Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=1)=[O:4].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][NH2:21]>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][NH:21][C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=1)=[O:4]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CN(C)C=O
Product: CCC(=O)c1c[nH]c(C(=O)NCc2ccc(F)c(F)c2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 3 (1 equivalent) in DMF, at ambient temperature, was added 3,4-difluorobenzyl amine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 6 was used without purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:27]=2)OC1>>[F:34][C:31]1[CH:30]=[C:29]([C:35]#[N:36])[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile as described in Example 1 to give 4,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.42-7.48 (2H, m), 7.57 (1H, dd, J 8 and 3), 7.61-7.66 (3H, m), 8.10 (1H, s), 9.02 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Br:15][C:16]1[CH:17]=[C:18]([C:24]2([C:30](O)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].S(Cl)(Cl)=O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([C:24]2([C:30]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(OC)c(Br)c2)CCOCC1
Temperature: 0 °C
Yield: 16.1 %

Procedure:
A mixture of diethyl malonate (2.8 g, 17 mmol) in 50 mL ACN was stirred at 0° C. This mixture was treated with MgCl2 (1.7 g, 17 mmol) in one portion and dropwise with TEA (3.9 g, 38 mmol). The resulting mixture was then stirred at room temperature for 2.5 hours. A mixture of 4-(3-bromo-4-methoxyphenyl)-tetrahydro-2H-pyran-4-carboxylic acid (5.5 g, 17 mmol) in thionyl chloride (21 g, 175 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN and added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours, M−1=455/457. The mixture was cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 1.25 g of the intermediate as a pale yellow oil. MS m/e=455/457 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:30]([N:32](CC)CC)C.N#CBr>ClCCl>[C:30]([N:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=1)#[N:32]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Agent: N#CBr
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(C#N)Cc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (12 g; 29.34 mmol) and triethylamine (4.5 ml; 32.27 mmol) in 100 ml of dichloromethane was treated under nitrogen with cyanogen bromide (10.3 ml of a 3M solution in dichloromethane; 30.9 mmol). After 1.5 hr, additional triethylamine (2 ml) and cyanogen bromide (2.5 ml) were added and stirred another 30 minutes. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water (three times) and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography using ethyl acetate-hexane mixtures (5–40% gradient) afforded ethyl 2-[4-(2-{cyano[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (10.9 g; 85% yield).
Reaction SMILES: C(NC(C)CNC(=S)SC)(=O)C.[C:13]([NH:16][CH2:17][CH:18]([NH:20][C:21](=[S:24])SC)[CH3:19])(=[O:15])[CH3:14].[N-:25]=[N+:26]=[N-:27].[Na+]>O1CCOCC1.O>[C:13]([NH:16][CH2:17][CH:18]([N:20]1[C:21]([SH:24])=[N:27][N:26]=[N:25]1)[CH3:19])(=[O:15])[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NC(C)CNC(C)=O
Agent: CSC(=S)NCC(C)NC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCC(C)n1nnnc1S
Yield: 27 %

Procedure:
A mixture of methyl N-(2-acetamidopropyl)dithiocarbamate and methyl N-[1-(acetamidomethyl)ethyl]dithiocarbamate (100 g) in dioxane (300 ml) and a solution of sodium azide (41 g) in water (270 ml) were stirred for 4.5 hours under reflux. The reaction mixture was concentrated to half volume under reduced pressure, washed with diethyl ether and acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with diethyl ether to give pale yellow powder of 1-[1-(acetamidomethyl)ethyl]-1H-tetrazole-5-thiol (26.32 g), mp 176° to 178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])[CH2:11][CH2:10]1)=[O:5].[C:30](OC(=O)C)(=[O:32])[CH3:31].[OH-].[NH4+]>O>[C:30]([NH:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])[CH2:13][CH2:14]1)=[O:5])(=[O:32])[CH3:31]
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 1 part of 2-amino-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluorobenzamide, 1 part of acetic acid anhydride and 15 parts of water is stirred for 30 minutes in a water-bath at 80°-90° C. The reaction mixture is cooled and alkalized with an ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 0.5 parts of 2-(acetylamino)-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluorobenzamide; mp. 210° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:9][NH:8][C:7]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=2[O:5]1.Cl.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26]>CN(C)C=O>[CH3:3][C:4]1([CH3:17])[CH2:9][N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-:26])[C:7]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=2[O:5]1
Reactant: CC1(C)CNc2ccc([N+](=O)[O-])cc2O1
Reactant: [O-][n+]1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2ccc([N+](=O)[O-])cc2O1
Temperature: 70 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
To a suspension of 0.38 g sodium hydride (60% in paraffin composition) in 14 ml dimethylformamide, was added 1.00 g 3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine, and 1.01 g 2-bromopyridine N-oxide hydrochloride was further added under ice-cooling, and the mixture was stirred for 16 hours at 70° C. The reaction mixture was poured to ice water, the resulting mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off from the dried solution under reduced pressure, the residue was subjected to column chromatography on silica gel, and elution was conducted by the use of a 3:1 mixture of chloroform and acetone, thus giving 0.34 g of 2-(3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide. Ethanolic solution of hydrogen chloride (a mixture of 1 ml concentrated hydrochloric acid and 5 ml ethanol) was then added to the product obtained above, the solvent was distilled off from the mixture, and the residue was recrystallized from acetone, thus giving 182 mg of 2-(3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]3)[C:15]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[CH2:19]3)[C:15]2=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(N)C3)C2=O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(NC(=O)c4cccc(F)c4)C3)C2=O)CC1

