Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[N:13]=[N:12][C:11](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][C:20]\2=[O:21])=[N:10]1)=[O:5])[CH3:2].[BH4-].[Na+].ClCCl>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[N:13]=[N:12][C:11](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:19][CH:20]\2[OH:21])=[N:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Yield: 37 %

Procedure:
(E)-3-({2-[3-(Ethoxycarbonyl)propyl]-2H-tetrazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (3.93 g) was reduced with sodium borohydride (281 mg) in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml) in a similar manner to that mentioned in Example 138 (c), and the crude product obtained by conventional extraction procedures was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (1:9 to 7:3) as the eluent to afford the title compound as a yellow oil (1.46 g, yield: 37%).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.FC(F)(F)C(O)=O.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]1[CH2:42][NH:41][CH2:40]1>>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]1[CH2:40][N:41]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: c1ccc2sc(C3CNC3)nc2c1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2sc(C3CN(c4c5c(nc6ccnn46)CCNCC5)C3)nc2c1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 3-benzothiazol-2-yl-azetidine trifluoroacetate was used as the amine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([NH:34][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])[CH:31]([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: CC(C)CN
Product: CC(C)CNc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 49 %

Procedure:
The title compound was prepared according to the procedure described for example 301 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and and Isobutylamine (49% yield, off white foam, MS (m/e): 484.5 (M+H, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: OB(O)c1ccccc1F
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(-c3ccccc3F)cnc2n1C
Temperature: 80 °C
Yield: 95.5 %

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (350 mg) and 1,4-dioxane (5 ml), 2-fluorophenylboronic acid (150 mg), tripotassium phosphate (600 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25 mg), and tris(dibenzylideneacetone)palladium(0) (14 mg) were sequentially added, heated to 80° C., and stirred with heating for 8 hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 349 mg of 2-(2-ethylsulfanylphenyl)-6-(2-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 58).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:35]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[S:35]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1ncccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1ncccc1C(=S)NCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A mixture of 2-amino-N-(4-benzyloxy-benzyl)-nicotinamide described in Example A-17 (220 mg, 0.67 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (670 mg, 1.7 mmol) and toluene (8 mL) was stirred at 80° C. for 15 minutes, then, refluxed for 45 minutes. After cooling, the precipitate was filtered, and the filtrate was evaporated in vacuo. Purification was carried out by NH silica gel column chromatography (ethyl acetate), and the title compound (28 mg, 0.080 mmol, 12%) was obtained as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[F:10][C:11]1[CH:12]=[C:13]([N:30]2[CH2:34][C@H:33]([CH2:35][N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[O:32][C:31]2=[O:41])[CH:14]=[CH:15][C:16]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH2:27][C@@H:26]([CH2:28]O)[O:25][N:24]=2)=[CH:21][CH:22]=1.CN(C=O)C.C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([N:30]2[CH2:34][C@H:33]([CH2:35][N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[O:32][C:31]2=[O:41])[CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:27][C@@H:26]([CH2:28][O:8][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[O:25][N:24]=2)=[N:19][CH:18]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: O=C(O)c1cnccn1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyrazine-2-carboxylic acid (118 mg, 0.95 mMol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 200 mg, 0.46 mMol), 4-(dimethylamino)pyridine (5 mg, 0.041 mmol) and DMF (2 ml) were combined and warmed to give a clear solution. The solution was allowed to cool to room temperature, and then diisopropylcarbodiimide (0.15 ml, 0.96 mmol) was added. The mixture was stirred for 18 hours, ethyl acetate was added, followed by washing with saturated NaCl. The organic layer was dried over sodium sulfate, evaporated, triturated with 1:5 ether:hexane, dissolved in 1:1 acetonitrile:methanol, adsorbed on silica gel and purified by chromatography (silica gel; elution with 1 to 10% methanol in dichloromethane). The product containing fractions were pooled and evaporated to give the title compound as a white solid, 159 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[C:17]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])(=[O:21])[C:18]([CH3:20])=O.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]([CH:4]([NH:5][C@H:18]([C:17]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:20])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:16]
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)C(Cc1c[nH]c2ccccc12)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In a manner similar to Example 16 tryptophan methyl ester is condensed with pyruvoyl-L-proline in the presence of sodium cyanoborohydride to yield N-[1-methoxycarbonyl-2-(3-indolyl)-ethyl]-alanyl-L-proline.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:28])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C2CCNC2)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 166.2 %

