Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[N:5][CH:6]=[C:7](Cl)[N:8]=2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH:41]=[CH:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:8]=2)[N:3]=1
Reactant: C=Cc1ccccc1
Reactant: CCCCCOc1nc(N)nc2ncc(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCOc1nc(N)nc2ncc(C=Cc3ccccc3)nc12
Yield: 72.9 %

Procedure:
A mixture of 1.5 g (5.6 mmoles) 2-amino-6-chloro-4-n-pentyloxypteridine (e.g. available following the procedure disclosed by Mohr et al. in Helv. Chem. Acta (1992) 75:2317), palladium acetate (63 mg, 0.28 mmoles), tri-o-tolylphosphane (682 mg, 2.24 mmoles), cuprous iodide (53 mg, 0.28 mmoles), styrene (1,3 ml., 11.3 mmoles) and triethylamine 3.1 ml, 22 mmoles) was stirred in dry acetonitrile (50 ml) under reflux for 90 hours. It was evaporated and the residue purified by silica gel column chromatography with chloroform. The product fraction was evaporated to give 1.37 g (yield: 72%) of an orange powder exhibiting, after recrystallization from a EtOAc/hexane mixture, a melting point (m.p.) range of 127–128° C.
Reaction SMILES: CN(C)CCCN=C=NCC.[ClH:12].[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:26][C@@H:25]([F:28])[C@@H:24]3[C@H:20]2[CH2:21][NH:22][CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48](O)=[O:49].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[ClH:12].[CH3:51][N:36]([CH3:35])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48]([N:22]1[CH2:21][C@@H:20]2[C@@H:24]([C@H:25]([F:28])[CH2:26][CH2:27][C:19]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23]1)=[O:49]
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CN(C)CCCOc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCOc1ccccc1CC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 50 cm3 of dry dichloromethane is added over 10 minutes to a solution, cooled to +4° C., of 0.72 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid, 0.03 g of 1-hydroxybenzotriazole in 75 cm3 of dichloromethane, followed by 0.37 cm3 of diisopropylethylamine. The reaction mixture is stirred for 3 hours at 0° C. and then washed twice with 50 cm3 of water and twice with 50 cm3 of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 21 cm3 of 0.1N hydrochloric acid, 50 cm3 of diethyl ether and 30 cm3 of water. The aqueous phase is separated and freeze-dried to give 0.85 g of (3aR, 7R,7aR)-2-([2-(3-dimethylaminopropoxy)phenyl]acetyl)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in the form of a white freeze-dried product.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH3:31])[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[CH3:21]>>[CH3:31][N:19]([CH3:18])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:24][CH:23]=1)[CH3:21]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(c1ccc(B(O)O)cc1)N(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)N(C)C)cc1
Yield: 60.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.8 mmol) was reacted with 4-[1-(dimethylamino)ethyl]phenylboronic acid (1.5 g, 6.3 mmol) to afford the desired product (1.1 g, 58%) as a white solid: ESI MS m/z 379 [C22H22N2O2S+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:36]([N-]C(C)C)(C)C.[Li+].P([O-])([O-])([O-])=O>C1COCC1>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)N(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise a solution of lithium diisopropylamide (LDA) (2.0 N in heptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling over a period of 10 min. After completion of the addition, the stirring was continued for an additional 20 min at the same temperature. To the resulting mixture was added dropwise Mel (0.5 mL) at 0° C., and stirred at room temperature for 15 h. The mixture was poured into a solution of phosphate buffer (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 10 mg (5%) of the title compound as a colorless oil: 1H-NMR (CDCl3) δ 7.64 (2H, d, J=8.3 Hz), 7.53-7.25 (7H, m), 6.89 (1H, s), 3.65-3.55 (2H, m), 3.14 (3H, s), 2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH:55]1[CH3:60])=[O:53])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:12]([C:9]2[N:10]=[CH:11][N:7]([C:3]3[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=3)[N:8]=2)=[O:14])[CH2:56][CH:55]1[CH3:60])=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: Cc1cccc(-n2cnc(C(=O)O)n2)c1