Procedure:
4-(7-Amino-1-oxo-2-aza-spiro[4.5]dec-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.57 mmol), 3-fluorobenzoic acid (0.080 g, 0.56 mmol), BOP (0.252 g, 0.57 mmol), and triethylamine (0.115 g, 1.14 mmol) in methylene chloride (5.0 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified with chromatography (ethyl acetate) to afford the title compound which is a mixture of two diastereomers (cis/trans: 3/2; under LC-MS method C, the first peak with RT of 1.47 min was assigned as cis, and the second peak with RT of 1.50 min was assigned as trans.). 1H NMR (400 MHz, CDCl3) δ 8.5 (s, 0.6 H), 7.60-7.68 (m, 1H), 7.36-7.50 (m, 2H), 7.14-7.20 (m, 1H), 5.92 (d, J=6.8 Hz, 0.4 H), 4.55-4.65 (m, 0.4 H), 4.04-4.38 (m, 3.6H), 3.20-3.30 (m, 2H), 2.71-2.86 (m, 2H), 1.28-2.25 (m, 23H). ESI-MS m/z: 474 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)=[O:18]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)CCCCCl
Product: O=C1CCc2cc(C(=O)CCCCCl)ccc2N1

Procedure:
Using 3,4-dihydroquinolin-2(1H)-one (2.94 g) and 5-chloropentanoyl chloride (3.7 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (1.59 g) having a melting point of 145 to 146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][CH2:13][CH2:14]3)=[C:10](C(O)=O)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:15]3[C:11]([S:12][CH2:13][CH2:14]3)=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1SCC2
Solvent: CCO
Product: Fc1ccc(-c2c(-c3ccncc3)cc3n2CCS3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazole-7-carboxylic acid (example 11, 120 mg, 0.35 mmol) is heated under argon in an oil bath firstly at 140° C. for 2 h and then at 180° C. for 3 h. After cooling to RT, the brown-red melt cake is digested with a little EtOH. The undissolved, red-brown substance is filtered off with suction, washed with ether and dried: 0.07 g.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].[CH2:22]([NH:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:24]([CH2:22][CH3:23])[CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:12]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: CCCCCCC(C)NCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCC(C)N(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
Triethylamine (2.02 g, 20 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-ethyl-N-(1-methylhept-1-yl)amine (3.15 g, 20 mmol) in toluene (25 mL). The reaction was stirred 2.5 h at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed twice with sat aq NaHCO3, followed with brine, then was dried (MgSO4), concentrated, and kugelrohr distilled under vacuum. The fraction which distilled at 157° C. was collected to afford 1.16 g of the title compound as an amber oil, a 38% yield.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.I[CH3:18].[H-].[Na+]>CN(C=O)C>[CH3:18][N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: CI
Reactant: Ic1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(I)cc2)nc2ccccc21
Yield: 61.8 %

Procedure:
2-(4-Iodophenyl)benzimidazole (200 mg, 0.6 mmol) was methylated with iodomethane (180 mg, 1.2 mmol, 2.0 eq.) and NaH (45 mg, 1.8 mmol, 3 eq.) in DMF (3 mL) for 18 h. Dilution with diethyl ether, washing with water, drying over Na2SO4, and chromatography (10→25% EtOAc/hexanes) gave 1-methyl-2-(4-iodophenyl)benzimidazole (124 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH2:10]([O:12][C:13]([C:15]#[C:16][C:17](OCC)=[O:18])=[O:14])[CH3:11].ClC1C=C2C(C(=O)C=C(C(OCC)=O)N2)=C(I)C=1>>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[C:4]2[C:3]=1[C:17](=[O:18])[CH:16]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[NH:5]2
Reactant: Nc1cc(Cl)cc(I)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: CCOC(=O)c1cc(=O)c2c(I)cc(Cl)cc2[nH]1
Product: CCOC(=O)c1cc(=O)c2c(Cl)cc(I)cc2[nH]1

