Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=O)=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([S:45]([N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46])[CH:39]=[CH:38]2>>[ClH:34].[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:51]3[CH2:52][CH2:53][CH2:54][N:48]([S:45]([C:40]4[CH:39]=[CH:38][C:37]5[C:42](=[CH:43][CH:44]=[C:35]([Cl:34])[CH:36]=5)[CH:41]=4)(=[O:47])=[O:46])[CH2:49][CH2:50]3)=[O:19])=[CH:16][C:11]=2[NH:10][CH:9]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCCNCC1
Agent: Cl
Product: O=C(c1ccc2nc[nH]c2c1)N1CCCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 71 except for the use of methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [Br-].[C:2]([C:5]([CH3:30])([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CS(C)=O.[C:35]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH3:29][C:5]([CH3:30])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:35](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[C:2]([OH:4])=[O:3]
Reactant: O=C(c1ccccc1)c1cccnc1
Reactant: CC(C)(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [Br-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CCC/C=C(/c1ccccc1)c1cccnc1)C(=O)O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (2.5 g, 60% oil dispersion) was washed with hexane, to make clean of the oil and dried under reduced pressure. Dimethylsulfoxide (25 ml) was added to it, and the mixture was heated under argon at 80° C. for 1 hour to produce dimsyl anions. The reaction solution was cooled at 10° C., and 5-carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (8 g, 16 mmole) was added, followed by stirring at room temperature for another 10 minutes. A dimethylsulfoxide solution (5 ml) containing 3-benzoylpyridine (3 g, 16 mmole) was added dropwise to the mixture solution, and after the completion of the dropwise addition, stirring was continued at room temperature for 30 minutes. Water (50 ml) was added to the mixture, which was then shaken. The organic layer was separated, and the water layer was adjusted to pH 6.0 with 2N hydrochloric acid. The product was extracted three times with ethyl acetate (50 ml). The ethyl acetate layers were combined, washed with water, dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development was effected with ethyl acetate to yield (E)+(Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2-a, 2-b) (2.2. g).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].O>C(Cl)(Cl)(Cl)Cl>[C:18]([C:9]1[CH:10]=[CH:11][C:6]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(C2CCNC2)cc1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
98 g (1 mole) of concentrated sulfuric acid were added dropwise to 29.4 g (0.2 mole) of 3-phenylpyrrolidine in 400 ml of carbon tetrachloride at 0°-5° C. After 15 minutes, 15.2 g (0.27 mole) of isobutylene were passed in gaseous form, the mixture was stirred for 1 hour at 0°-5° C. and hydrolysis was carried out with 400 ml of water at 20° C. The organic phase was separated off and the aqueous phase was extracted with twice 100 ml of dichloromethane. Working up of the organic phases gave 42 g of a crude product, which was fractionated under reduced pressure to give 13.4 g (33%) of a colorless oil of boiling point 84°-87° C./0.5 mbar.
Reaction SMILES: N([C:4]1[CH:9]=[C:8](N=C=O)[CH:7]=[CH:6][C:5]=1[CH3:13])=C=O.[N:14](C1C=CC=C(N=C=O)C=1C)=[C:15]=[O:16].C[N:28]([CH:30]([OH:33])CC)C.C(O)C>C1(C)C=CC=CC=1>[CH:8]1[CH:9]=[CH:4][C:5]([CH:13]([N:28]=[C:30]=[O:33])[N:14]=[C:15]=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: Cc1c(N=C=O)cccc1N=C=O
Reactant: CCC(O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C=NC(N=C=O)c1ccccc1