Procedure:
To a stirred solution of (RS)-3-[4-(4-chloro-benzoylamino)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.36 g) in THF (30 ml) was added dropwise a solution of hydrogen chloride in dioxane (22 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to 0° C. and the ensuing crystals were collected by filtration, washing with diethyl ether, and then dried in vacuo at 60° C. to afford (RS)-4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide hydrochloride (1.65 g, 83%) as a white crystalline solid. MS (ISP): 303.2 ([{37Cl}M+H]+), 301.3 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH3:42]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (28.58 g) obtained in Example 23-4 was dissolved in anhydrous DMF (560 ml) and added with triethylamine (20.35 ml) and ethyl bromoacetate (12.14 ml) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in ethyl acetate and washed with water, followed by drying with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (21.265 g) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O.O.[OH-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21

Procedure:
A mixture of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (5.0 g), prepared in a similar manner to that described in Example 11, water (50 ml) and isopropyl alcohol (50 ml) was heated to 50°. Aqueous sodium hydroxide solution (1 M; 3 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was cooled in an ice bath and the product isolated by filtration, washed with water (10 ml), and then isopropyl alcohol (10 ml) to give the crude product (3.3 g). A sample of the crude product (2.0 g) was crystallised from industrial methylated spirit (112 ml) to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p 221.5°-223° (1.7 g). The product was heated at 90° with grinding to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 235°-236° (1.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of the compound of Example 14A (23.2 g, 0.138 mol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (35 mL, 0.165 mol) and n-butyllithium in hexane (2.5 M, 58 mL, 0.145 mol)) in dry tetrahydrofuran (100 mL). The solution was stirred at −78° C. for 1 h, and then a large excess of methyl iodide was added. The solution was stirred at −78° C. for 30 min and was then warmed to ambient temperature for 18 h. The solution was quenched by addition of saturated ammonium chloride solution and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution, followed by drying (Na2SO4) and concentration in vacuo. The residue was distilled under reduced pressure (70-75° C./0.5 mm Hg) to afford the title compound (21.9 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.49 (d, J=7.35 Hz, 3 H) 3.70 (m, 4 H) 7.01 (m, 2 H) 7.27 (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:25]4[CH:24]=[C:23]([C:22]([F:31])([F:30])[F:21])[S:27][CH:26]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1csc(C(F)(F)F)c1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.5 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (300 mg), (5-(trifluoromethyl)-3-thienyl)methanol (352 mg) and triphenylphosphine (877 mg) in THF (10 ml) was added bis(2-methoxyethyl) azodicarboxylate (783 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPA-IPE to give the title compound (70.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13].P(Cl)(Cl)(Cl)=O>C(OCC)C.[Cu].[Zn]>[CH2:1]([CH:2]1[CH2:3][C:12](=[O:13])[C:11]1([Cl:16])[Cl:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCc1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1CC(Cc2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a room temperature mixture containing allylbenzene (1.84 g, 15.6 mmol), zinc-copper couple (5.1 g, 78 mmol) and diethylether (60 ml) was added dropwise a solution of trichloroacetylchloride (2.96 ml, 26.5 mmol) and phosphorus oxychloride (2.46 ml, 26.5 mmol) in diethylether (20 ml). The reaction mixture was stirred at room temperature for 1 hour, filtered and the filtrate was partially concentrated. The residue was neutralized with saturated NaHCO3. The aqueous phase was extracted with diethylether. The combined organic phases were washed successively with H2O and brine, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (hexane) to provide (RS)-3-benzyl-2,2-dichlorocyclobutanone (0.71 g, 20%) as a yellow oil, MS: m/e=228.1 (M-H+).
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46](O)=[O:47])[CH:23]=[CH:24][C:25]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].[NH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57].Cl>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57])=[O:47])[CH:23]=[CH:24][C:25]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Reactant: NCCCCCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)NCCCCCCO)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMT-MM) (138 mg, 0.50 mmol) was added to a solution of N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (200 mg, 0.46 mmol) (disclosed in WO 01/05746) and 6-aminohexanol (60 mg, 0.51 mmol) in THF (4.0 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into 1 N HCl (aq.) and was extracted with EtOAc (×2). The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM/MeOH/NH3(aq.) 95:5:0.5 as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([OH:15])[C:7]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]1[CH3:14].[Li][CH2:17]CCC.CI>C1COCC1>[CH3:17][O:15][C:2]1([CH3:1])[C:3]([CH3:14])=[CH:4][CH2:5][CH2:6][C:7]1([CH3:13])[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: [Li]CCCC
Reactant: CC(C)=CCC1(C)CCC=C(C)C1(C)O
Solvent: C1CCOC1
Solvent: CI
Product: COC1(C)C(C)=CCCC1(C)CC=C(C)C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 1,2,6-trimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enol (5.00 g, 24.0 mmol) in THF (80 ml) was added n-BuLi (1.6M in hexane, 16.5 ml, 26.4 mmol) at 0° C. After the mixture was stirred for 30 min, methyl iodide (5.18 g, 36.5 mmol) was added. The mixture was stirred at room temperature over night and then poured on ice and extracted with MTBE. The organic phase was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled (bp. 75° C./0.2 Torr) to yield 5.0 g (93%) of an colorless oil containing 2 isomers: 1H-NMR (400 MHz, CDCl3): 5.64 (bs, 1H, 2-H), 5.23-5.15 (m, 1H, CH2CH═C(CH3)2), 3.30, 3.28 (2s, 3H, O—CH3), 2.22-2.12 (m, 1H), 1.99-1.88 (m, 3H), 1.75-1.58 (m, 10H), 1.20,1.18 (2s, 3H), 0.93, 0.79 (2s, 3H) ppm. MS (EI): 222 (M+, 1), 190 (11), 175 (10), 147 (60), 121 (100), 112 (30), 105 (57), 91 (40), 79 (25), 69 (14), 41 (45). IR (ATR): 2966s, 2926s, 1449s, 1377s, 1083vs, 858m cm−1.
Reaction SMILES: [N-]=[C:2]=[O:3].[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])[CH:5]=[CH2:6]>C1(C)C=CC=CC=1>[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])[CH:5]=[CH2:6].[C:4]([O:8][CH2:9][CH2:2][OH:3])(=[O:7])[CH:5]=[CH2:6]
Reactant: [N-]=C=O
Agent: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCO

