Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CCOC(C)=O>O1CCOCC1.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:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.4 %

Procedure:
A mixture of (±)-2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.0061 mol), described in International Patent Specification WO 00/39082, tributyl (1-ethoxyethenyl)-stannane (0.0091 mol) and Pd(PPh3)4 (0.0007 mol) in dioxane(30 ml) was stirred at 80° C. for 24 hours, cooled and poured out into ice water. EtOAc was added and the mixture was filtered over celite. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.8 g of (±)-4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-(1-ethoxyethenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:14](Cl)=[O:15]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:6]=[C:14]=[O:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(F)c(F)cc1Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1cc(F)c(F)cc1Cl

Procedure:
2-Chloro-4,5-difluorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and employed in stage b without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].[CH3:17][N:18]=[C:19]=[S:20].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:17][NH:18][C:19]([C:9]1[C:8]2[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][C:11]([CH3:13])([CH3:14])[C:10]=1[OH:15])=[S:20]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2CC1=O
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
To a mixture of 3.2 g of 6-nitro-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 1.2 g of methyl isothiocyanate, and 40 ml of dried N,N-dimethylformamide was added 1.9 g of potassium t-butoxide while stirring under cooling with ice. The mixture was stirred for 3 hours under ice-cooling and then allowed to stand for 12 hours. Ice-water was added thereto, and the mixture was made acidic with hydrochloric acid and then extracted with methylene chloride. The organic layer was re-extracted with 2N NaOH. The aqueous layer was made acidic with hydrochloric acid and re-extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solution: n-hexane:ethyl acetate =10:1) and recrystallized from a mixed solvent of methylene chloride and n-hexane to obtain 2.33 g of N-methyl-6-nitro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH:24]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:8].[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][N:13]1[CH2:12][CH:11]([OH:23])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:24]=[C:2]([NH:1][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH:3]=[CH:4][C:5]=1[F:25]
Reactant: O=C1CCOCC1
Reactant: Nc1ccc(F)c(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cc(NC2CCOCC2)ccc1F
Temperature: 17 °C
Reaction time: 4 h
Yield: 26.3 %

Procedure:
A solution of 5-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluorobenzamide (372 mg, 1.08 mmol), dihydro-2H-pyran-4(3H)-one (108 mg, 1.08 mmol) and AcOH (0.05 mL) in MeOH (20 mL) was stirred at 17° C. for 2 h. Then NaBH3CN (109 mg, 1.63 mmol) was added and the resulting solution was stirred at 17° C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to afford the title product (121.5 mg, Yield 17.5%). 1H NMR (CD3OD, 400 MHz): δ 7.16-7.07 (m, 3H), 7.03 (dd, J=2.9, 5.9 Hz, 2H), 6.95 (dd, J=8.9, 10.7 Hz, 1H), 6.79 (td, J=3.6, 8.8 Hz, 1H), 4.11 (quin, J=6.0 Hz, 1H), 3.98 (d, J=11.5 Hz, 2H), 3.80-3.69 (m, 2H), 3.64-3.40 (m, 5H), 2.98-2.81 (m, 4H), 2.72-2.60 (m, 2H), 1.99 (d, J=12.8 Hz, 2H), 1.56-1.39 (m, 2H). LCMS (m/z): 428.2 (M+1).
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.85 g NaH with 70.0 ml THF is cooled to −30° C. and 5.0 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition there is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 7.9 g 4-bromobenzenesulfonylchloride is added by -30° C. The suspension is stirred at ambient temperature for 3 h. The mixture is treated with water and then it is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 7.0 g of a colorless solid are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16]1>C(O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([CH3:20])[CH3:14])[CH3:2]
Reactant: CC1(C)CCCN1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CN1CCCC1(C)C
Yield: 61.5 %

Procedure:
Ethylchloroacetate (0.15 ml, 1.37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2,2-dimethyl-pyrolidine (0.280 mg, 2.06 mmol) were suspended in ethanol (3 ml) and subjected to microwave irradiation at 120° C. for 45 min. The resultant mixture was suspended in diethyl ether (30 ml), extracted with 2M hydrochloric acid (30 ml) and the organic layer discarded. The aqueous layer was treated with a slight excess of 4N sodium hydroxide solution and extracted with diethyl ether (3×30 ml). The organic layers were combined, dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford (2,2-dimethyl-pyrrolidin-1-yl)-acetic acid ethyl ester (156 mg).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>>[CH2:1]([O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Nonyloxylpyrimidine-2-yl)benzoic acid (1.88 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-nonyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13](O)[CH2:14][CH2:15][OH:16]>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:16][CH2:15][CH2:14][CH2:13][O:4]1
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Reactant: OCCCO
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(C2(CCl)OCCCO2)c1
Reaction time: 5 h