Procedure:
The partially capped toluylene diisocyanate was prepared by reacting a technical grade mixture of 1.95 kg of 2,4-diisocyanatotoluene (11.2 mol) and 490 g of 2,6-diisocyanatotoluene (2.8 mol) with a mixture of 720 g of dimethylaminopropanol (9.1 mol) and 320 g of ethanol (7 mol) at 50° C. in 900 g of toluene.
Reaction SMILES: [CH2:1](N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:11](CC)CC)C.C[S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH2:1]([S:17]([NH2:11])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Previous intermediate from step 1 was dissolved in 2 mL of dichloromethane and triethylamine (0.035 mL, 0.249 mmol) was added. Solution was cooled to 0° C. and methane sulfonylchloride (0.020 mL, 0.238 mmol) was added. Reaction mixture was warmed to room temperature, stirred overnight, then concentrated under reduced pressure. Residue was purified by silica gel column chromatography (10-90% ethyl acetate in hexanes) to yield the intermediate benzylsulfonamide (35 mg, 78%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CCCCCC.O1CCCC1>[C:3]([CH2:5][C:6]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:4]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(CC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(CC#N)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
Sodium hydride (53% dispersion in oil) (5.17 g, 0.1 mole) was washed by decantation with hexane (2×150 ml), tetrahydrofuran (THF) (150 ml) and was finally suspended in THF (150 ml). Diethyl 2-(cyanomethyl)malonate (26.4 g, 0.11 mole) in THF (20 ml) was added dropwise over 45 minutes keeping the internal temperature at 18° C. to 22° C. (with ice bath cooling). The resulting suspension cleared over 15 minutes when 2-chloro-5-nitropyridine (14.22 g, 0.09 mole) was added to give a deep magenta solution. The resulting solution was refluxed for 3 hours and the solvent was removed on the rotary evaporator. The resulting oil was partitioned between water (200 ml) and chloroform (200 ml), the pH was adjusted to ~7 (concentrated hydrochloric acid), and the chloroform was run off. The aqueous layer was extracted with a further (2×250 ml) chloroform, the extracts were combined, dried over magnesium sulphate and the solvent was removed to give the title compound as an amber oil. Ether (25 ml) was added and the solution was allowed to crystallise to give the title compound (18.48 g). m.p. 66°-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:6][C:7]=1[CH2:8][NH:9][CH:10]=O.P(Cl)(Cl)(Cl)=O>>[ClH:1].[Cl:1][C:2]1[C:7]2[N:6]([CH:10]=[N:9][CH:8]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Product: Cl
Yield: 192.1 %

Procedure:
A solution of tert-butyl 4-{5-chloro-6-[(formylamino)methyl]-3-(methoxycarbonyl)pyridin-2-yl}piperazine-1-carboxylate (670 mg, 2.2 mmol) in phosphoryl chloride (5.0 mL, 54 mmol) was heated to 70° C. for 30 minutes. Evaporation gave the desired compound (700 mg, 98%). LCMS calculated for C13H16ClN4O2 (M+H)+: m/z=295.1. found: 294.9.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (Peak II from chiral separation, Example 4, Step 1). LCMS (M+H)+=482.1. 1H NMR (300 MHz, DMSO-d6) δ: 14.25 (s, 1H), 9.77 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 5.83-5.70 (m, 1H), 3.94 (s, 6H), 3.55-3.49 (m, 2H), 3.13 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1.O>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:27]([Cl:31])=[CH:26][N:25]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(N2CCCCC2)ccc1Nc1nc(Cl)ncc1Cl
Reaction time: 72 h
Yield: 58.8 %

Procedure:
To a solution of 2-amino-5-piperidin-1-yl-benzamide (1.05 g, 4.6 mmol, Heterocyclic Comm. 2001, 7, 473-480) in THF (10 mL) was added K2CO3 (0.76 g, 5.5 mmol) and 2,4,5-trichloropyrimidine (0.84 g, 4.6 mmol). After stirring for 72 h, addition of water (5 mL) gave a precipitate that was removed by filtration and washed with water (5×3 mL) and ether (3×2 mL) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-piperidin-1-yl-benzamide as a yellow solid (0.99 g) that was used without further purification in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([N+:23]([O-])=O)=[CH:17][CH:16]=3)=[O:11])=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>[Ni].O>[NH2:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11])=[C:21]2[OH:22]
Reactant: [H][H]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc([N+](=O)[O-])cc2c1O
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Yield: 84.5 %

