Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].[Br:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[C:16]([F:21])[CH:15]=1.O>CS(C)=O>[Br:13][C:14]1[CH:19]=[C:18]([O:10][CH2:9][C:8]([F:12])([F:11])[F:7])[CH:17]=[C:16]([F:21])[CH:15]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Br)cc(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a 50 mL flask flushed with nitrogen, equipped with a stir bar and cooled in a water bath was added potassium tertbutoxide (1.2 g, 11 mmol, 95%). DMSO was added (4 mL) followed by addition of a solution of 2,2,2-trifluoroethanol (1.1 g, 11 mmol) in DMSO (1 mL). The water bath was removed and 1-bromo-3,5-difluorobenzene (1.1 mL, 9.5 mmol) was added and the reaction mixture stirred at room temperature for 1 h. An additional portion of 2,2,2-trifluoroethanol was added (1.1 g, 11 mmol) and the reaction mixture stirred for 14 h. Additional potassium tertbutoxide (0.24 g, 2.2 mmol, 95%) was added followed by addition of a further aliquot of 2,2,2-trifluoroethanol (0.44 g, 4.4 mmol) and the resulting turbid solution stirred for 2 h. Water was added (200 mL), and the aqueous phase extracted with ether (1×200 mL). The organic portion was then washed successively with water (2×200 mL) and saturated NaCl solution (2×200 mL), dried over Na2SO4, decanted and concentrated under reduced pressure yielding a crude yellow liquid (2.1 g). A portion of the crude product (1.3 g) was purified by distillation under reduced pressure at 80° C. yielding 1-bromo-3-fluoro-5-(2,2,2-trifluoroethoxy)benzene as a colorless oil (0.70 g, 35% yield). 1H NMR (CDCl3, 400 MHz): 7.05 ppm (d, 1H), 6.90 ppm (s, 1H), 6.55 ppm (d, 1H), 4.32 ppm (q, 2H).
Reaction SMILES: C(OP([CH:9]1[S:13][CH2:12][CH2:11][S:10]1)(OCC)=O)C.CCCCCC.C([Li])CCC.[CH:25]1[CH:30]=[CH:29][C:28]([C:31]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=O)=[CH:27][CH:26]=1.[Cl-].[Na+]>O1CCCC1>[O:35]([C:34]1[CH:26]=[CH:27][C:28]([C:29](=[C:9]2[S:10][CH2:11][CH2:12][S:13]2)[CH2:30][CH3:25])=[CH:31][CH:33]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOP(=O)(OCC)C1SCCS1
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=C1SCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
2-Diethoxyphosphoryl-1,3-dithiolan, 3.0 g, was dissolved in 30 ml of tetrahydrofuran and 7.75 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -65° C. The mixture was stirred at the same temperature for an hour. Then, a solution of 2.55 g of 4-phenoxypropiophenone in 9 ml of tetrahydrofuran was dropwise added to the mixture at the same temperature. The reaction mixture was gradually warmed to room temperature overnight. This suspension was poured onto saturated sodium chloride aqueous solution and the mixture was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 2.60 g of the product.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:21][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CBr)c2ccccc12
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)c1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CC(C)c2ccccc2)[nH]n1
Yield: 6.9 %

Procedure:
Hydrazine hydrate (0.134 mL, 2.76 mmol) was added to a stirring room temperature solution of 56 0.7230 g, 2.76 mmol) in EtOH (2.8 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (50 min): The reaction was concentrated and purified by preparative reverse phase HPLC with the following conditions: 0 to 24 min, 55:45 H2O:CH3CN; 24-25 min, 55:45 to 0:100H2O:CH3CN; 20 mL/min.; λ=214 nM; 100 mg/mL, 0.2 mL/injection. 0.0489 g of 57 was obtained. 