Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[C:10]([C:12]1[CH:13]=[C:14]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:15]=[C:16]([CH:20]=1)[C:17]([OH:19])=O)#[N:11].Cl.[NH2:27][C:28]([NH2:30])=[NH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:10]([C:12]1[CH:13]=[C:14]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:15]=[C:16]([CH:20]=1)[C:17]([N:27]=[C:28]([NH2:30])[NH2:29])=[O:19])#[N:11]
Reactant: N=C(N)N
Reactant: N#Cc1cc(C(=O)O)cc(-n2cccc2)c1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N=C(N)N)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
2-Chloro-1-methylpyridinium iodide (3.6 g) was added to a mixture of 5-cyano-3-(pyrrol-1-yl)benzoic acid (2.0 g), guanidine hydrochloride (2.7 g) and triethylamine (7.2 ml) in N,N-dimethylformamide (30 ml), and the mixture was stirred for 4 hours at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and water, and adjusted to pH 10 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with ether to give 2-[5-cyano-3-(pyrrol-1-yl)benzoyl]guanidine (1.49 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH2:24]([O:20][C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
At 0° C., diethyl azodicarboxylate (3.4 mL) was added to a THF solution (13 mL) of 4-amino-3-nitrophenol (1.0 g), benzyl alcohol (1.0 g) and triphenyl phosphine (1.9 g), and stirred at room temperature for 5 hours. The reaction liquid was diluted with ethyl acetate, and the organic layer was washed with aqueous 1 N sodium hydroxide solution, aqueous saturated sodium hydrogencarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/8 to 3/7) to obtain 4-(benzyloxy)-2-nitroaniline (1.2 g) as a red solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:38])(C)C.CCCCCC>CC(CC)=O>[ClH:38].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:9]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Agent: CCC(CC)C(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one (654 mg, 1.5 mmol) was dissolved in ethyl methyl ketone (5 mL), and water (15 μL) and TMSCl (210 μL) were added and the mixture was stirred overnight. Hexane (10 mL) was then added. The precipitated solid matter was isolated by filtration and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 671 mg (95%).
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]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=O)[CH2:21][CH2:20][CH2:19]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2].C([O-])(=O)C.[Na+].Cl.[CH3:32][O:33][NH2:34].O>C(O)C>[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]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=[N:34][O:33][CH3:32])[CH2:19][CH2:20][CH2:21]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=O)CCC3)cc2c1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=NOC)CCC3)cc2c1
Temperature: 65 °C
Yield: 81.3 %

Procedure:
To a solution of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-formyl-cyclobutyl)-2-methylsulfanyl-acetamide (125 mg) in ethanol (10 ml) was added sodium acetate (50 mg) and O-methyl hydroxylamine hydrochloride (44 mg), at room temperature. The mixture was heated to 65° C. during 1 hour. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate (2×10 ml). The organic phase was washed with sat. aq NaCl solution, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. Purification by flash chromatography (ethyl acetate/cyclohexane, 1/1) gave 2-(3-ethynyl-quinolin-6-yloxy)-N-[1-(methoxyimino-methyl)-cyclobutyl]-2-methylsulfanyl-acetamide (110 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[F:11].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>[Cu]I.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[O:13])=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2ccccc2=O)cc1F
Yield: 84.9 %

Procedure:
A mixture of 4-bromo-2-fluoro-benzoic acid methyl ester (1.17 g, 5.0 mmol), 2-hydroxypyridine (0.72 g, 7.5 mmol, 1.5 eq), K2CO3 (1.38 g, 10.0 mmol, 2.0 eq), CuI (0.48 g, 2.5 mmol, 0.5 eq), and N,N′-dimethylethylenediamine (0.22 mL, 2.6 mmol, 0.5 eq) was heated in refluxing toluene (6 mL) for 8 h. After cooling, EtOAc was added. The mixture was filtered through a pad of silica gel and rinsed with EtOAc. The desired fractions were concentrated in vacuo to give essentially pure 2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoic acid methyl ester (1.05 g, yield: 84%). 1H NMR (CDCl3) δ 8.07 (t, J=8.0 Hz, 1H), 7.14 (m, 1H), 7.33–7.27 (m, 3H), 6.64 (m, 1H), 6.28 (m, 1H), 3.96 (s, 3H) ppm. LC/MS (ESI) 248.05 (M+H), tR=2.05 min (10–90% MeOH in H2O with 10 mM NH4OAc in a 4-min run).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[CH3:14][C:15]1(C(O)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].N>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][C:12]=1[C:15]1([CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C(=O)O)CCCCC1
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(c2cc(Cl)nnc2Cl)CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Concentrated sulphuric acid (10.7 ml, 0.2 mol) was added to a solution of 3,6-dichloropyridazine (10 g, 67 mmol) in water (250 ml). This mixture was heated to 70° C. before addition of 1-methylcyclohexane carboxylic acid (9.67 g, 68 mmol). Silver nitrate (2.3 g, 13.5 mmol) in water (5 ml) was then added over one minute followed by ammonium persulphate (45.6 g, 0.2 mol) in water (95 ml) added over 20 minutes. Upon complete addition, the reaction was stirred for an additional 5 minutes and then allowed to cool to room temperature. The mixture was cooled to 0° C. (ice/water bath) and basified with concentrated aqueous ammonia solution (internal temperature <10° C.). The aqueous phase was extracted with dichloromethane (3×350 ml) and the combined extracts washed with brine (350 ml), dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica using 0→5% ethyl acetate in dichloromethane as eluent to give the required product. (5.93 g). 1H NMR (250 MHz, CDCl3) δ1.33-1.74 (6H, m). 1.43 (3H, s), 1.80-1.96 (2H, m), 1.97-2.12 (2H, m), 7.49 (1H, s); MS (ES+) m/e 249 [MH]+. 247 [MH]+. 245 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:27])[C:23]([F:26])([F:25])[F:24].[F-].C[N+](C)(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:27])([F:21])[C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Temperature: -25 °C
Reaction time: 4.5 h
Yield: 115.9 %