Procedure:
N-[(4-chlorophenyl)methyl]-4-hydroxy-6-nitro-3-quinolinecarboxamide (500 mg) is suspended in 50 mL of freshly degassed dimethylformamide and treated with 0.5 mL of 50% Raney nickel in water (Aldrich). The mixture is agitated under 45 psi hydrogen pressure for 24 h, and then it is filtered through celite. The solvent is removed by evaporation at reduced pressure and the residue is suspended in 5 mL of absolute ethanol and it is collected by filtration. After drying at 0.1 torr/100 ° C./1.5 h, the product is obtained as 387 mg of a pale yellow powder.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([S:19][CH2:20][CH2:21][C:22]([O:24]C)=O)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]>CO.C(OCC)(=O)C>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([S:19][CH2:20][CH2:21][C:22]([NH:2][NH2:3])=[O:24])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Yield: 68.5 %

Procedure:
Hydrazine monohydrate (16 mL, 324 mmol) is added to a room temperature solution of methyl 3-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate (3.5 g, 10.8 mMol) in methanol (110 mL). The reaction mixture is heated at reflux for 2 hours, then cooled, diluted with ethyl acetate and washed six times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation provides a crude solid which is chromatographed on a column of silica with methanol/chloroform (5/95) to afford 2.4 g (64%) of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide, mp 107.0°-110.0° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>ClCCl>[OH:15][C:14](=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:13][C:12](=[O:16])[CH3:11]
Reactant: C=C1CC(=O)O1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Product: CC(=O)CC(O)=C1C(=O)OC(C)(C)OC1=O
Yield: 80 %

Procedure:
The above procedure is a modification of the procedure described in the literature at Kang, J; Kim, Y; Park, M; Lee, C.; Kim, W. Synthetic Communications (1984), 14(3), 265-9. In essence Meldrum's acid was reacted with diketene in dichloromethane in the presence of TEA at 20-25° C. for 2 hours to give 80% of 5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([NH:21]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(O)C.[ClH:33]>C(O)C>[ClH:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Yield: 96 %

Procedure:
To a solution of 1,1-dimethylethyl (1RS,2RS)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate (2.1 g, 5.08 mmol) in ethanol (25 ml) was added 20% hydrogen chloride ethanol solution (25 ml) and the mixture was heated under reflux for 1 hr. The reaction solution was evaporated under reduced pressure, and the residue was washed with diethyl ether to give (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (1.7 g, 96%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C([Cl:27])=O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])[C:6]([Cl:27])=[O:7]
Reactant: O=C(O)C(CCCCl)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)C(CCCCl)c1ccccc1C(F)(F)F
Reaction time: 1.5 h