1H (CDCl3, 300 MHz): δ 10.77 (1H, broad s), 7.36-7.14 (5H, m), 6.49 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.16-2.86 (3H, m), 1.33 (3H, t, J=7.0 Hz), 1.27 (3H, d, J=5.9 Hz) ppm. 13C (CDCl3, 75 MHz): δ 162.01, 145.94, 145.75, 141.50, 128.43, 126.76, 126.32, 106.98, 60.87, 39.94, 34.64, 21.34, 14.12 ppm. DEPT (CDCl3, 75 MHz): CH3 carbons: 21.34, 14.12; CH2 carbons: 60.87, 34.64; CH carbons: 128.43, 126.77, 126.32, 106.98, 39.94 ppm. HPLC: 10.052 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[CH:5]=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 1-L round-bottomed flask was charged with 3,4-dichlorobenzaldehyde (25.0 g, 143 mmol), 2-methylpropane-2-sulfinamide (17.3 g, 143 mmol), and 200 mL of THF. To this was added Ti(OEt)4 (65.2 g, 286 mmol) over 5 min. The reaction was stirred at rt for 5 h and then poured onto brine. The resulting white precipitate was removed by filtration, and the filter cake was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layers were combined and dried (MgSO4), filtered, and concentrated to give (E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=[CH:15]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C3CN(C(=O)OC(C)(C)C)C3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ccc3c2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-(1-Triisopropylsilanyl-1H-indol-5-yl)-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 64% purity, 1.63 mmol) was dissolved in THF (20 ml). Tetrabutylammonium fluoride (3.25 ml, 1 molar solution in THF) was added and the reaction mixture was stirred for 5 minutes at room temperature. The reaction mixture was concentrated, and the residue was dissolved in H2O (50 ml) and diethyl ether (50 ml). The crude product was purified by silica gel chromatography with dichloromethane as eluent, yielding the purified product (275 mg, 51% for 2 steps).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:20])=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10]([C:21]([OH:23])=O)=[C:9]1[CH:24]([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][NH2:32]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:20])=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10]([C:21]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([F:36])=[C:28]([F:27])[CH:29]=2)=[O:23])=[C:9]1[CH:24]([CH3:25])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)O)c2cc(F)c([N+](=O)[O-])cc2n1Cc1ccccc1
Reactant: NCc1ccc(F)c(F)c1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c([N+](=O)[O-])cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylic acid (Compound 170) and 3,4-difluorobenzylamine by General Procedure C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH2:16]>CC(C)=O>[CH:1]1[C:2](=[O:16])[CH:3]=[CH:4][C:5]2=[N:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=12
Reactant: O
Reactant: C1=Cc2ccccc2Nc2ccccc21
Solvent: CC(C)=O
Product: O=c1ccc2nc3ccccc3ccc-2c1
Temperature: 4 °C
Yield: 34 %

Procedure:
To a solution of Na2HPO4 (2.5 g, 9.32 mmol) in water (95 mL) was added (KSO3)2NO (1.8 g, 12.7 mmol). This solution was added to a solution of the (Z)-5H-dibenzo[b,f]azepine (0.5 g, 2.59 mmol) in acetone (50 mL). This reaction mixture was stirred at 4° C. over night. The solid was filtered and the filtrate was evaporated. The residue was dissolved in ether and water. The 2 layers were split. The organic layer and the solid were mixed and evaporated. The crude product was purified by flash chromatography to afford title compound 374 (170 mg, 34%). MS (m/z): 207 (M+H). Step 2: (Z)-5H-dibenzo[b,f]azepin-2-ol (375)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[C:36](=[O:42])[CH:35]=[CH:34]2.C(OC(=O)C)C.[ClH:49]>C(OCC)(=O)C.CN(C=O)C>[ClH:49].[ClH:49].[CH3:41][N:37]1[C:38]2[C:33](=[CH:32][C:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:11]([CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[CH3:7])[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]1=[O:42]
