmol) in ethanol (200 ml) was added 2N aqueous sodium hydroxide solution (70 ml, 140 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, acidified with 1N hydrochloric acid and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (15.0 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[CH2:19]([N:21]([CH2:34][CH3:35])[CH2:22][CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH3:20].C(Cl)Cl>O>[CH2:34]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:30])=[CH:32][CH:33]=1)[CH3:35]
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.2 g. (0.05 mol.) of 2-(4-methoxyphenyl)benzofuran and 14.6 g. (0.05 mol.) of 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride in 100 ml. of methylene chloride is added 39.1 g. (0.15 mol.) of stannic chloride. The reaction mixture is stirred for 1.5 hours at ambient temperature then poured into water. The layers are separated and the organic phase is washed with aqueous sodium carbonate until basic and water, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:25]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[S:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: c1cc2ccsc2cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a cold (−78° C.) solution of thieno[2,3-c]pyridine (524 mg, 3.88 mmol) in anhydrous THF (50 mL) was added n-butyllithium (2.66 mL, 4.26 mmol) dropwise. The mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (1.254 mL, 4.65 mmol) in anhydrous THF (10 mL) was added, and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a period of 2 to 3 hours. Saturated aqueous sodium bicarbonate was added. The aqueous phase was extracted with diethyl ether (3×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The desired fractions were collected to give the title compound as a clear oil (1.1 g, 67%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.32 Hz, 9H), 1.08-1.38 (m, 12H), 1.45-1.71 (m, 6H), 7.59 (s, 1H), 7.76-7.93 (m, 1H), 8.41 (s, 1H), 9.23 (s, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[C:33]([OH:36])([CH3:35])[CH3:34]>>[OH:36][C:33]([C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:29][N:31]=1)([CH3:35])[CH3:34]
Reactant: CC(C)(O)C(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3cccc(C(F)(F)F)c3)C2)CC1
Product: CC(C)(O)c1noc(C2CC(c3cccc(C(F)(F)F)c3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.24 mmol) of the compound from Example 152A and 45 mg (0.37 mmol) of the compound from Example 77A were reacted according to the General Method 2. Yield: 45 mg (35% of theory)
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]([C:41]1[N:42]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[C:60]([S:62]([CH3:65])(=[O:64])=[O:63])[C:59]([CH2:66]O)=[C:58]([F:68])[CH:57]=3)=[CH:52][C:51]=2[F:69])[CH:43]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[N:45]=1)([CH3:40])[CH3:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([O:11][P:9]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:66][C:59]2[C:60]([S:62]([CH3:65])(=[O:63])=[O:64])=[CH:61][C:56]([C:53]3[CH:54]=[CH:55][C:50]([N:42]4[CH:43]=[C:44]([C:46]([OH:49])([CH3:47])[CH3:48])[N:45]=[C:41]4[C:38]([C:32]4[C:33]([Cl:37])=[CH:34][CH:35]=[CH:36][C:31]=4[Cl:30])([CH3:40])[CH3:39])=[C:51]([F:69])[CH:52]=3)=[CH:57][C:58]=2[F:68])=[O:28])=[CH:24][CH:25]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(CO)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Reactant: O=C(O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(COC(=O)Cc4ccc(OP(=O)(OCc5ccccc5)OCc5ccccc5)cc4)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-Dimethylaminopyridine (0.19 g, 1.6 mmol) was added to a solution of 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetic acid (0.67 g, 1.6 mmol), 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (prepared in the manner described in PCT Publication No. WO 2010/138598, 0.4 g, 0.6 mmol), and N,N′-dicyclohexylcarbodiimide (0.37 g, 1.8 mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt for 30 mins. After this time, the reaction mixture was filtered, and the organic solvents were removed under reduced pressure to yield the crude product. The crude product was purified by column chromatography using a mixture of CHCl3 and methanol (9:1) to afford (4′-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-3,3′-difluoro-5-(methylsulfonyl)biphenyl-4-yl)methyl 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetate (0.4 g, 0.4 mmol, 60% yield). 1H NMR (400 MHz, CHCl3-d) δ 1.60 (s, 6H), 2.03 (s, 6H), 2.99 (s, 3H), 3.65 (s, 2H), 5.11 (d, J=8.4, 2H), 5.67 (s, 2H), 6.62 (s, 1H), 6.88 (t, J=7.6, 1H), 6.8-7.98 (m, 22H), 7.98 (s, 1H). LCMS: (Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% MeCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% MeCN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min) retention time: 2.38 min; LCMS (ES-API), m/z 1005.2 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[C:56]([F:58])[CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[C:56]([F:58])[CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 113.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, N-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methanesulfonamide (Intermediate 23) (160 mg, 0.267 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (111.89 mg, 0.321 mmol) in sodium carbonate (84.89 mg, 0.801 mmol) Pd(PPh3)2Cl2 (9.7 mg, 0.013), Toluene/ethanol/water (7/7/2 mL) to afford 210 mg of the crude compound. MS: m/z=692.1 (M+1).
