Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[NH2:13])[NH:9][C:8](=[O:14])[CH:7]2[CH:15]([CH3:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:15]([CH:7]1[C:6]2[C:10](=[CH:11][C:12]3[NH:13][C:24]([C:23]4[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[N:3][C:4]=3[CH:5]=2)[NH:9][C:8]1=[O:14])([CH3:17])[CH3:16]
Reactant: CC(C)C1C(=O)Nc2cc(N)c(N)cc21
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)NC(=O)C4C(C)C)cc1
Reaction time: 2 h

Procedure:
2.8 g. (13.6 mmol) 5,6-diamino-3-isopropylindolin-2-one dihydrochloride were suspended in 10 ml. methylene chloride, mixed with 2.55 g. (15 mmol) p-methoxybenzoyl chloride and 4.55 g. (45 mmol) triethylamine added dropwise thereto at 25° C. The reaction mixture was stirred for 2 hours, evaporated and worked up with water. The residue was heated under reflux for about 24 hours in 75 ml. ethanol and 75 ml. concentrated hydrochloric acid, evaporated and rendered neutral with 2N ammonia solution. The residue filtered off with suction was recrystallised from ethyl acetate/methanol. There were obtained 2.1 g. (48.2% of theory) of the title compound; m.p. 326°-328° C.
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]=[CH:11][N:12]([S:14](=[O:19])(=[O:18])[N:15]([CH3:17])[CH3:16])[CH:13]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].Cl>O1CCCC1.CCCCCC>[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]([CH:27]=[O:28])[N:12]([S:14](=[O:18])(=[O:19])[N:15]([CH3:16])[CH3:17])[CH:13]=1
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)n1cnc(-c2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1cc(-c2ccc(Cl)cc2Cl)nc1C=O
Temperature: 25 °C