Reactant: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Reactant: Cc1ccccc1CNCCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1CN(CCCCCOc1ccc2c(ccc(=O)n2C)c1)CCc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Potassium carbonate(360 mg) and (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine(591 mg) were added to a DMF solution (6.5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one(650 mg). The mixture was stirred at 60° C. for 8 hours. Ice water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate: methanol: aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(1.0 ml) was added to an ethyl acetate solution(20 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound(270 mg) as a pale yellow amorphous solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Sodium hydride (461 mg, 11.5 mmol) was slowly added to a solution of 3-bromo-6-nitro-1H-indole (2.32 g, 9.61 mmol) in tetrahydrofuran (10.0 mL). After stirring for 5 min, benzenesulfonyl chloride (1.47 mL, 11.5 mmol) was added dropwise over 10 min. The reaction was stirred an additional 1.5 h before quenching with 5.0 mL of methanol, followed by 10.0 mL water and 20.0 mL methylene chloride. The precipitate was filtered off and washed with an excess of methylene chloride and methanol to give a crème-colored powder for 3-bromo-6-nitro-1-(phenylsulfonyl)-1H-indole (2.80 g, 7.35 mmol, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH2:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:25][N:26]([CH:28]=O)[CH3:27]>C(Cl)Cl>[CH3:25][N:26]([CH:28]=[N:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH2:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:27]
Reactant: CN(C)C=O
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OCC
Temperature: 55 °C

Procedure:
To a stirred solution of methyl 2-amino-4,5-diethoxybenzoate (4.79 g, 20 mmol) in 20 ml of DMF at 0° C. was added phosphorous oxychloride (2.24 ml, 24 mmol) during 15 m. The mixture was warmed to 55° C. and stirred for 45 m. The resulting solution was diluted with methylene chloride, cooled to 0° C., and treated with 80 ml of precooled N/1 sodium hydroxide during 5 m. The organic layer was separated and washed at 0° C. with with water. The solution was dried and concentrated to give an amber oil; NMR (CDCl3) δ 3.00(s, ME2N).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[N:1]1([S:44]([C:40]2[CH:39]=[C:38]([C:34]3[CH:33]=[C:32]([C:18]4[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=5)[N:19]=4)[CH:37]=[CH:36][N:35]=3)[CH:43]=[CH:42][CH:41]=2)(=[O:45])=[O:46])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCCC1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of pyrrolidine (0.065 g, 0.91 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example 1.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.17 g, 85%). MS (ISP) 578.6 [(M+H)+]; mp 184° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([C:13]([NH:15][CH:16]([C:18]1[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=1)[N:23](C1CCCCO1)[N:22]=[CH:21]3)[CH3:17])=[O:14])=[CH:6]2.CO>>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([CH:16]([NH:15][C:13]([C:7]3[CH2:8][O:9][C:10]4[C:5]([CH:6]=3)=[CH:4][C:3]([Cl:2])=[CH:12][CH:11]=4)=[O:14])[CH3:17])=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: CC(NC(=O)C1=Cc2cc(Cl)ccc2OC1)c1ccc2c(cnn2C2CCCCO2)c1
Agent: Cl
Solvent: CO
Product: CC(NC(=O)C1=Cc2cc(Cl)ccc2OC1)c1ccc2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a stirred solution of 6-chloro-N-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-2H-chromene-3-carboxamide (178 mg, 0.4 mmol) in methanol (5 mL, 0.1 mol) at room temperature. The mixture was heated to 50° C. and stirred for 1 hour. TLC indicated complete reaction, so after allowing to cool, the mixture was concentrated under vacuum and the residue partitioned between sat'd NaHCO3 (30 mL—care: initial evolution of gas as reaction with excess acid ensues) and EtOAc (50 mL). The organic layer was washed with brine (1×20 mL), dried (MgSO4), filtered and the solvent removed under vacuum to leave a crude solid. The solid was triturated with EtOAc (10 mL) and filtered. The filter cake was washed with EtOAc (2×3 mL) to give the product (35 mg). m/z=354.3 (M+1)+. 