Procedure:
5-Chloro-2-(2-trifluoromethylphenyl)valeric acid obtained in Preparation Example 2-3 (500 mg) was dissolved in tetrahydrofuran (9 mL). Dimethylformamide (0.1 ml) and oxalyl chloride (184 μL) were added at 0° C. and the reaction was initiated at room temperature. After 1.5 hours, concentration under reduced pressure gave an oil (532 mg), which was used directly for the next reaction as a crude product.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>>[C:1]([N:19]1[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)N1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(C(C)C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-isopropylpiperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:28][CH2:27][C:22]3(OCC[O:23]3)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.Cl.CCOC(C)=O>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzamide (120 mg, 0.289 mmol) in dioxane (1 mL) and water (0.25 mL) was treated with 12 N HCl (0.25 mL). After 1.5 h, the mixture was poured into EtOAc and water. The organic layer was washed with satd sodium bicarbonate (2×), brine, dried with sodium sulfate, and concentrated yielding 100 mg of the title compound; which was used without further purification.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:32])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=1)=[O:21])=[CH:11]2.C(=O)=O.CC(C)=O>C(Cl)Cl>[Br:5][C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:32])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=1)=[O:21])=[CH:11]2
Reactant: COc1ccc2cc(CN(C)C(=O)c3cn(C)c4ccccc34)ccc2c1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1cn(C)c2ccccc12
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A solution of 1.0 M boron tribromide in methylene chloride (55.0 mL, 54.9 mmol) in 50 mL of methylene chloride was added under nitrogen dropwise over 1.5 h to a solution of 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (8.0 g, 18.3 mmol), prepared in the previous step, in 300 mL of methylene chloride at dry ice-acetone temperature. The dry ice-acetone bath was replaced with an ice bath immediately after the addition. The reaction stirred at ice bath temperature for 2 h. At ice bath temperature, the reaction was quenched by the dropwise with water. The reaction was partitioned between methylene chloride and water. A solid formed in the organic layer and was collected by filtration. The solid was dried under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (6.5359 g, 84%) as a white solid, mp 189-190° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#N.[OH-:11].[Na+].C(O)C.[OH2:16]>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:16])=[O:11]
Reactant: [OH-]
Reactant: N#CCc1ccccc1I
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccccc1I

Procedure:
A solution of 2-(2-iodophenyl)acetonitrile (2.82 g) in a mixture of 1:1 (v/v) ethanol/water (70 ml) was treated with sodium hydroxide (2.4 g) and stirred at reflux for 4 hours. The resultant solution was cooled to ambient temperature, concentrated to 30 ml, diluted with water (100 ml) and washed with ethyl acetate (2×100 ml). The organic layers were combined and extracted with 2M aqueous sodium hydroxide solution (100 ml). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and filtered. The solid collected was washed with water and vacuum dried to give 2-(2-iodophenyl)acetic acid (1.45 g) as a solid, m.p. 110-113° C.; microanalysis; found: C, 36.9; H; 2.7%; C8H7IO2 requires: C, 36.7; H, 2.7%; NMR: 3.7(2H, s), 7.0(1H, m), 7.4(2H, m), 7.8(2H, d); 12.5(1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](N)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].N(OCCC(C)C)=O.C[Si](C)(C)[Br:29].C(=O)(O)[O-].[Na+]>BrCBr>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:29])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N)c(-c2ccc(F)cc2)n1
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Product: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-amino-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester (1.26 g, 5.10 mmol, 1.0 eq) in dibromomethane (25 ml) was added isoamyl nitrite (0.85 ml, 6.29 mmol, 1.2 eq) at room temperature. The resulting suspension was added over 30 minutes at room temperature to a dibromomethane (5 ml) solution of trimethylbromosilane (0.82 ml, 5.90 mmol, 1.15 eq). The mixture was stirred for 2 hours at room temperature after which time the turbid solution was added to aqueous sodium bicarbonate (10%, 15 ml). The phases were mixed, separated and the organic layer dried over magnesium sulfate, concentrated in vacuo and purified by chromatography on silica gel using a gradient of heptane to 10% ethyl acetate in heptane to afford 5-Bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester as white crystals. Yield=0.81 g (51%). 1H NMR (250 MHz, DMSO): δ 3.92 (3H, s), 7.38 (2H, t, J=8.98 Hz), 7.76-7.81 (2H, m), 8.98 (1H, s). HPLC-MS=100%; 2.13 min (MW=311; M+1=313.0).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29]1[CH:56]=[CH:55][C:54](Br)=[CH:53][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[CH2:21]([O:28][C:29]1[CH:56]=[CH:55][C:54]([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)=[CH:53][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccoc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Water (0.5 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan (0.070 g), sodium carbonate (0.076 g), and bis(triphenylphosphine)palladium(II) dichloride (4.2 mg) were added to an ethylene glycol dimethyl ether (1.7 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.17 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-80% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate as a white solid.