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17]([S:20][CH3:21])SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1C=[CH:29][CH:28]=[CH:27][C:26]=1S.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.O>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=1)=[O:13])[CH3:16]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c1sc1ccccc12
Temperature: 140 °C
Yield: 55.1 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (475 mg, 1.27 mmol) and 2-aminobenzenethiol (200 mg, 1.60 mmol) in toluene (5 mL) was heated to dryness and continued heating neat at 140° C. for 1 h. Toluene (30 mL) and K2CO3 (350 mg, 2.53 mmol) were added to the reaction and it was heated for an additional 1 h. The reaction mixture was cooled to rt and EtOAc (100 mL) and H2O (50 mL) were added. The layers were separated and the organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude solid was triturated in Et2O to afford the desired product as a yellow solid (260 mg, 55%). MS (m/z): 372 (MH+). 1H NMR (DMSO-d6) δ: 9.37 (d, 1H), 9.30 (s, 1H), 8.06 (m, 1H), 7.65 (m, 1H), 7.54 (m, 1H), 4.35 (q, 2H), 2.78 (s, 3H), 1.34 (t, 3H).
Reaction SMILES: [H-].[Na+].COCCO[Al+]OCCOC.[H-].CC(O)CC.[CH2:20]([O:22][C:23]([N:25]1[C:34]2[C:29](=[N:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=2)[C@@H:28]([NH:37][C:38]2[N:43]=[C:42]([CH2:44][C:45]3[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=3)[C:41]([CH:59]=[CH:60][C:61]#[N:62])=[CH:40][N:39]=2)[CH2:27][C@H:26]1[CH2:63][CH3:64])=[O:24])[CH3:21].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.[Cu](Br)Br>[CH2:20]([O:22][C:23]([N:25]1[C:34]2[C:29](=[N:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=2)[C@@H:28]([NH:37][C:38]2[N:43]=[C:42]([CH2:44][C:45]3[CH:46]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:48]=[C:49]([C:51]([F:53])([F:52])[F:54])[CH:50]=3)[C:41]([CH2:59][CH2:60][C:61]#[N:62])=[CH:40][N:39]=2)[CH2:27][C@H:26]1[CH2:63][CH3:64])=[O:24])[CH3:21]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC#N)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Br[Cu]Br
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Solvent: CCC(C)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC#N)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a suspension (1 ml) of copper bromide (227 mg) in tetrahydrofuran is added dropwise 65% solution (982 mg) of bis(2-methoxyethoxy)aluminum sodium hydride in toluene under ice-cooling, and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is cooled to −78°C., and thereto is added 2-butanol (0.29 ml). Subsequently, a solution (0.5 ml) of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanovinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) in tetrahydrofuran is added thereto dropwise, and the mixture is stirred at the same temperature for 2 hours. After allowing to warm to room temperature, the mixture is stirred for additional 2 hours. To the reaction solution is added a saturated aqueous ammonium chloride solution, and the mixture is partitioned by adding ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by tin layer silica gel chromatography (hexane: ethyl acetate=2:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanoethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (74 mg). MS (m/z): 637 [M+H]+
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C:15](=[O:17])[CH:14]=[CH:13][N:12]2C(O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)=O)=[C:7]([CH3:31])[CH:6]=1>CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C:15](=[O:17])[CH:14]=[CH:13][NH:12]2)=[C:7]([CH3:31])[CH:6]=1
Reactant: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1
Yield: 161 %

Procedure:
Sodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture was refluxed for two hours, and the solvent was removed in vacuo. The residue was partitioned between water (10 mL) and AcOEt (15 mL). The layers were separated, and the aqueous phase was extracted with further AcOEt (4×10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1(OB(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[CH2:6][NH2:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)Oc1ccccc1
