Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#[CH:2].[CH3:11][CH2:12][CH2:13][CH2:14][SnH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:6]1[CH2:7][CH2:8][C:3](/[CH:1]=[CH:2]/[Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH3:11])([OH:10])[CH2:4][CH2:5]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC1(O)CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/C1(O)CCN(C)CC1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Ethynyl-1-methylpiperidin-4-ol (Exploratory Library; 3.34 g; 24 mmol) and PdCl2(PPh3)2 (337 mg; 0.48 mmol) were dissolved and stirred in THF (100 ml), cooled in a water bath to 180C, while Bu3SnH (7.6 ml; 28.8 mmol) was added dropwise within 3 minutes. The reaction mixture was stirred at room temperature for 4 hours, poured directly on a column of SiO2 and chromatographed (EtOAc/MeOH/NH3 95/5/0.5) to deliver the title compound as a greenish oil (3.45 g; 33%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:38]([CH:47]=O)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:29]([O:33][C:34]([N:36]1[CH2:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:38]([CH2:47][N:16]2[CH2:15][CH2:14][C:11]3([C:10](=[O:19])[N:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)[CH2:18][CH2:17]2)[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Reactant: COc1ccc(CN2CCC3(CCNCC3)C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCN(C[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4c4ccccc4)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.41 g of 2-(4-methoxy-benzyl)-2,8-diaza-spiro[4.5]decan-1-one hydrochloride (12.3 mmol) in dichloromethane (50 mL) was added triethylamine (1.71 mL, 12.3 mmol) followed by 3.85 g of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (12.3 mmol) in dichloromethane (75 mL) and stirred for 1 h at room temperature. Sodium triacetoxyborohydride (3.91 g, 18.4 mmol) was then added and the reaction mixture stirred overnight at room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccnc2)cc1-c1nc(-c2ccccn2)no1
Yield: 8.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (101.8 mg, 0.625 mmol) and Pd(PPh3)4 (36.1 mg, 0.0312 mmole) in a solution of 2M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) was heated overnight at 105° C. Standard work up afforded 8.7 mg (9%) 3-(2-pyridyl)-5-[2-fluoro-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:20]=3[NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:36])[C:20]=3[NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)=[O:14])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cnn2c(Nc3cccc4ncccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4ncccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 3.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-phenylpiperidine-1-carbonyl)-7-(5-quinolylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.065 g, 0.6 mmol), the title compound (0.002 g, 3%) was obtained.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].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>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:4]6[N:3]([CH3:2])[CH:7]=[CH:6][N:5]=6)[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: Cn1ccnc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nccn5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(1-Methyl-1H-imidazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (251 mg; compound B93) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (218 mg; compound C10) and HATU (271 mg) in DCM (7 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 52 to afford the title compound after purification by preparative HPLC as a solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:17])[CH3:16])[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>O.CCO>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:17])[CH3:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A mixture of 1-[4′-(trifluoromethyl)-3-biphenylyl]ethanone (300 mg, 1.14 mmol) in water (1 mL) and EtOH (5 mL) was treated portion-wise with sodium borohydride (57 mg, 1.50 mmol) and then stirred at rt for 1.5 hours. The reaction was then quenched by the addition of saturated aqueous NH4Cl, diluted with CHCl3 and the layers separated. The organic layer was then dried (Na2SO4), filtered and reduced to give the title compound (274 mg).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[C:24]([OH:26])[CH:25]=1.[K+].[Br-]>CCOC(C)=O>[OH:26][C:24]1[CH:25]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:21]=[CH:22][C:23]=1[O:27][CH3:28]
Reactant: COc1ccc(N)cc1O
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1O
Yield: 54 %

Procedure:
Prepared from VII and 5-amino-2-methoxyphenol. Flash chromatography eluent (EtOAc). Yield: 54%; yellow solid; mp 248° C.; IR (KBr) νmax/cm−1 2921, 2851, 2227, 1724, 1647, 1616, 1583, 1509, 1460, 1334, 1287, 1263, 1218, 1172, 1148, 1120, 1036, 973, 953, 864, 833; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=8.7 Hz), 8.05 (m, 1H), 7.77 (d, 1H, J=8.7 Hz), 7.94 (d, 2H, J=8.7 Hz), 6.65 (m, 1H), 3.77 (s, 3H); HRMS calcd for C17H12N5O2S (M+H+): 350.0712, found 350.0715.
Reaction SMILES: FC1C=CC(C([N:10]2[CH2:15][CH2:14][C:13]3[N:16]=[C:17](CO)[O:18][C:12]=3[CH2:11]2)=O)=CC=1.BrC1C=C(C)C=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.CCOC(C)=O.[Cu](I)I>[N:16]1[C:13]2[CH2:14][CH2:15][NH:10][CH2:11][C:12]=2[O:18][CH:17]=1
Reactant: O=C(c1ccc(F)cc1)N1CCc2nc(CO)oc2C1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cc1ccnc(Br)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1nc2c(o1)CNCC2
Temperature: 120 °C
Reaction time: 60 h
Yield: 30 %