Procedure:
To 4-(2,4-Dichlorophenyl)-1-(dimethylsulphamoyl)imidazole, (8.0 g) in tetrahydrofuran (125ml), maintained under a dry nitrogen atmosphere at -60° was added 2.6M butyllithium in hexane (10.57 ml). The solution was stirred and after a short time dimethylformamide (2.9 ml) was added. The mixture was warmed slowly to room temperature and then added to dilute hydrochloric acid. The product was extracted with ethyl acetate and the extract washed with water, dried the solvent evaporated and the solid residue recrystallised from toluene to give 4-(2,4-dichlorophenyl)-1-(dimethylsulphamoyl)-2-formylimidazole, m.p. 148°-157° (dec.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([O:24][CH3:25])[N:3]=1.[S-2:26].[Na+].[Na+]>CN(C=O)C>[OH:21][C@@H:18]([CH2:19][OH:20])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([SH:26])[N:3]=[C:4]([O:24][CH3:25])[C:5]=2[C:22]#[N:23])=[CH:11][CH:12]=1
Reactant: [S-2]
Reactant: COc1nc(Cl)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(S)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.278 mmol) of 2-chloro-4-(4-{[(2S)-2,3-dihydroxypropyl]oxy}phenyl)-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 5 ml of DMF, 26 mg (0.334 mmol) of sodium sulphide are added and the mixture is stirred at room temperature for 4 hours. The reaction mixture is reacted further without any further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ncc[nH]1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ncc[nH]1
Yield: 76 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-2-carboxamide was prepared using the method of Example 34(d) starting from 1H-imidazole-2-carboxylic acid (0.206 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). The crude product was washed with 0.1 M HCl, 1M NaCO3, water and brine. Yield 76%. 1H-NMR (400 MHz; DMSO): δ 1.23 (d, 3H), 4.31 (dd, 1H), 4.38 (dd, 1H), 4.41-4.50 (m, 1H), 6.94 (d, 1H), 7.07 (s, 1H), 7.24 (dd, 1H), 7.84 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.17 (dd, 1H), 8.65 (d, 1H), 12.95 (s, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C1COCC1.[CH2:12]([C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:12]([C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
Triphenyl methylphosphonium bromide (13.1 g, 0.037 mol) was suspended in toluene (150 mL) and was treated with 1M potassium tert-butoxide in THF (28.8 mL, 0.8 equivalents) at 25° C. for 16 hrs. This solution was added dropwise to a suspension of Example 4C in toluene (100 mL) at −78° C. over 15 min. After 1.5 h, the mixture was warmed to 25° C. and partitioned between saturated ammonium chloride (100 mL) and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvents were evaporated. The oil was redissolved in ether:hexanes (10 mL, 1:1) and filtered to remove triphenylphosphine oxide. The filtrate was evaporated and the crude residue was purified using ethyl acetate:hexanes (1:6) to give 2.4 g (49%) of the title compound.
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=O)(OCC1C=CC=CC=1)=O.[BH4-].[Na+].[Br:21][C:22]1[CH:23]=C(N2CCC=C2)[CH:25]=[N:26][CH:27]=1>COCCOC.C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:13]([CH:12]2[CH2:16][CH2:17][CH2:18][NH:11]2)[CH:25]=[N:26][CH:27]=1
Reactant: Brc1cncc(N2C=CCC2)c1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Brc1cncc(C2CCCN2)c1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Carbobenzyloxy-L-proline (37.4 g, 150 mmol) was dissolved in DME (100 mL) and cooled to 0° C. with stirring. Sodium borohydride (1.89 g, 50 mmol) was added in portions (gas evolution) and the resulting mixture was stirred for 2 h at 25° C. affording a colorless solution. The solvents were removed in vacuo and the resulting gum dissolved in methylene chloride (50 mL). To this solution was added a mixture of 5-bromo-3-(2-pyrrolin-1-yl)pyridine (5.63 g, 25 mmol) and carbobenzyloxy-L-proline (6.23 g, 25 mmol) in methylene chloride (50 mL) and this was stirred at 25° C. for 36 h. The solvent was removed in vacuo and 6M HCl (200 mL) was added to the residue. The resulting solution was extracted with isopropyl acetate (200 mL) and the phases separated. The acidic aqueous phase was basified with solid NaOH to pH 14 and then extracted with methylene chloride (3×200 mL). The combined methylene chloride extracts were washed with brine (150 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica gel with ethyl acetate, then methanol:ethyl acetate (1:19 to 1:9) as eluants to afford 5-bromo-3-(2-pyrrolidinyl)pyridine (4.1 g, 72%) obtained as a pale yellow oil. LRMS (EI) m/e 227 (C9H11N281 Br--H+), 225 (C9H11N279Br--H+); 1H NMR (DMSO-d6, 300 MHz) δ 8.53 (d, J=2.2 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 4.17 (t, J=7.7 Hz, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.00 (m, 1H), 2.07 (s, 1H), 2.00-1.77 (m, 2H), 1.63 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[Cl:22]C1C=C(C=CC=1)CC(C(O)=O)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[CH:15]=1)=[C:5]2[Cl:21]
Reactant: O=C(O)C(Cc1cccc(Cl)c1)C(=O)O
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: Clc1cccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)c1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(3-chlorobenzyl)malonic acid (Intermediate 5: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:18][C:17]=1[CH3:39])(C)(C)C>ClCCl>[CH3:39][C:17]1[CH:18]=[C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])[CH:20]=[CH:21][C:16]=1/[CH:15]=[CH:14]/[C:13]([OH:40])=[O:12]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of (E)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid tert-butyl ester from Example E45.2 (338 mg, 0.76 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. Solvents were removed in vacuo and azeotroped with dichloromethane to yield the title compound (337 mg, 80%).
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH:38]([C:41]1[CH:42]=[C:43]([CH:47]([CH3:51])[CH2:48][CH:49]=O)[CH:44]=[CH:45][CH:46]=1)([CH3:40])[CH3:39].O>C1COCC1>[CH:38]([C:41]1[CH:42]=[C:43]([CH:47]([CH3:51])[CH2:48][CH:49]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[CH3:13])[CH:44]=[CH:45][CH:46]=1)([CH3:40])[CH3:39]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=CCC(C)c1cccc(C(C)C)c1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
A solution of 1-(2-naphthyl)ethyltriphenylphosphonium bromide (2.30 g, 4.62 mmol, 1.0 equiv.) in THF (16 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 2.9 mL, 4.62 mmol, 1.0 equiv.) at 0° C., the red-brown suspension was stirred at 0° C. for 15 min. 3-(3-Isopropylphenyl)butanal (1.32 g, 6.94 mmol, 1.5 equiv.) in THF (2 mL) was added, and the mixture was stirred at 0° C.→70° C. for 18 h. After addition of H2O, the aqueous layer was extracted with hexanes (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3) to yield 0.57 g (38%) of the title compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11]([O:13][C:14](=O)[O:15]CC)[CH3:12].[H-].[Na+]>C(O)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a mixture of 4-fluoroacetophenone (20.0 g, 0.145 mol), ethanol (1 mL) and diethylcarbonate (100 mL) is added sodium hydride (60%, 12.0 g, 0.29 mol) at 0° C. portionwise over a period of 30 min. Afterwards the reaction mixture is allowed to warm to room temperature and stirred for 3 h. Thereafter, the reaction is quenched with aqueous 10% HCl and extracted with ethyl acetate (2×100 mL). The ethyl acetate layer is dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel (230-400 mesh) in ethyl acetate and hexane (1:99 to 5:95) as eluent and 25 g (83%) of ethyl 3-(4-fluorophenyl)-3-oxopropanoate are obtained as light yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:15][CH:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.38 *s,12H), 1.44 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.45 (m,1H), 5.10 (s,1H), 6.97 (m,1H), 7.20 (m,3H), 8.45 (s,1H).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15]OC2=O)=[C:8]([C:17]([O:19]C)=O)[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[Cl-].[Na+]>CN(C)C=O>[C:1]([C:4]1[C:9]2[O:10][C:11]3([C:17](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C(C)=O)c1OC1CCOC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)c1cccc2c1OC1(CC1)C2=O
Reaction time: 5 h
Yield: 8.6 %