Procedure:
An isocyanate derived cross-linking agent (Collonate L manufactured by NIPPON POLYURETHANE INDUSTRY CO., LTD.) 15 parts was added to a polymer 100 parts (converted from a solid content 40% of toluene solution) that comprises a copolymer obtained by copolymerizing butyl acrylate 100 parts, acrylonitrile 5 parts, and acrylic acid 5 parts, and mixed to prepare an adhesive. The adhesive was applied using an applicator on a polyester film (50 micrometers) so that a thickness of the adhesive layer after dried is 10 micrometers, and then dried for 3 minutes by the hot-air dryer at 130 degrees C. to obtain a desired carrier sheet.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]3[N:27]=[C:28]([N:31]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]4)[S:29][CH:30]=3)[CH2:20][CH2:19]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH3:38].[OH-].[Na+].CO>C1COCC1>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[S:29][CH:30]=[C:26]([CH2:25][N:21]3[CH2:22][CH2:23][CH2:24][N:18]([C:17]4[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[C:9]([CH3:38])[CH:10]=[C:11]5[C:16]=4[N:15]=[CH:14][CH:13]=[CH:12]5)[CH2:19][CH2:20]3)[N:27]=2)[CH2:36][CH2:35]1
Reactant: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(Cc2csc(N3CCC(O)CC3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cccnc2c(N2CCCN(Cc3csc(N4CCC(O)CC4)n3)CC2)c1OCCCC(=O)O
Reaction time: 3 h

Procedure:
The product from step 3 (3.27 mmol) was dissolved in THF (10.9 mL), and 1 N aq. NaOH (6.54 mL, 6.54 mmol) was added, followed by MeOH (5.5 mL). This solution was allowed to stir for 3 h, then concentrated. The crude product was then purified on a reverse phase column (MeCN:H2O+0.1% TFA), and the combined product fractions were basified to pH 9 using NH4OH, then extracted with CH2Cl2 (3×50 mL). The combined organic was then concentrated. The residue was lyophilized from MeCN/H2O to give the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.70 (dd, 1H, J=1.4, 4.2 Hz), 7.96 (dd, 1H, J=1.4, 8.2 Hz), 7.35 (s, 1H), 7.22 (dd, 1H, J=4.4, 8.0 Hz), 6.71 (s, 1H), 4.12-4.05 (m, 4H), 4.05-3.82 (m, 4H), 3.80-3.72 (m, 4H), 3.62-3.56 (m, 2H), 3.49-3.40 (m, 4H), 3.22-3.15 (m, 2H), 2.58 (t, 2H, J=7.0 Hz), 2.41 (s, 3H), 2.24-2.17 (m, 4H), 1.98-1.90 (m, 2H), 1.69-1.59 (m, 2H). MS (ES) m/z 540.5 (M+H+).