Procedure:
A mixture of 18.3 g [0.1 mol] of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 15.2 g [0.2 mol] of trimethylene glycol, 1.9 g [0.01 mol] of p-TsOH hydrate and 150 ml of xylene is heated to boiling with a water trap for about 5 hours. Part of the xylene is then distilled off, and the reaction mixture is extracted at room temperature with 30 ml of saturated aqueous NaCl solution and twice with 100 ml of water each time. The organic phase is dried over sodium sulfate and concentrated in vacuo, and all volatiles are distilled off up to about 87° C. under 0.25 mbar. 22.9 g of residue remain with, according to GC, 83.9% product (79.8% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[C:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]3[N:1]=[C:3]2[CH2:2][CH2:7][CH3:6])=[CH:12][CH:13]=1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)OCCc1ccc(-n2c(CCC)nc3c(C)cc(C)nc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and butyryl chloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:16]([N:24]=[C:25]=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:25]([NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:26]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: c1ccccc1
Product: O=C(NC(=O)c1ccccc1)NC1CCN2CCc3ccccc3C2C1
Yield: 72.4 %

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (0.260 g) and benzoyl isocyanate (0.213 g, 5% excess) were condensed together in benzene (50 ml) in a manner analogous to that of Example 1 to give the title compound (0.325 g). Crystallization from EtOH/HCl afforded the hydrochloride (0.343 g). m.p. 171.0° C. C21H23N3O2.HCl.2H2O requires C, 59.78; H, 6.69; N, 9.96%, Found: C, 60.06; H, 6.50; N 9.89%.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C@H:2]3[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:3]3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@H](N2CCN(c3cccc(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-benzyl 3-oxocyclopentanecarboxylate (1.5 g, 6.87 mmol), 1-(3-fluorophenyl)piperazine (1.36 g, 7.56 mmol) in 1,2-dichloroethane (25 ml) were added 1-(3-fluorophenyl)piperazine (1.36 g, 7.56 mmol), glacial acetic acid (0.4 ml, 6.87 mmol) and Sodium triacetoxy borohydride (2.18 g, 10.31 mmol). The mixture was stirred at 25° C. for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain the title compound as the major diastereomer (1.2 g, 45.7%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[N:13](OCCC(C)C)=[O:14]>CCO>[CH2:1]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[N:13]=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C)nn1C
Reactant: CC(C)CCON=O
Solvent: CCO
Product: CCCCNc1c(N=O)c(C)nn1C

Procedure:
To a stirred solution of 5-butylamino-1,3-dimethylpyrazole (4.0 g, 23.9 mmol) in EtOH (100 mL) there was added dropwise, under nitrogen, isoamyl nitrite (35 mL) and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by tlc (SiO2, developed with EtOAc/hexanes [3:2]) and when no starting material remained, the solution was evaporated to dryness. This mixture was purified by chromatography on a SiO2 column (400 mL) developed with EtOAc/hexanes (40:60). The faster components were eluted first (one of which is the isomeric N-nitroso derivative which can be isomerized with acid to yield additional product) followed by the Step C compound (3.23 g, 69%) as reddish crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH:8]=[N:7]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:18][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)CCCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CCCn1ncc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dimethyl-{3-(6-nitro-indazol-1-yl)-propyl}-amine (0.400 g, 1.61 mmol), iron powder (0.897 g, 16.1 mmol), and ammonium chloride (0.0430 mg, 0.811 mmol) in a 4:1 solution of ethanol/H2O was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4) and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.95 (m, J=14.75, 7.63 Hz, 2 H), 2.28 (m, 6 H), 2.38 (t, J=6.95 Hz, 2 H), 4.18 (t, J=6.95 Hz, 2 H), 5.30 (s, 2 H), 6.50 (m, 2 H), 7.35 (m, 1 H), 7.71 (s, 1 H); MS (DCI/NH3) m/z 219 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[CH3:18][C:19]1[N:20]=[C:21]([CH2:25][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=323.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:11]=[CH2:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]12([CH2:39][NH:40][C:41](=[O:50])[C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[C:44](Cl)[CH:43]=3)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>O.CN(C)C=O>[C:29]12([CH2:39][NH:40][C:41](=[O:50])[C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[C:44]([CH2:12][CH2:11][CH2:10][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:43]=3)[CH2:30][CH:31]3[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]3)[CH2:36]1)[CH2:38]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Reactant: C=CCO[Si](C)(C)C(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 60 °C
Yield: 248.6 %