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonium fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered through Celite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine is added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO, and 1.6 g (10 mmol) of pyridine SO3 complex is added in portions over 10 minutes. It is stirred over 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12](Br)[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36]>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([NH:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Reactant: NC[C@H](O)CO
Solvent: CC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(NC[C@H](O)CO)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
100 mg (0.183 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)pyridine-3,5-dicarbonitrile were initially charged in 2 ml of acetone, 834 mg (9.159 mmol) of (2S)-3-aminopropane-1,2-diol were added and the mixture was stirred at 80° C. for 12 h. A further 834 mg (9.159 mmol) of (2S)-3-aminopropane-1,2-diol were then added, and the mixture was stirred at 80° C. for a further 12 h. The reaction mixture was concentrated and the product was isolated by preparative HPLC. This gave 19 mg (19% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]=3)[CH:9]=2)[N:4]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:3]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.NC1C=C(B(O)O)C=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]1[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]3[N:15]=[CH:14][N:13]([C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:12]=3)=[CH:7][CH:6]=2)[C:2]([C:7]2[CH:6]=[C:5]([NH2:4])[CH:10]=[CH:9][CH:8]=2)=[N:3]1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Agent: [Fe+2]
Agent: Nc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Yield: 79 %

Procedure:
To a solution of 2-{3-bromo-5-[1 (triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazolyl}perhydro-2H-pyran (1.0 g, 1.69 mmol) in ethylene glycol dimethyl ether, (20 mL), 3-amino phenyl boronic acid was added as a solid (0.393 g, 2.53 mmol), followed by [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.196 g, 0.169 mmol), and potassium phosphate (1.79 g, 8.45 mmol). The reaction mixture was heated to reflux temperature of the solvent for 12 h. The crude reaction mixture was partitioned between ethyl acetate and water. The organic extracts were dried over Na2SO4. The desired product was isolated as a beige solid after column chromatography purification (SiO2, 25–50% ethyl acetate in hexanes) (0.801 g, 79% yield): ES-MS (m/z) 603 [M+1]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]=[O:13])[CH:7]=[CH:8][C:9]=1[F:10].[CH3:14]I>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:14])[CH:12]=[O:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=CNc1ccc(F)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C=O)c1ccc(F)c(Cl)c1
Temperature: 0 °C

Procedure:
17.5 g of sodium hydride (57% in mineral oil) was added, in portions, to a stirred solution of 55.5 g of 1A and 71 g of methyl iodide in 250 ml of tetrahydrofuran at room temperature. The resulting mixture was stirred and refluxed for 2 hours, poured into ice water and filtered. The solid was washed with water, dried and recrystallized from hexane to give N-(3-chloro-4-fluorophenyl)N-methylformamide (5A), as a white crystalline solid, mp: 47°-48° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.F[C:30]1C=CC(N2C(C(OCC)=O)=C(C)N=C2S)=CC=1.FC1C(F)=CC=C(F)C=1CBr.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:30])[N:10]=[C:9]2[S:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Agent: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)nc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (58) was prepared in a similar manner as that described for the synthesis of compound 10 using 1-(4-fluorophenyl)-2-mercapto-4-methyl-1H-imidazole-5-carboxylate (57) (500 mg, 1.78 mmol), 2,3,6-trifluorobenzyl bromide (560 mg, 2.49 mmol) and potassium carbonate (736 mg, 6 mmol) in acetone (18 mL).
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.S(Cl)(Cl)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Reactant: NCc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccccc1)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after conversion into the acid chloride using thionyl chloride and reaction with benzylamine, 2′-phthalimidomethylbiphenyl-2-carboxylic acid benzylamide was obtained. 1.2 g (2.7 mmol) of the product were dissolved in 55 ml of methanol and treated with 1.35 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the reaction mixture was concentrated and the residue was taken up in methylene chloride. After filtering off the 2,3-dihydrophthalazine-1,4-dione formed, the mother liquor was concentrated and the residue was purified by flash chromatography using methylene chloride/methanol 30:1. 0.49 g of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide was obtained.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[Si:21]([O:20][CH2:19][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][NH:8][CH2:9]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Temperature: 55 °C
Yield: 98.7 %