Procedure:
Treatment of 3-chloro-5-iodoaniline (1.4 g) with diethylacetylene dicarboxylate (0.93 ml), as described in Example 1b, gave a mixture (1.83 g) of ethyl 5-chloro-7-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylate [δ (360 MHz, DMSO-d6) 1.37 (3H, t, CH2CH3), 4.40 (2H, q, CH2CH3), 6.59 (1H, s, 3-H), 7.61 (1H, s, 6-H), 8.32 (1H, s, 8-H) and 11.90 (1H, bs, NH)] and ethyl 7-chloro-5-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylate [δ (360 MHz, DMSO-d6) 1.37 (3H, t, CH2CH3), 4.40 (2H, q, CH2CH3), 6.63 (1H, s, 3-H), 7.90 (1H, s, 6-H), 8.04 (1H, s, 8-H) and 11.90 (1H, bs, NH)].
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[C:12]([CH3:17])=[CH:13][C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][C:14]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:13]=[C:12]([CH3:17])[C:11](=[O:18])[C:10]([CH3:9])=[CH:15]1
Reactant: CC1=CC(=O)C=C(C)C1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C(C)=C1
Yield: 80 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,6-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.60 g of the desired product (yield 80%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][CH2:15]/[C:16](/[CH3:25])=[CH:17]/[CH2:18][CH2:19]/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23].C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[CH3:24]/[C:20](/[CH2:19][CH2:18]/[CH:17]=[C:16](\[CH3:25])/[CH2:15][CH2:14][CH:13]=[C:12]([CH3:26])[CH3:11])=[CH:21]\[CH:22]=[O:23]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
To a CH2Cl2 solution (15 mL) of oxalyl chloride (7.81 mL, 87.7 mmol) was added dimethyl sulfoxide (12.5 mL, 175.4 mmol) dropwise over 30 min at -60° C. The resulting clear solution was stirred at this temperature for 20 min. A solution of trans, trans-farnesol (Aldrich Chemical Co.) (15 g, 67.5 mmol) in CH2Cl2 (325 mL) was added dropwise over 15 min. The reaction mixture became cloudy white during addition. The heterogeneous reaction mixture was stirred at -60QC for 30 min, whereupon triethylamine (56.4 mL, 405 mmol) was added dropwise over 10 min. The reaction mixture became thick. The reaction mixture was allowed to warm to RT over 1 h. Ethyl ether (800 mL) was added and the organic layer was washed with H2O (500 mL), brine (500 mL) and dried over MgSO4. Evaporation gave 15 g (100%) of title compound as a crude oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C
Yield: 71.6 %

Procedure:
To a stirred solution of methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (1.5 g, 4.6 mmol) in acetonitrile (15 mL) was added cesium carbonate (2.63 g, 8.1 mmol) and methyl iodide (2.86 g, 20.32 mmol). The mixture was heated at 80° C. for 7 h. On completion, the reaction was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated to afford methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)-2-methylbenzoate (1.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([O:18][CH3:19])[C:15]([OH:17])=O)=[CH:8][CH:7]=2)#[CH:2].Cl.[CH3:21][O:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25].CN(C1C=CC=CN=1)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([O:18][CH3:19])[C:15]([NH:27][C:24]([CH3:26])([CH3:25])[CH2:23][O:22][CH3:21])=[O:17])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(OC)C(=O)O)cc2c1
Reactant: COCC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cnc2ccc(OC(OC)C(=O)NC(C)(C)COC)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of (3-ethynyl-quinolin-6-yloxy)-metoxy-acetic acid (150 mg) in dry dimethylformamide (7 mL) were added 2-metoxy-1,1-dimethyl-ethylamine hydrochloride (81 mg) N-ethyldiisopropylamine (0.25 mL), dimethylaminopyridine (catalytic quantity) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (297 mg). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured over brine and extracted twice with ethyl acetate (thrice). The organic layer was washed with water then with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by chromatography eluting with cyclohexane/ethyl acetate (7:3 by volume), to give 2-(3-ethynyl-quinolin-6-yloxy)-2-methoxy-N-(2-methoxy-1,1-dimethyl-ethyl)-acetamide (172 mg) as an oil.
Reaction SMILES: O1CCCC1.[CH:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][N:7]=1.CC(C)([O-])C.[K+].[N:22](OC(C)(C)C)=[O:23]>O>[CH:6]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11](=[N:22][OH:23])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)ON=O
Reactant: c1cc2c(cn1)CCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: ON=C1CCCc2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a nitrogen atmosphere, tetrahydrofuran (125 mL) solution of 6.5 mL of 5,6,7,8-tetrahydroisoquinoline was added to tetrahydrofuran (100 mL) solution of 11.4 g of potassium tert-butoxide, and stirred at room temperature for 18 hours. Next, 17.5 mL of tert-butyl nitrite was dropwise added to the reaction liquid at 0° C., and stirred at room temperature for 18 hours. Saturated saline water was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was crystallized from water/ethanol to obtain 6.06 g of the entitled compound as a pale brown solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.