Procedure:
A mixture of α-[(6-acetyl-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone (3.5 g), 1,8-diazabicyclo[5,4,0]-7-undecene (0.14 g) and sodium chloride (1.1 g) in N,N-dimethylformamide (66.5 ml) was stirred at 150°-160° C. for 5 hours. The solvent was distilled off under reduced pressure and the residue was subjected to chromatography on silica gel. The fraction eluted with dichloromethane was recrystallized from CHCl3 -hexane to give 7-acetylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (0.22 g) as colorless needles melting at 114°-115° C.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([OH:21])[CH:5]=1.Cl[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:21][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:5]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Agent: [Na]
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a stirred suspension of sodium hdride (320 mg of 60%, 8 mmoles, washed with n-pentane) in DMF (15 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.289 g, 4 mmoles) and the mixture stirred for 20 minutes followed by addition of chloroacetophenone (619 mg, 4 mmoles). The mixture was stirred 4 hours, poured into ice-cold water (50 ml) whereupon a solid separated out. This was isolated by filtration, dried and recrystallized from methanol to give 810 mg (50%) of the title compound as white solid mp 153°-4°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.64 (bs, 1H); 8.2 (s, 1H); 8 (m, 2H); 7.6 (m, 3H); 6.22 (s, 1H); 5.36 (s, 2H); 4.4 (s, 2H); 3.52 (m, 2H); 2.64 (m, 6H); 1.01 (m, 6H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].[CH:17](=[O:21])/C=C/C>>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:16])[CH:4]([CH2:1]/[CH:2]=[CH:3]/[CH:17]=[O:21])[CH2:13][CH2:12]2
Reactant: C/C=C/C=O
Reactant: C=CCC1CCc2cc(OC)ccc2C1=O
Product: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O

Procedure:
The title compound 54 is prepared according to the procedure reported in step C of Example 8 with tetralone 53 (1.1 g, 5.09 mmol) and crotonaldehyde (1.43 g, 20.34 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum/EtOAc=4:1) afford the title compound 54 as an off-white solid. (Yield 0.95 g, 76%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29](Cl)=[O:30])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:29]([C:23]1[CH:22]=[N:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:24]=1[C:25]([F:28])([F:26])[F:27])=[O:30]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-3-trifluoromethyl-phenylamine (0.007 g; 0.039 mmol) was added to a suspension of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.010 g; 0.032 mmol) and PS-DIEA (0.1 g) in acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time PS-TSCl (0.2 g) high loading was added to remove the excess amine. After an additional 12 h of shaking, the reaction mixture was filtered and concentrated to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. LCMS m/z=449.9 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[O:12])[CH:7]=[C:6]([CH2:19][CH3:20])[C:4]=1[NH2:5])[CH3:2].[C:21](Cl)(Cl)=[S:22].O.C(=O)([O-])[O-].[Ca+2]>ClCCl>[CH2:19]([C:6]1[CH:7]=[C:8]([N:10]([CH:11]=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:5]=[C:21]=[S:22])[CH3:20]
Reactant: S=C(Cl)Cl
Reactant: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1N=C=S

