Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@@:10]3([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:25]1([CH2:28][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@:10]3([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 3,14-dimethoxy-8α-methylmorphinan-6-one hydrochloride (26) (0.83 g, 2.36 mmol), cyclopropylmethyl bromide (0.51 g 3.78 mmol), anhydrous sodium carbonate (1.6 g, 15.09 mmol) and ethanol (20 ml) was refluxed at oil bath temperature of 110° C. for 18 hours with stirring under a nitrogen atmosphere. The resulting product was filtered and the residue washed with ethanol (3×35 ml). The filtrate was concentrated under reduced pressure give 0.689 g of a solid product which was purified by chromatography on silica gel using graded methanol/chloroform mixtures to provide 0.362 g (41.5% theory) of 17-cyclopropylmethyl-3,14-dimethoxy-8α-methylmorphinan-6-one (30) as a tan foamy solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cc(O)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc(OCc2ccccc2)c1

Procedure:
To a solution of 173 mg. (1 m mole) of 3-hydroxy-5-chlorobenzoic acid in 2 ml. of dimethylformamide is added 85 mg. (2 m moles) of 56.6% sodium hydride in an oil suspension. After ten minutes, the resulting suspension is treated with 130 mg. (1 m mole) of benzyl chloride and the mixture heated to 100° C. for one hour. The reaction mixture is then cooled, diluted with 5 ml. of water, and extracted with ether. The aqueous phase is separated, acidified with 6N hydrochloric acid and the product extracted with ether. The ether solvent is removed in vacuo and the residual product triturated with water and filtered. The dried product is sublimed at 125° C. and 0.02 mm of pressure to provide 50 mg. of the desired produce, m.p. 127-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.00 g, 4.77 mmol), 2-chloro-4-fluoronitrobenzene (1.68 g, 9.55 mmol), and potassium carbonate (1.98 g, 14.3 mmol) in 4:1 DME/water (20 mL) in a sealed vessel was heated to 100° C. with stirring. After 18 hours the mixture was treated with an additional 2.00 g portion of potassium carbonate, heated at 100° C. for another 15 hours, and then stirred at RT for 3 days. The mixture was partitioned between EtOAc and water. After separating the phases, the aqueous portion was extracted with two additional portions of EtOAc. The combined EtOAc solutions were washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) to afford a tacky, yellow foam. This material was crystallized from hexane/EtOAc to give the title compound (1.78 g, 65%) as a light yellow solid. LCMS (m/z, ES+)=574 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][CH2:11][C@@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C([BH3-])#N.[Na+].C(ON)C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCCC.O>[CH2:1]([O:8][NH:9][CH2:10][CH2:11][C@@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](CC=NOCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NOCc1ccccc1
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: COC(=O)[C@@H](CCNOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 2.5 h
Yield: 49.1 %

Procedure:
J1) To a stirred solution of methyl (2R)-4-[(benzyloxy)imino]-2-[(tert-butoxycarbonyl)-amino]butanoate (1.7 g, 5.0 mmoles) and dry methanol (50 mL) was added sodium cyanoborohydride (0.31 g, 5.0 mmoles) followed dropwise addition of a 1M solution of 4-toluenesulfonic acid (N.B. crystal water present in commercial 4-toluenesulfonic acid has to be removed by azeotropic evaporation with benzene or toluene prior to use) in dry methanol at such a rate so as to keep pH of the mixture at 3–4 (moist indicator paper). After stirring at 22° C. for 2.5 hours TLC and LC indicated a complete reaction. The methanol was stripped off by rotary evaporation leaving a white solid which was taken up in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Filtration and concentration by rotary evaporation gave 1.7 g of a crude which was chromato-graphed on silica with ethyl acetate/n-heptane (1:5 through 1:3) as eluents. To rid the product from traces of O-benzylhydroxylamine it was chromatographed once more on silica using dichloromethane and dichloromethane/methanol (98:2) as eluents to afford 0.83 g (49% yield) of the subtitle compound as a colourless oil. MS (APCI) m/z 339 (M+1). 1H NMR (CDCl3) δ 7.40–7.27 (m, 5H), 5.47 (br d, J=8 Hz, 1H), 4.74 (s, 2 H), 4.41–4.31 (m, 1H), 3.72 (s, 3H), 3.10–2.93 (m, 2H), 2.20–2.05 (m, 1H), 1.88–1.78 (m, 1H) and 1.43 (s, 9H) ppm.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[CH3:39][N:29]([CH3:28])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(C)CCc1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CCN(C)C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[CH:22]/[C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C:25]=2[CH:24]=1)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[OH-].[Na+]>C1COCC1.CO>[CH:24]1[C:25]2[CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][C:23]=1/[CH:22]=[CH:21]/[CH2:20][OH:19]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)Cc1ccccc1-2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: OC/C=C/c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Under an atmosphere of nitrogen a 1M solution of DIBAL-H in toluene (80 ml, 80 mmol) was added dropwise at −70° C. over 20 min. to a stirred solution of (E)-3-(9H-fluoren-2-yl)-acrylic acid ethyl ester (5.3 g, 20.0 mmol) in dry THF (150 ml) and the mixture stirred for 30 min. Methanol (2 ml) was added, followed by saturated aqueous Rochelle's salt (100 ml), and 1N NaOH. The aqueous phase was separated and further extracted with dichloromethane. The combined organic phases were washed with water (300 mL), dried (MgSO4), filtered and concentrated in vacuo yielding 4.1 g (92%) of (E)-3-(9H-fluoren-2-yl)-prop-2-en-1-ol.
Reaction SMILES: C(Cl)CCl.[CH3:5][NH:6][CH2:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl.C[C:20]1([CH3:37])[CH2:26][O:25][C:24]2[CH:27]=[C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)[CH:29]=[N:30][C:23]=2[NH:22][C:21]1=[O:36].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:37][C:20]1([CH3:26])[O:25][C:24]2[CH:27]=[C:28](/[CH:31]=[CH:32]/[C:33]([N:6]([CH3:5])[CH2:7][C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:35])[CH:29]=[N:30][C:23]=2[NH:22][C:21]1=[O:36]
Reactant: CNCc1[nH]c2ccccc2c1C
Reactant: CC1(C)COc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)C(=O)N3)[nH]c2ccccc12
Reaction time: 8 h
Yield: 82.6 %

