Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:18]([OH:34])[C:19]([N:21]1[CH2:32][C@@H:31]([Cl:33])[CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])(C)(C)C.[CH3:42][O:43][C:44]1[C:52]2[O:51][C:50](C(O)=O)=[CH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1>>[CH3:42][O:43][C:44]1[C:52]2[O:51][C:50]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:18]([OH:34])[C:19]([N:21]3[CH2:32][C@@H:31]([Cl:33])[CH2:30][C@H:22]3[C:23]([NH:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])=[CH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc3ccccc3)[C@H](O)C(=O)N3C[C@@H](Cl)C[C@H]3C(=O)NC(C)(C)C)oc12
Yield: 65.4 %

Procedure:
Following a procedure similar to that described in Example 16, but using 155 mg (0.26 mmol) of (4S)-1-[(2S,3S)-3-(N2 -t-butoxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide (prepared as described in Example 65) and 50 mg (0.26 mmol) of 7-methoxy-2-benzofurancarboxylic acid, 114 mg of the title compound were obtained as a colorless powder, melting at 125°-136° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][NH2:22].C(OCC)C.CCCCCC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
1-(4-Benzyloxyphenyl)propan-2-one (2.28 g) was added to a solution of 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.75 g) in dry toluene (100 ml) and the solution was boiled under reflux for 90 minutes in an apparatus incorporating a water-trap. The solution was cooled and the solvent removed under reduced pressure. The residue, dissolved in methanol (100 ml), was cooled to less than 10° C. and treated portionwise with sodium borohydride (3.0 g) over 30 minutes, with stirring. The mixture was stirred for one hour at room temperature and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried (magnesium sulphate), filtered and evaporated to dryness to give a solid. Trituration of the solid with diethyl ether followed by addition of hexane and filtration gave N-[2-(4-benzyloxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine of analytical purity, mp 95°-99° C., as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](O)C[N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@H:18]2[C@@H:19]([O:27][CH2:28][CH3:29])[CH2:20][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.40–7.25, 5.20–5.13, 4.76, 4.11, 3.98, 3.73–3.60, 3.51–3.31, 2.70, 2.47, 1.31–1.24, 1.15; IR (liq.) 2972, 2342 (w), 1948 (w), 1709 (s), 1567, 1552, 1498 (s), 1470 (s), 1449 (s), 1420 (s), 1397 (s), 1350, 1126, 1100 (s), 1080, cm−1
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[CH3:21][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][O:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH2:5][CH2:4][N:3]=1
Reactant: N#Cc1ccc(C2CCNC(=O)C2)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Into a round-bottom flask, was placed a solution of 4-(2-oxopiperidin-4-yl)benzonitrile (347.2, 220 mg, 1.10 mmol, 1.00 equiv) in dichloromethane (10 mL). Trimethyloxonium tetrafluoroborate (244.2 mg, 1.65 mmol, 1.50 equiv) was slowly added and the resulting mixture was stirred for 2 h at room temperature. The pH was carefully adjusted to 8 with sodium bicarbonate (aq.). The organic layer was washed with 2×20 mL of H2O, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 212 mg (90%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:27][N:26]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: Clc1ccc(-c2ccccc2)cn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(n1)oc1c(-c3ccc(-c4ccccc4)cn3)cccc12
Yield: 42.3 %

Procedure:
A mixture of 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (3.0 g, 9.70 mmol), 2-chloro-5-phenylpyridine (2.024 g, 10.67 mmol), Pd2(dba)3 (0.178 g 0.192 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.319 g, 0.776 mmol), potassium phosphate (7.21 g, 34.0 mmol), toluene (70 mL) and water (7 mL) was degassed with nitrogen and then refluxed overnight. It was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using ethyl acetate in hexanes to give 2-methyl-8-(5-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (1.38 g, 4.10 mmol, 42.3% yield).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:12]C1C=CC(C(O)=O)=NC=1.FC1N=C(C(O)=O)C=CC=1>>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([NH:10][NH2:11])=[O:9])=[N:7][CH:2]=1
Reactant: NNC(=O)c1cccc(F)n1
Reactant: Cc1ccc(C(=O)O)nc1
Agent: O=C(O)c1cccc(F)n1
Product: Cc1ccc(C(=O)NN)nc1

Procedure:
5-Methyl-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 5-methyl-2-pyridinecarboxylic acid (5-methylpicolinic acid, CAS [4434-13-3], commercially available e.g. from Allichem or Ryan Scientific) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:51]1([CH3:64])[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:52]=1>CN(C=O)C.O>[O:27]=[C:25]([N:61]1[CH2:62][CH2:63][CH:58]([O:57][C:53]2[CH:52]=[C:51]([CH3:64])[CH:56]=[CH:55][CH:54]=2)[CH2:59][CH2:60]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 55 %