Procedure:
Copper iodide (17 mg, 0.09 mmol) was added to a stirred suspension of {5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridin-2-yl}methanol (50 mg, 0.18 mmol), 2-bromo-4-methylpyridine (0.04 mL, 0.36 mmol), cesium carbonate (118 mg, 0.36 mmol) and N,N-dimethylglycine (18 mg, 0.18 mmol) in 1,4-dioxane (1 mL) in a sealed tube and under nitrogen. The mixture was stirred at 120° C. for 60 hours. The mixture was diluted with AcOEt and washed with a 16% aqueous solution of NH4OH. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N solution of ammonia in MeOH in DCM 0/100 to 4/96). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was purified by RP HPLC on (C18 XBridge 19×100 5 um). Mobile phase (Gradient from 80% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 20% ACN to 0% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 100% ACN). The solvents were evaporated in vacuo to yield 5-[(4-fluorophenyl)carbonyl]-2-1[(4-methylpyridin-2-yl)oxy]methyl}-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine (6.7 mg, 10% yield) as a colourless oil. C20H18FN3O3 1H NMR (400 MHz, CDCl3) δ ppm 2.30 (s, 3 H), 2.72 (br. s., 2 H), 3.69 (br.s., 2 H), 4.75 (br. s., 2 H), 5.43 (s, 2 H), 6.65 (s, 1 H), 6.75 (d, J=5.1 Hz, 1 H), 7.13 (t, J=8.4 Hz, 2 H), 7.40-7.52 (m, 2 H), 8.01 (d, J=5.1 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[N+](C1C=CC([O:19][C:20]([C:22]2[C:30]3[S:29][C:28]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:27][C:26]=3[C:25]([O:37][CH3:38])=[CH:24][CH:23]=2)=O)=CC=1)([O-])=O>CN(C)C=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:20]([C:22]1[C:30]2[S:29][C:28]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[N:27][C:26]=2[C:25]([O:37][CH3:38])=[CH:24][CH:23]=1)=[O:19])#[N:9]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(N3CCCCC3)nc12
Reactant: Cn1ncc(C#N)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCCCC3)nc12
Yield: 75.5 %

Procedure:
Starting from 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (125 mg) in dimethyl formamide (10 ml), sodium hexamethyldisilazide in tetrahydrofuran (1.1 ml, 1.0 M), and 4-methoxy-2-(piperidin-1-yl)benzothiazole-7-carboxylic acid 4-nitrophenyl ester (210 mg). Purification by flash chromatography (eluent 5% methanol in dichloromethane) followed by trituration with ethyl acetate yielded the title compound as an off-white solid (152 mg). TLC Rf 0.48 (ethyl acetate); Mpt 290-291° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([N:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C1COCC1>[C:35]([O:34][C:32]([N:39]1[CH2:42][CH:41]([O:43][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)[CH2:40]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2cccnc2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
To 315 mg (1.2 mmol) of PPh3 in 5 mL of dry THF at −20° C. was added 189 μL (1.2 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 173 mg (1 mmol) of N-Boc-3-hydroxyazetidine and 2 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 95 mg (1 mmol) of 3-hydroxypyridine at once. The solution was then slowly heated to 70° C. and allowed to stir at 70° C. overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (2:1, Hexane:Ethyl Acetate) to obtain 160 mg (64% yield) of a yellow oil: 1H NMR (300 MHz, CD3OD) δ 8.27 (1H, d, J=4.8 Hz), 8.18 (1H, d, J=2.7 Hz), 7.23 (1H, m), 7.05 (1H, m), 4.92 (1H, m), 4.34-4.00 (2H, AB, J=6.6, 9.7 Hz), 1.45 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH:6]=1.C([Li])CCC.CCCCCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([CH:28]=[O:29])[CH:3]=[N:4]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-n2cc(Br)cn2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-n2cc(C=O)cn2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a −78° C. solution of 4-bromo-1-(4-methoxyphenyl)-1H-pyrazole (506 mg, 2.0 mmol) in anhydrous tetrahydrofuran (20 mL) was added n-butyllithium in hexane (0.95 mL, 2.4 mmol). The reaction was stirred for 2 h at −78° C. N,N-dimethylformamide (292 mg, 4 mmol) was added and the reaction continued to stir at −78° C. for 1 h, then at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (80 mg, 20%) as a yellow oil. 1H NMR (400 MHz, CDCl3, δ): 9.95 (s, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.62 (d, J=9.2 Hz, 2H), 7.01 (d, J=9.2 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH3:7])[CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO>[CH3:11][O:9][C:8]([CH:4]1[CH2:3][CH:2]([OH:1])[CH2:6][N:5]1[CH3:7])=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN1CC(O)CC1C(=O)O
Solvent: CO
Product: COC(=O)C1CC(O)CN1C