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
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: Cc1cccc(-n2cnc(C(=O)N3CCN(C(=O)OC(C)(C)C)C(C)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.00 g (9.84 mmol) 1-m-tolyl-1H-[1,2,4]-triazole-3-carboxylic acid was stirred with 3.30 g (10.3 mmol) TBTU and 2.50 mL (14.6 mmol) DIPEA in 30 mL DCM at RT. After 10 min, 2.05 g (9.84 mmol) 2-methyl-piperazine-1-carboxylic acid tert-butyl ester was added and the reaction mixture was stirred at RT for 12 h. The solvent was removed by distillation. The residue was taken up in water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7])#[N:2].[CH3:19][Mg]Br.Cl>O1CCCC1>[C:6]([C:5]1[CH:4]=[C:3]([CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=1)[C:1]#[N:2])(=[O:7])[CH3:19]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 0.76 mmol) in anhydrous tetrahydrofuran (2 mL) stirred on an ice bath was added methylmagnesium bromide (0.96 M solution in ether, 0.95 mL, 0.91 mmol), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with 1 M hydrochloric acid, and extracted with ethyl acetate, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 3-acetyl-5-(trifluoromethyl)benzonitrile (162 mg, 100%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].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>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Yield: 44.8 %

Procedure:
The compound was prepared according to general procedure E with 5-chlorovanillin (2.7 mmol) in dry acetone (25 ml), anhydrous K2CO3 (3.5 mmol), and ethylbromoacetate (4.05 mmol) at reflux for 1 h30. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 957 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 330 mg of purified compound were obtained (45% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.27 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 4.87 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H), 9.90 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.1, 57.5, 62.1, 70.5, 112.3, 125.8, 128.9, 134.0, 149.7, 154.5, 169.5, 191.2. MS (ESI): m/z 272.9 and 274.9 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>>[F:30][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COC(=O)c1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 83.6 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 466 mg of methyl 5-amino-2-fluorobenzoate in place of the 2,4-difluoroaniline. 625 mg of methyl 2-fluoro-5-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:36])[CH:30]=2)[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:36])[CH:30]=3)[CH:26]=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cn1cc(-c2cccc(Br)n2)ccc1=O
Product: Cn1cc(-c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)ccc1=O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (38 mg, 0.12 mmol) and 6-bromo-1′-methyl-2,3′-bipyridin-6′(1′H)-one (33 mg, 0.12 mmol) as starting materials.
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][OH:23])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:29]([O:23][CH2:22][C@H:2]([OH:1])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
tert-butyl (1R,2R)-2,3-dihydroxy-1-(4-(trifluoromethyl)phenyl)-propylcarbamate (11 g, 32.8 mol) in 100 mL DMF was cooled in an ice-water bath. 1H-imidazole (8.2 mL, 72 mol) was added in one portion, and the mixture was stirred for 10 minutes under nitrogen. tert-butyldimethylsilylchloride (5.43 g, 36.0 mmol) in 20 mL DMF was added via syringe. The reaction was monitored by TLC. After 16 hours, DMF was evaporated under high vacuum. 150 mL distilled water was added, and the resulting mixture was extracted into diethyl ether (2×200 mL). The ether layer was washed with saturated aqueous ammonia chloride and dried over sodium sulfate. After removing the solvent, the product was obtained as a white solid (14.0 g, yield=95%). 1H NMR (400 MHz, CD3OD) δ ppm 0.08-0.12 (m, 6H) 0.97 (s, 9H) 1.43 (s, 9H) 3.50 (s, 1H) 3.63 (s, 1H) 3.85 (s, 1H) 4.81 (s, 1H) 7.53-7.58 (m, 2H) 7.60-7.66 (m, 2H).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]([NH:11][C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)=[O:10])[CH:5]=1>O.CO.C1COCC1>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]([NH:11][C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)=[O:10])[CH:5]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cc(C)on1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H]2CCc3ccc(C(=O)O)cc32)no1