Procedure:
DIPEA (155 mg, 1.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (100 mg, 0.4 mmol) in DMF (2 mL) followed by HOBt (54 mg, 0.4 mmol) and EDCI.HCl (84 mg, 0.44 mmol). After 2 minutes 4-m-tolyloxy-piperidine hydrochloride (107 mg, 0.4 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid collected. The solid was purified by washing with 10% MeOH in CHCl3 to afford 92 mg (56% Yield) 5-phenyl-1H-pyrazole-3-carboxylic acid [2-oxo-2-(4-m-tolyloxy-piperidin-1-yl)-ethyl]-amide. LC/MS [M+H]+: 419, 95.4%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.6 (m, 1H), 8.0 (m, 2H), 7.8 (m, 2H), 7.4 (m, 4H), 7.2 (m, 2H), 6.8 (m, 3H), 4.6 (m, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.3 (s, 3H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]([CH3:21])=[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]=3[C:13]=2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:4]=1.[H-].[Na+].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:30]([O:29][C:27]([C:13]1[C:14]2[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:21])[N:17]([C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:18]=2[CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)OCc3ccccc3)c12
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n(C(=O)c2ccccc2)c2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
1.5 g of benzyl 5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-ethoxycarbonyl-2-methylindol-4-carboxylate was dissolved in 50 ml of tetrahydrofuran, and 0.176 g of 60% sodium hydride was added thereto. The mixture was stirred at room temperature for 30 minutes. Then, 0.51 g of benzoyl chloride was dropwise added thereto at room temperature, and the mixture was stirred for 4 hours. After concentration under reduced pressure, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 1.67 g (yield: 92%) of the desired compound. mp: 128°-132.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[C:28](=O)[C:29](OC)=[O:30].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[C:28]1[C:29](=[O:30])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO)cccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCO)cccc45)C(=O)NC3=O)c21
Temperature: 60 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (105 mg, 0.55 mmol) and methyl 2-(7-hydroxypropyl-1H-indol-3-yl)oxoacetate (146 mg, 0.56 mmol) in DMF (2.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (1.7 mL, 1.7 mmol) dropwise over 25 min. The reaction was heated to 60° C. and stirred for 12 h. The reaction mixture was then cooled to room temperature and quenched with 1.0 N hydrochloric acid (5.0 mL). The mixture was extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 3:47:50 MeOH/EtOAc/CH2Cl2) gave the title compound (196 mg, 87%) as a red solid, mp 183–185° C. 1H NMR (300 MHz, DMSO-d6) 11.81 (s, 1H), 11.12 (s, 1H), 7.87 (m, 1H), 7.61 (m, 1H), 7.28 (m, 1H), 6.98 (m, 3H), 6.50 (m, 2H), 6.29 (m, 1H), 3.68 (s, 3H), 3.41 (m, 2H), 2.78 (m, 2H), 1.76 (m, 2H). MS (electrospray, m/z) 398 [C24H21N3O3−H]−
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=C(C=CC=1OC)C[N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][C:35](=[CH:38][C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:46])[CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1.O>CN(C=O)C>[F:46][C:40]1[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=1[CH:38]=[C:35]1[CH2:36][CH2:37][N:32]([C:30]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=3)[CH2:28][CH2:27]2)=[O:31])[CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 4.4 %

Procedure:
4-Fluorobenzoic acid methyl ester (125 mg, 0.807 mmol) was dissolved in DMF (3.0 mL), and potassium carbonate (150 mg, 1.08 mmol) and the compound (200 mg, 0.538 mmol) obtained in Example 36 (1) were added thereto, followed by stirring overnight while heating at 120° C. After the reaction mixture was cooled to room temperature, water was added thereto. After extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100), thereby giving the title compound (11.0 mg, 4%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2cccnc2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2cccnc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 6-bromo-2-(pyridine-3-yl)chroman-4-one (1.0 g, 3.3 mmol) in anhydrous DCM (20 mL) was added TiCl4 (1 M solution in DCM, 2.5 g, 13.2 mmol) dropwise within 15 minutes at room temperature in absence of light. It was stirred for another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.35 g, 7.26 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (687 mg, 64%), which was used for next step without further purification.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:15][C:16]2[CH:33]=[CH:32][C:19]3/[C:20](=[CH:29]/[C:30]#[N:31])/[C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH2:23][CH2:24][C:18]=3[CH:17]=2)[C:8](=[O:14])[CH2:9][C:10]([O:12]C)=[O:11])[CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:15][C:16]2[CH:33]=[CH:32][C:19]3/[C:20](=[CH:29]/[C:30]#[N:31])/[C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH2:23][CH2:24][C:18]=3[CH:17]=2)[C:8](=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[CH:2]=1
Reactant: COC(=O)CC(=O)N(Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N)c1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#C/C=C1\c2ccccc2CCc2cc(CN(C(=O)CC(=O)O)c3cccc(-c4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
[step 2] (E)-[2-(N-(Biphenyl-3-yl)-3-methoxy-3-oxopropanamido)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (52 mg, 0.10 mmol) obtained in step 1 was dissolved in ethanol (2 mL), 2 mol/L aqueous sodium hydroxide solution (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was adjusted to pH 2 with 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reversed-phase liquid chromatography (water/acetonitrile=7/3 to 1/9) to give the title compound (compound 44) (30 mg, 60%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][C:15]#[N:16])(=O)=O.[I-:17].[Na+].CCCCCC.C(OCC)(=O)C.O>C(#N)C>[I:17][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][C:15]#[N:16]
Reactant: CS(=O)(=O)OCCCn1cccc1CC#N
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: N#CCc1cccn1CCCI