Procedure:
4-Hydroxy-1-methyl-pyrrolidine-2-carboxylic acid (0.27 g, 1.85 mmol) was dissolved in 5 ml methanol at room temperature and (trimethylsilyl)diazomethane (2M solution in hexane) was added until solution become yellow. The mixture was concentrated down to afford crude 4-hydroxy-1-methyl-pyrrolidine-2-carboxylic acid methyl ester, which was converted to 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-1-methylpyrrolidine-2-carboxylic acid following the same procedure as for the preparation of (1R,2R)-2-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)methyl]cyclopentanecarboxylic acid.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:7][C:6]1[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])=[CH:3][S:4][CH:5]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cc1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cscc1-c1ccccc1C=O
Temperature: 150 °C
Yield: 78 %

Procedure:
In a microwave vial, 3-bromo-4-methyl-thiophene (653 mg, 3.69 mmol), 2-formyl phenylboronic acid (500 mg, 3.36 mmol) and 7 ml of actonitrile were mixed together. 6.7 ml of 1N aqueous sodium carbonate was added to above solution, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried with sodium sulfate. The organic solvent was evaporated to give crude product, which was purified by ISCO CombiFlash column to give 530 mg of 2-(4-methyl-thiophen-3-yl)benzaldehyde, yield: 78%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Yield: 78.3 %

Procedure:
The compound was prepared according to general procedure E with 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (1.8 mmol) in dry acetone (20 ml), anhydrous K2CO3 (2.4 mmol), and ethylbromoacetate (2.7 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 395 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 361 mg of purified compound were obtained (79% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.25 (t, J=, 3H), 3.98 (s, 3H), 4.21 (q, J=, 2H), 4.89 (s, 2H), 7.34 (dd, J=10.3 and 1.6 Hz, 1H), 7.40 (t, J=1.6 Hz, 1H), 9.88 (d, J=1.6 Hz, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.0, 57.6, 62.1, 70.3, 110.0, 111.8 (d, J=20.6 Hz), 133.1 (d, J=7.2 Hz), 141.8 (d, J=12.7 Hz), 154.5 (d, J=4.5 Hz), 156.0 (d, J=246 Hz), 169.7, 191.3. MS (ESI): m/z 256.9 [M+H]+.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH:24]=1)[CH2:30][O:31][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: OCc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1OCc1cc(F)ccc1O
Temperature: 100 °C
Yield: 3.6 %

Procedure:
To a solution of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (211.2 mg, 0.70 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (100 mg, 0.70 mmol) in N-methylpyrrolidinone (3 mL) was added cesium carbonate (687.8 mg, 2.1 mmol) and the mixture was heated at 100° C. for 2 hours. The reaction was cooled to 25° C., filtered and purified by reverse phase HPLC using a gradient of acetonitrile/water (10 to 99%) and HCl as a modifier to yield 2-[(5-fluoro-2-hydroxy-phenyl)methoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (159) (10.5 mg, 3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.49 (s, 1H), 10.04 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.05-6.91 (m, 2H), 6.91-6.79 (m, 2H), 6.61 (dd, J=7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm. ESI-MS m/z calc. 422.09. found 423.3 (M+1)+; Retention time: 1.83 minutes (3 minutes).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:5]
Reactant: Cc1ccc(-c2c(C(C)N=[N+]=[N-])nc3scc(C)n3c2=O)cc1
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(C)N)nc3scc(C)n3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 7-(1-azidoethyl)-3-methyl-6-(4-methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.050 g, 0.15 mmol) in tetrahydrofuran (2 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.23 mL, 0.23 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product (40 mg), which was used directly in next step. LCMS calculated for C16H18N3OS (M+H)+: m/z=300.1. Found: 300.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[NH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1)=[O:15]
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2cccnc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-pyrrolidin-3-ylpyridine (8.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.0 mg). Calcd for C19H16ClN3O2: 353.0931, found 353.0932.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#N)=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C[OH:30]>C(O)=O.O.[Ni].[Al]>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[O:30])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Agent: [Ni]
Agent: [Al]
Solvent: O
Solvent: O=CO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C=O)cc23)C1
Temperature: 25 °C
Yield: 91 %

Procedure:
Dissolve (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (200 mg, 0.53 mmol) in 88% formic acid (10 ml) and water (1 mL). Add aluminum-nickel catalyst (50/50 wt %) and heat at 90° C. for 24 h. Add water (1 mL) and heat for an additional 24 h. After cooling to room temperature, add methanol and filter off the catalyst through Celite®. Dilute with ethyl acetate and basify to pH=10 using 10% potassium carbonate. Separate the phases and wash the organic phase with 10% potassium carbonate. Dry the organic portion over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound as an orange oil (181 mg, 91%). Use the crude product without further manipulation. MS (m/z): 378.2 (M+1).