1H NMR (400 MHz; DMSO-d6) δ 13.00 (s, 1H), 8.64 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (m, 1H), 7.32-7.24 (m, 3H), 6.86 (d, J=8.4 Hz, 1H), 5.21-5.13 (m, 1H), 4.97-4.88 (m, 2H), 1.48 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A solution of 4-(phenylsulfonyl)benzoic acid (80 mg, 0.3 mmol) in dichloromethane (15 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) and triethylamine (61 mg, 0.6 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(phenylsulfonyl)benzamide as a light yellow solid (108 mg, 90.7%). LRMS (M+H+) m/z: calcd 396.11. found 396. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.63 (t, J=4.8 Hz, 1H), 8.03-7.98 (m, 6H), 7.76-7.63 (m, 3H), 5.88 (s, 1H), 4.31 (d, J=4.8 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:38][C:39]1[CH:75]=[CH:74][CH:73]=[CH:72][C:40]=1[CH2:41][NH:42][C:43]([C@@H:45]1[C:49]([CH3:51])([CH3:50])[S:48][CH2:47][N:46]1[C:52](=[O:71])[C@@H:53]([OH:70])[C@@H:54]([NH:62][C:63](=[O:69])[C@H:64]([CH:66]([CH3:68])[CH3:67])[NH2:65])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:44]>C(OCC)(=O)C>[CH3:38][C:39]1[CH:75]=[CH:74][CH:73]=[CH:72][C:40]=1[CH2:41][NH:42][C:43]([C@@H:45]1[C:49]([CH3:51])([CH3:50])[S:48][CH2:47][N:46]1[C:52](=[O:71])[C@@H:53]([OH:70])[C@@H:54]([NH:62][C:63](=[O:69])[C@H:64]([CH:66]([CH3:68])[CH3:67])[NH:65][C:13](=[O:15])[CH2:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:44]
Reactant: O=C(O)COc1cccc2cnccc12
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)COc2cccc3cnccc23)C(C)C)CSC1(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
5-isoquinolinyloxyacetic acid (64 mg), HOBt (43 mg), and EDC.HCl (60 mg) were added to H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% NaHCO3 and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was reprecipitated from ethyl acetate/n-hexane to obtain the title compound (168 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1.O>CN(C)C=O>[C:20]1([C:18]2[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][N:15]([CH2:14][C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:39][C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)[CH:5]=4)[CH:10]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (599 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Picolyl chloride (230 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[6-(3-pyridylmethoxy)-2-naphthylmethyl]-3-pyrrolyl]propionate (647 mg, yield: 88%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].NC(N)=[S:15].O.N>C(O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:15])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CCl)cc1
Reactant: NC(N)=S
Agent: N
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc(CS)cc1
Yield: 80.9 %

Procedure:
A mixture of 2.00 g (10.9 mmol) 1-allyloxy-4-chloromethyl-benzene and 917 mg (12.1 mmol) thiourea in 3.0 ml ethanol was heated to reflux for 7 h. Solvents were distilled off and the crystalline residue was washed with cold ethanol and isolated by filtration. After addition of 2.5 ml ethanol, 1.0 ml water and 0.7 ml 25% aqueous ammonia, the mixture was heated to reflux for 1 h. Ethanol was distilled off, then acidified with 0.5 ml half conc. HCl and extracted with ethyl acetate. The solution was dried over MgSO4 and solvents were removed in vacuo to yield 1.59 g (81%) colorless oil, which was used immediately.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:12][C@H:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH3:11]
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)c1cccc(N)c1
Yield: 99.9 %

Procedure:
A mixture of (1S)-1-(3-nitrophenyl)ethanamine (13.1 g, 79.4 mmol) and 10% palladium on carbon (0.75 g) in methanol (250 mL) was stirred vigorously under an atmoshphere of hydrogen for 19 hours. After this time the mixture was filtered through a pad of Celite and the pad was washed with methanol (800 mL). The combined filtrates were concentrated under reduced pressure to give 3-[(1S)-1-aminoethyl]aniline as a brown solid (10.8 g, 100%).