Procedure:
With stirring, a solution of 24.0 g of 2,6-diethyl-4-(N-phenyl-N-formylamino)aniline in 80 ml of dichloromethane are added dropwise at 0° to 10° C. to 13.4 g of thiophosgene, 100 ml of dichloromethane, 60 ml of water and 19 g of calcium carbonate. The reaction mixture is stirred for 2 hours at room temperature and then filtered. The organic phase is separated, washed with 50 ml of water, dried over sodium sulfate and then concentrated by evaporation. The title compound of formula ##STR15## is obtained in the form of a crystalline powder which melts at 77°-78° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4
Reactant: Cc1ccc2[nH]c3c(c2c1)N1CCC3CC1
Reactant: C=Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C2CCN1CC2

Procedure:
The coupling of 8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (80 mg, 0.38 mmol; Example 211) and 2-methyl-5-vinylpyridine (85 mg, 0.71 mmol; prepared as described in International Publication No. WO 2001017968) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 0.87-1.08 (m, 2H), 1.64-1.87 (m, 2H), 2.39 (s, 3H), 2.41 (s, 3H), 2.42-2.52 (m, 2H), 3.07-3.20 (m, 5H), 4.38-4.52 (m, 2H), 6.93 (dd, J=8.2, 1.2 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 7.26 (dd, J=5.8, 2.1 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.36 (s, 1H), 7.77 (d, J=2.1 Hz, 1H); MS (APCI) m/z 332 (M+H)+.
Reaction SMILES: [O:1]([C:19]1[CH:26]=[C:25]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][C:20]=1[CH:21]=O)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:36]([C:38]1[C:39](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:40][C:41]([CH3:45])([CH3:44])[C:42]=1[CH3:43])#[N:37]>C(O)C>[O:1]([C:19]1[CH:26]=[C:25]([N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=[CH:23][C:20]=1[CH:21]=[CH:43][C:42]1[C:41]([CH3:44])([CH3:45])[O:40][C:39](=[C:46]([C:47]#[N:48])[C:49]#[N:50])[C:38]=1[C:36]#[N:37])[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 60 °C
Yield: 72.6 %

Procedure:
In 5 ml of ethanol were dissolved 200 mg (0.41 mmol) of 2-(tert-butyldiphenylsiloxy)-4-dibutylaminobenzaldehyde and mg (0.45 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 60° C. for 3 hours, the precipitate was separated by filtration and washed with methanol. The crystal was purified by silica gel column chromatography and washed with methanol to give 199 mg of a dark brown crystal having a mp of 220-221° C. (yield: 72.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[N:19]=[C:18](Br)[CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(N)c2n1
Reactant: Cc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cccc3ccc(C)nc23)n1
Yield: 68 %

Procedure:
To a flask were added 4.2 g of 2-methylquinolin-8-amine, 4.6 g of 6-methyl-2-bromopyridine, 3.3 g of sodium tert-butoxide, and 75 ml toluene. The mixture was purged thoroughly with nitrogen and 44 mg of 1,1′-bis(diphenylphosphino)ferrocene and 18 mg of palladium acetate were added. The reaction mixture was heated to 80 C for 16 hours, and then cooled to 22 C. After quenching with 100 ml of water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 120 ml of 1M hydrochloric acid, and then basified with 3M sodium hydroxide. Following extraction with 75 ml of ethyl acetate and washing with 30 ml of water, the solvent was removed. The product was purified by dissolving in a hot mixture of 20 ml of 2-propanol and 5 ml of water, and after cooling to 5 C, the product was filtered, washed with 50% 2-propanol, and dried, resulting in 4.5 g of a tan solid.