Reaction time: 5 h
Yield: 59 %

Procedure:
LiOH (3.0 g, 42.66 mmol, 8 eq) in water (30 ml) was added dropwise to a cooled (0° C.) solution of (R)-methyl 3-(5-methylisoxazole-3-carboxamido)-2,3-dihydro-1H-indene-5-carboxylate (B-25) (1.6 g, 5.3 mmol, 1 eq) in MeOH:THF (1:1, 60 ml), and stirring was carried out for 5 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in water (50 ml), adjusted to pH 2 with KHSO4 and extracted with DCM (2×100 ml). The combined organic phases were washed with sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. Yield: 59% (900 mg, 3.14 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[N:5][N:6]=1.[H][H]>CO.C(OCC)(=O)C.[Ni]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccccc2[N+](=O)[O-])o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccccc2N)o1
Yield: 99.5 %

Procedure:
A mixture of 2-methyl-5-(2-nitro-phenyl)-[1,3,4]oxadiazole (0.73 g) and 50% Raney Ni (1 mL) in methanol (5 mL) and ethyl acetate (25 mL) was shaken under 50 psi of hydrogen for 3 hours. Filtration through celite and concentration of the filtrate provided 0.62 g of 2-methyl-5-(2-amino-phenyl)-[1,3,4]oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, 1H), 7.26 (dd, 1H), 6.76 (m, 2H), 5.81 (bs, 2H), 2.61 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[NH:19][C:18](=[O:27])[C@@H:17]([NH2:28])[CH2:16][C:15]2=[CH:29][CH:30]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[NH:19][C:18](=[O:27])[C@@H:17]([NH:28][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:16][C:15]2=[CH:29][CH:30]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NS(C)(=O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Amine 47 (200 mg) was dissolved in anhydrous DMF (5 mL). Methane-sulfonyl chloride (39 μL) and DIPEA (0.175 mL) were added and the reaction mixture was stirred at rt for 18 h before being partitioned between chloroform and 1M hydrochloric acid. The aqueous phase was extracted three more times with chloroform and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 40 mg, 17%. Rf=0.12 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: Clc1cccc(I)c1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(Cl)c4Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.68–6.94 (m, 12H), 6.68 (d, 1H, J=2.8 Hz), 3.69 (s, 2H), 3.15–3.02 (m, 2H) 2.54–2.42 (m, 2H), 2.18–2.02 (m, 2H), 1.88–1.76 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 520.1 (M+H)+.
Reaction SMILES: CC1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:7])N=1.IC1N[N:23]=[C:22](C)[C:21]=1C.IC1NC(C)=NC=1C>>[CH3:21][C:22]1[C:5]([CH3:7])=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[NH:3][N:23]=1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Reactant: Cc1n[nH]c(I)c1C
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]nc(C)c2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 5-iodo-3,4-dimethyl-1H-pyrazole (compound 59.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 245 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=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>[Cl:1][C:2]1[CH:3]=[C:4]([C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:29])[CH3:30])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(F)(F)F)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.18 g, 0.29 mmol), 4-trifluoromethylphenylboronic acid (0.07 g, 0.36 mmol), sodium carbonate (0.09 g, 0.86 mmol) in THF (26 mL) and water (13 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.02 g, 0.01 mmol). Raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.12 g of (R)-3-(3,5-Dichloro-4′-trifluoromethyl-biphenyl-4-ylmethyl)-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[S:18]1[C:22]([C:23](O)=[O:24])=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2.C(=O)([O-])O.[Na+]>O>[S:18]1[C:22]([C:23]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:24])=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.33 g (1.9 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 0.46 g (5.5 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 2 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 0.48 g (yield: 93%) of 4,4-difluoro-3-methyl-3-butenyl benzo[b]thiophene-2-carboxylate.