Procedure:
A mixture of 117 g (0.31 mol) of 1-benzyl-3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenyl pyrrolidine (from Step D), 31.5 g (0.50 mol) ammonium formate, 20.0 g of 20% palladium hydroxide on carbon in 1.5 L of MeOH was heated at 55° C. for 2.5 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was dissolved in 1 L of CH2Cl2, washed with 300 mL of 10% NH4OH solution, 200 mL of sat'd NaCl, dried over MgSO4 and concentrated to afford 89.2 g (99%) of the title compound: 1H NMR (400 MHz) δ−0.09 (s, 3H), −0.08 (s, 3H), 0.77 (s, 9H), 2.25-2.30 (m, 1H), 2.84-2.96 (4H), 3.18 (dd, J=11.2, 3.2, 1H), 3.29-3.36 (m, 1H), 3.44 (dd, J=10.0, 6.0), 3.56 (dd, J=10.0, 4.4, 1H); ESI-MS 292 (M+H); HPLC A: 3.44 min.
Reaction SMILES: CN(C)C=O.[CH2:6]([NH:14][C:15](=[O:30])[C:16]([CH3:29])=[CH:17][C:18]1[CH:23]=[C:22](OC)[C:21](OC)=[CH:20][C:19]=1[NH2:28])CC1C=CC=CC=1.[N+](C1C=CC(OC(=O)C(C)=CC2C=CC=CC=2N)=CC=1)([O-])=O.[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1N>C(Cl)Cl.CO.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[CH2:6][NH:14][C:15](=[O:30])[C:16]([CH3:29])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:28]
Reactant: Nc1ccc2ccccc2c1
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Agent: CC(=Cc1ccccc1N)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1N)C(=O)NCc1ccc2ccccc2c1
Yield: 199.7 %

Procedure:
Into 4 ml of dimethylformamide, 0.65 g (2.2 mmol) of (E) 3-(2-aminophenyl)-2-methyl-2-propenoic acid p-nitrophenyl ester and 0.69 g (4.4 mmol) of 2-naphtylamine (manufactured by Aldrich Chemical Co., Inc.) were dissolved; and, with 0.36 ml of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.) being added thereto, the mixture was reacted at room temperature for 20 hours. After the completion of the reaction was verified by TLC, ethyl acetate and water were added to the mixture. The resulting ethyl acetate layer was fractionated, and was washed several times with a 5% aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. After the washed solution was dried with magnesium sulfate anhydride, the solvent was evaporated under a reduced pressure, whereby a crude product was obtained. This product was refined by a silica gel column chromatography (developing solvent: methylene chloride/methanol=95/5), whereby 1.39 g of the aimed compound were obtained (yield: quantitative).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23]Br>>[CH3:19][O:18][C:4]1[CH:3]=[C:2]([O:1][CH2:23][CH2:22][O:21][CH3:20])[CH:7]=[CH:6][C:5]=1[CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COCCBr
Reactant: COC(=O)CC(CC(C)C)c1ccc(O)cc1OC
Product: COCCOc1ccc(C(CC(=O)OC)CC(C)C)c(OC)c1

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)-5-methylhexanoate (prepared as described in Preparation 58B) and 2-methoxyethyl bromide, the title compound was obtained as an oily substance.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:34])[C:20]=1[CH2:21][CH:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[OH:23].[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH3:49])[C:46](O)=[O:47])=[CH:41][CH:40]=1)[CH:36]([CH3:38])[CH3:37].[NH4+].[Cl-]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(Cl)CCl>[Cl:34][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([Cl:14])[C:20]=1[CH2:21][CH:22]([O:23][C:46](=[O:47])[C@H:45]([C:42]1[CH:43]=[CH:44][C:39]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:40][CH:41]=1)[CH3:49])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)[C@@H](C)c2ccc(CC(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
(1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) (EDC. HCl) (345 mg, 3 eq.) is added to a solution of 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanol (200 mg, 1 eq.), (S)-2-(4-isobutyl-phenyl)-propionic acid (148 mg, 1.2 eq.) and 4-dimethylaminopyridine (DMAP) (37 mg, 0.5 eq.) in dry CH2Cl2 (8 mL) at room temperature under nitrogen atmosphere. The mixture is stirred at room temperature overnight, then it is treated with a saturated solution of NH4Cl (20 ml) and extracted with EtOAc (2×20 ml). The combined organic layer are dried over Na2SO4 and the solvent is evaporated. The crude is purified by flash chromatography on silica gel in gradient elution (from petroleum ether/EtOAc 9/1 v/v to petroleum ether/EtOAc 7/3 v/v) to yield 259 mg of pure compound.