Procedure:
EDC (402 mg, 1.0 mmol) was added to a solution of N-methyl(3-methyl-1H-indol-2-yl)methanamine (135 mg, 0.7 mmol), (E)-3-(3,3-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-8-yl)acrylic acid hydrochloride (240 mg, 0.8 mmol), HOBT.H2O (101 mg, 0.7 mmol) and DIPEA (0.58 mL, 2.7 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (234 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ 10.62-10.58 (rotamers, s, 1H), 10.09 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.51-7.49 (m, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.03-6.90 (m, 3H), 4.90-4.73 (rotamers, s, 2H), 4.05 (s, 3H), 2.23 (s, 3H), 1.17 (s, 6H); MS (ESI): m/e 419.4 (C24H26N4O3+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: NCc1ccncc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1ccncc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=537.96 (M+H+); retention time=0.56 minutes.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:25][C:26]1[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][C:27]=1[C:35](=[O:37])[CH3:36].CS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:35]([C:27]1[C:26]([NH:25][C:10]([C:8]2[N:9]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[O:6][CH:7]=2)=[O:12])=[C:31]([Cl:32])[C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:37])[CH3:36]
Reactant: CC(C)Nc1nc(C(=O)O)co1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(NC(=O)c2coc(NC(C)C)n2)c1Cl
Reaction time: 2 h
Yield: 28.2 %

Procedure:
To 2-isopropylaminooxazole-4-carboxylic acid (1.9 g, 10.9 mmol) in DCM (10 ml) was added CDI (1.8 g, 10.9 mmol). The mixture was then stirred at it for 2 h, followed by addition of 1-(2-Amino-3-chloro-4-methoxyphenyl)ethanone (prepared according to Raboisson, P. J.-M. B., et al., WO2007014926, p 78; 1.4 g, 8.7 mmol) and CH3SO3H (2.1 mL, 32.8 mmol), and then stirred for 18 h at rt. The reaction mixture was diluted with DCM (100 mL) and washed with 1N HCl (2×100 mL). To the collected DCM layer was added K2CO3 (3.02 g, 21.88 mmol) and stirred for 2 h at rt. The solution was filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with EtOAc/hexane, to give 2-isopropylamino-oxazole-4-carboxylic acid (6-acetyl-2-chloro-3-methoxyphenyl)amide (863 mg, 22% yield). LCMS found 382 [M+H]+.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\Cl.C(N)CCC.[O:10]([CH2:17][C:18]#[CH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:1]/[CH:2]=[CH:3]\[C:19]#[C:18][CH2:17][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCOc1ccccc1
Reactant: Cl/C=C\Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: Cl/C=C\C#CCOc1ccccc1
Reaction time: 5.5 h
Yield: 67.6 %