Procedure:
A solution of 8 g. of 1-(3-methansulfonyloxypropyl)pyrrol-2-acetonitrile (0.33 moles) in dry acetonitrile (270 ml.) containing dry sodium iodide (12.2 g., 0.081 moles) is stirred under reflux for 40 min. (t.l.c., silica gel, hexane-ethyl acetate, 1:1). The reaction is cooled to 40°, water (50 ml.) is added, and the solvent is then removed in vacuo almost to dryness. To the residue is added saturated sodium chloride solution (300 ml.) and dichloromethane (350 ml.). The organic phase is separated combined with the dichloromethane extracts of the aqueous phase (3×150 ml.), and washed successively with saturated sodium chloride solution, saturated sodium sulfite solution (once) and dilute sodium chloride solution. The solution is dried with sodium sulfate and evaporated in vacuo giving 1-(3-iodopropyl)pyrrol-2-acetonitrile which is an oil (7.7 g) having the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21]([CH3:23])=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:25][OH:26])[C:3]=1[S:21]([CH3:23])=[O:22]
Reactant: CS(=O)c1c(C=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 61.1 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde (2.74 g), hydroxylamine hydrochloride (0.99 g) and pyridine (1.68 g) was stirred in methanol at 46° C. for 2.8 hours, evaporated, washed (water) and crystallized from ethanol to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.74 g) as a white solid m.p. 2.19-221° C. (decomposition). Compound 1.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.FC(F)(F)C(O)=O.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47](=[O:57])[CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47](=[O:57])[CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][CH2:55][N:54]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:53][CH2:52]2)=[CH:43][CH:42]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: O=C(CCCC1CCNCC1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1)c1ccc(F)cc1
Yield: 55.5 %

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (40 mg, 0.092 mmol, Aldehyde 5) and 4-(4-(4-fluorophenyl)-4-oxo-butyl)piperidine trifluoroacetate (43 mg, 0.119 mmol from Step D) using the procedure described in Example 26, Step F to provide 28 mg (56%) of the title compound. 1H NMR (500 MHz, CD3OD) δ1.15-1.5 (m, 9H), 1.58-2.05 (m, 10H), 2.33-2.35 (m, 1H), 2.49-2.52 (m, 1H), 2.7-2.8 (m, 2H), 2.92-2.94 (m, 1H), 2.95-2.98 (t, 2H, J=7), 3.1-3.13 (m, 1H), 3.3-4.8 (m, 6H), 7.18-7.21 (m, 2H) 7.26-7.29 (m, 1H), 7.31-7.34 (m, 4H), 8.01-8.5 (m, 2H). ESI-MS: 549 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[N:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([N:24]6[CH:28]=[CH:27][CH:26]=[N:25]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc(-n3cccn3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-n5cccn5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-pyrazol-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 79.1.1) to give the title compound as a white solid. (HPLC: tR 2.64 min (Method A); M+H=437 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.68-8.66 (m, 1H), 8.59-8.57 (m, 1H), 8.16-8.12 (m, 2H), 8.10-7.98 (m, 3H), 7.87-7.85 (m, 1H), 7.60-7.58 (m, 1H), 6.62-6.59 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[C:14]=2[CH3:15])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccc(O)cc2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Yield: 93.8 %

Procedure:
To 300 ml of a solution of 18.7 g (0.051 mole) of 2-(4-methoxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone in methylene chloride, 25.0 g (0.010 mole) of boron tribromide was added dropwise. After stirring the resultant mixture at room temperature for 15 hours, the reaction mixture was poured into water, followed by neutralization with sodium hydrogen carbonate. Deposited crystals were collected by filtration and washed with aceton, thereby affording 16.9 g of 2-(4-hydroxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone having a melting point of not lower than 300° C.