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane at 0.5 M in tetrthydrofuran (2.78 mL, 1.39 mmol) was added to neat (allyloxy)(tert-butyl)dimethylsilane (0.15 mL, 0.69 mmole). The mixture was heated to 60° C. for 2 hours under nitrogen. The reaction was subsequently cooled to room temperature and a solution of potassium phosphate (0.37 g) in water (1 mL) was added slowly. A solution of N-(1-adamantylmethyl)-2,5-dichloroisonicotinamide (0.20 g, 0.59 mmol; prepared as described in WO 01/94338) in dimethylformamide (3 mL) was added followed by tetrakis(triphenyphosphine)palladium (0) (7 mg). The solution was heated to 70° C. for 2 hours; allowed to cool to room temperature then partitioned between ethyl acetate (20 mL) and brine (10 mL). The aqueous phase was further extracted with ethyl acetate (2×20 mL) and the combined organics were washed with brine (20 mL); dried over magnesium sulphate; filtered and evaporated under vacuum to give the crude product (0.70 g) as a yellow oil, which was used, as such, without any further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:21])=[C:5]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#N.CC(C[AlH]CC(C)C)C.[O:31]1CCCC1>>[CH3:18][N:17]([CH3:19])[C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[O:31])[C:4]=2[F:21])=[O:20])=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C#N)c2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: CN(C)c1ccc(C(=O)Nc2cccc(C=O)c2F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-cyano-2-fluorophenyl)-4-(dimethylamino)benzamide (2.18 g, 7.70 mmol) in tetrahydrofuran (150 mL) at −78° C. was added DIBAL-H (23.09 mL, 23.09 mmol) over 20 min. The mixture was stirred at −78° C. for 1 h before it was allowed to warm to room temperature and stirred at room temperature for 4 hr. The mixture was poured into ice/water (600 mL) and stirred at room temperature for 30 min. The mixture was extracted with CH2Cl2 (4×100 mL). The combined extract was filtered through CELITE®, washed with brine (80 mL), and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum provided a crude product (1.83 g) as a pale yellow solid. This product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[CH2:18]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10 g of 2,5-difluorophenol was dissolved in 120 ml of dimethylformamide, and 21 g of potassium carbonate and 8.57 ml of allyl bromide were added to the resulting solution in this order at room temperature. The resulting mixture was stirred at 80° C. for one hour, followed by the addition of water. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was subjected to silica gel chromatography (developer: 5% ethyl acetate/n-hexane) to give 13 g of the title compound as a colorless oil.
Reaction SMILES: B.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]#[N:13])=[C:6]2[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21].Cl.N>O1CCCC1>[NH2:13][CH2:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=2
Reactant: N#Cc1[nH]c2ccc(Cl)cc2c1-c1c(F)cccc1F
Agent: B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NCc1[nH]c2ccc(Cl)cc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane in tetrahydrofuran (7 ml of a 1M solution) is added to a solution of 1 g (3.46 mol) of 5-chloro-3-(2,6-difluorophenyl) indole-2-carbonitrile in 15 ml of dry tetrahydrofuran. The solution is stirred at room temperature for 2 hours and then refluxed for half an hour and cooled to room temperature. 5 ml of 5N aqueous HCl is added dropwise and the mixture is refluxed for 20 minutes. The mixture is then poured onto a mixture of ice and aqueous 10 percent ammonia, and the precipitate is extracted with chloroform. The chloroform layer is washed with water and dried over magnesium sulfate, filtered and evaporated to dryness. Recrystallization from chloroform (charcoal) affords colorless crystals; m.p. 212°-214°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 1.0 g (5.9 mole) of 4-amino-3-chlorobenzoic acid, 0.8 g (7.0 mole) of 4-amino-1-methyl-piperidine and 4.14 mL (23 mmole) of ethyldiisopropyl amine in 20 mL of dimethylformamide was added a solution of 2.4 g (6.4 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 5 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hours, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 1.41 g of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide as a solid.
Reaction SMILES: [C:1]([O:4][CH:5]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:22]>C(O)(=O)C.O.[OH-].[Na+]>[CH3:8][C:7]([C:6]1[N:22]=[C:1]([CH3:2])[O:4][C:5]=1[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C(=O)C(C)(C)C)C(=O)C(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Yield: 92.5 %

Procedure:
A solution of 4-(acetyloxy)-2,2,6,6-tetramethyl 3,5-heptanedione (22 g, 0.09 mol) in acetic acid (100 mL) is treated with ammonium acetate (44 g). The reaction mixture is heated at reflux overnight. The reaction mixture is diluted with water and neutralized (to pH 5) by the addition of aqueous sodium hydroxide. The product is extracted into ethyl acetate (3×150 mL) and the combined organic layers are washed with 0.1 N NaOH, water, and then brine. The organic layer is dried and evaporated. The residue is taken up in hexane (50 mL) and applied to a pad of silica gel (500 g). The silica pad is eluted with hexane (100 mL). Then the product is eluted from the silica with hexane/ethyl acetate (4:1) to give 18.6 g (91%) of 1-[4-(1,1-dimethylethyl)-2-methyl-5 oxazolyl]-2,2-dimethyl-1-propanone as an oil.