Procedure:
To a 1 L flask under Argon was added CuI (7.86 g, 41.2 mmol) and Pd(PPh3)4 (5 g, 4.3 mmol). The catalyst was covered with 600 mL of degassed THF, cis-1,2-dichloroethylene (50 g, 516 mmol), and butylamine (68 mL, 688 mmol). Phenoxy-2-propyne (45 g, 340 mmol) was added neat over 10 min and the reaction mixture stirred for 5.5 h. Air was bubbled through the reaction mixture for 15 min and the reaction filtered through a pad of celite and washed with pentane. The filtrate was washed with water and brine and the aqueous fractions extracted with ether. The organic fractions were combined, dried (MgSO4), filtered through celite and concentrated. The residue was chromatographed over silica gel (hexane) to give 44.3 g of a yellow oil (67%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]1[C:28]([CH2:29][OH:30])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=[C:25]([CH3:38])[N:24]=1>ClCCl>[CH3:22][C:23]1[C:28]([CH:29]=[O:30])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=[C:25]([CH3:38])[N:24]=1
Reactant: Cc1cc(-c2ccc(F)cc2)c(CO)c(C)n1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(F)cc2)c(C=O)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (7 mmol) of pyridinium dichromate are added in portions to 1.0 g (4.3 mmol) of the compound from Example 29 in 20 ml of dichloromethane, the mixture is stirred for 2 h at 25° C., after concentrating chromatographed over 150 g of silica gel using dichloromethane/methanol 10:1 and 0.71 g of product are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:27][CH2:26]3)=[CH:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]3)=[CH:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of ethyl {4-[(2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]piperazin-1-yl}acetate (0.500 g) in a mixed solvent of tetrahydrofuran (15 ml) and methanol (5 ml) was added 2N aqueous sodium hydroxide solution (1.5 ml), and the mixture was stirred at 50° C. for 2 hr. 10% Aqueous citric acid solution, ethyl acetate, sodium chloride and tetrahydrofuran were successively added to the reaction solution, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to give the title compound (0.360 g, yield 76%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[CH2:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[C:16]1C(OC)=CC(C(OC)=O)=C(Cl)C=1.C([O-])([O-])=O.[K+].[K+].[B-](F)(F)(F)C=C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[CH2:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: C=Cc1cc(Cl)c(C(=O)O)cc1OC
Reactant: COC(=O)c1cc(OC)c(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1cc(Cl)c(C(=O)OC)cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-Chloro-5-methoxy-4-vinylbenzoic acid: A 25 mL round bottomed flask was charged with methyl 4-bromo-2-chloro-5-methoxybenzoate (640 mg, 2.29 mmol), K2CO3 (665 mg, 4.81 mmol), potassium trifluoro(vinyl)borate (920 mg, 6.87 mmol), PdCl2(dppf) (84 mg, 0.11 mmol) and anhydrous DMSO (15 mL) and stirred at 80° C. for 2 h. The reaction was allowed to cool, water (150 mL) was added and then extracted several times with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a brown residue. The crude product was purified via flash chromatography eluting with 15% Et2O/hexanes to give methyl 2-chloro-5-methoxy-4-vinylbenzoate as a yellow oil (440 mg, 85%). To a 25 mL round bottomed flask containing methyl 2-chloro-5-methoxy-4-vinylbenzoate (440 mg, 1.94 mmol) and MeOH (10 mL) was added 1N NaOH (2 mL, 2.04 mmol) and reaction stirred at ambient temperature for 18 h. The reaction mixture was concentrated to give a solid residue. The residue was dissolved in water and extracted 1× with 50% Et2O/hexanes. The aqueous layer was made acidic with 2N HCl and extracted 2× with CH2Cl2, dried over MgSO4, filtered and concentrated to afford the title compound as a white solid (0.39 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=0.5 Hz, 1H), 7.52 (s, 1H), 6.98 (ddd, J=17.7, 11.2, 0.6 Hz, 1H), 5.87 (dd, J=17.7, 1.1 Hz, 1H), 5.45 (dd, J=11.2, 1.1 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.CSC.C(OCC)C.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CSC
Product: Brc1ccc(CCCN2CCOCC2)cc1
Reaction time: 24 h
Yield: 78 %

Procedure:
A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) at room temperature was treated with 5M BH3/dimethylsulfide in diethyl ether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3N aqueous HCl (10 mL), heated to reflux for 1 hour, and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane to provide the desired product (565 mg, 78%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]>C(OCC)C>[CH3:1][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][S:26]([C:29]([F:32])([F:30])[F:31])(=[O:28])=[O:27])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
With cooling with ice, potassium carbonate (152 mg, 1.10 mmol) and iodomethane (0.137 mL, 2.20 mmol) were added to a DMF solution (3.0 mL) of methyl 3-hydroxy-5-trifluoromethane-sulfonyloxybenzoate (300 mg, 1.00 mmol), and stirred at room temperature for 17 hours. The reaction mixture was diluted with diethyl ether (30 mL), washed with water and aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:43])[CH:30]([NH2:42])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([OH:43])[CH:30]([NH:42][C:12](=[O:14])[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cccc2ccccc12)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 1-naphthaleneacetic acid (160 mg, 0.86 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (175 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl>[C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: OCc1ccccc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccccc1O
Reaction time: 0.5 h

Procedure:
2-Hydroxybenzyl alcohol (1.0 g) was dissolved in methylene chloride (20 ml), the solution was slowly added dropwise with pyridine (0.65 ml) and acetyl chloride (0.57 ml) under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was added with saturated aqueous ammonium chloride, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (1.22 g).