Reactant: NCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
18.25 g of 3-bromobenzylamine hydrochloride, 17.39 g of sodium carbonate in aqueous solution (120 ml) and 1.90 g of tetrakis(triphenylphosphine)palladium (0) were added to toluene (240 ml) under a nitrogen atmosphere. The resulting solution was mixed with 10.00 g of phenylboric acid in ethanol (120 ml) at room temperature with stirring and refluxed under heating for 2 hours. After the reaction, the reaction solution was cooled to room temperature, poured into saturated aqueous sodium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent to give 11.18 g of crude 3-phenylbenzylamine as a brown viscous liquid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[C:28]([N+:30]([O-])=O)[CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[C:17]([F:33])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>O.CC(C)=O.[Zn]>[NH2:30][C:28]1[CH:29]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:33])[CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cc([N+](=O)[O-])c3[nH]ccc3c2)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cc(N)c3[nH]ccc3c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Zn dust (123 mg, 1.88 mmol) was added to a solution of N-(tert-butyl)-3′-fluoro-4′-(7-nitro-1H-indol-5-yl)-[1,1′-biphenyl]-2-sulfonamide (23 mg, 0.19 mmol) and NH4Cl (101 mg, 1.88 mmol) in water (0.75 mL) and acetone (3.76 mL). The mixture was stirred at rt for 1 hour and then filtered through Celite. The resulting filtrate was concentrated to dryness and then taken up in water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated to dryness to give the title compound (23 mg, 28%). MS (ESI): mass calcd. for C24H24FN3O2S, 437.16; m/z found, 438.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=8.0, 1.3, 1H), 8.17-8.10 (m, 1H), 7.63-7.56 (m, 2H), 7.54-7.48 (m, 1H), 7.42 (s, 1H), 7.38 (dd, J=7.8, 1.7, 2H), 7.32 (dd, J=11.4, 1.8, 1H), 6.86 (m, 1H), 6.62 (dd, J=3.2, 2.0, 1H), 3.78-3.68 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-piperazin-1-yl-phenol (1.78 g, 10 mmol) in DMF (20 mL) was added bromomethyl-benzene (1.71 g, 10 mmol) dropwise and then the reaction was stirred at room temperature for 16 h. The mixture was poured into water and pH was adjusted to 7 with sat. aqueous NaHCO3, and then extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with water and dried over anhy. Na2SO4. After removing the solvent under vacuum, the title compound was obtained (1.1 g, 41%) and MS (ESI) m/z 269 (M+H). 1H NMR (400 MHz, CDCl3) δ 2.62 (t, J=4.8 Hz, 4H), 3.08 (t, J=4.8 Hz, 4H), 3.57 (s, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.28-7.34 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([F:33])[CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:7]([C:6]1[C:2]([NH:1][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([F:33])[CH:28]=2)=[N:3][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1)(=[O:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(N)n2)CC1
Reactant: Fc1cc(Br)ccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CC1
Temperature: 95 °C

Procedure:
To a microwave vial was added tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (5.0 g, 14 mmol), 4-bromo-2-fluoropyridine (2.5 g, 14 mmol), K3PO4 (6.1 g, 29 mmol), and dioxane (72 mL). The mixture was degassed with bubbling argon for 5 minutes. Pd2(dba)3 (0.7 g, 0.7 mmol) and X-Phos (1.0 g, 2.2 mmol) were then added, and the vial was sealed and heated to 95° C. for 5 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc, filtered through celite, and eluted with EtOAc. The filtrate was concentrated in vacuo, and the resulting yellow oil was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes) to afford the title compound, Example #9-1.