Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH3:14]>>[NH2:14][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: N
Product: N#Cc1ccc(C(F)(F)F)c(N)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A closed pressure tube charged with 3-fluoro-4-trifluoromethyl-benzonitrile (10.0 g; 52.9 mmol) and liquid NH3 (60 mL) was heated for 6 days at 90° C. The tube was cooled to −60° C. and opened. The mixture was allowed to stir for 1 h at rt, washed with brine, extracted with EtOAc, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]4[CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.67 (m, 1 H), 1.80-1.89 (m, 3 H), 2.90 (s, 3 H), 3.19-3.29 (m, 2 H), 3.34-3.41 (m, 1 H), 3.53-3.61 (m, 1 H), 3.64-3.71 (m, 1 H), 3.77-3.87 (m, 1 H), 3.97-4.08 (m, 1 H), 4.14 (s, 2 H), 4.35 (t, J=6.18 Hz, 2 H), 7.10-7.18 (m, 2 H), 7.26 (t, J=5.76 Hz, 1 H), 7.40 (dd, J=8.14, 5.48 Hz, 2 H), 8.11 (s, 1 H), 8.55 (s, 1 H), 10.39 (t, J=5.97 Hz, 1 H), 17.10 (s, 1 H); ES+ MS: 519 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([N:19]=[C:20]=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Cl)c(O)c2)no1
Temperature: 70 °C

Procedure:
A mixture of 5-amino-2-chlorophenol (1.0 g, 6.97 mmol) and 5-tert-butyl-3 isocyanatoisoxazole (1.16 g, 6.97 mmol) in toluene (40 mL) was heated at 70° C. overnight. It was purified by silica gel chromatography with 0-25% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3-hydroxyphenyl)urea as solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH:35]1([N:39]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1>CN(C=O)C.O.C(N(CC)CC)C>[CH:35]1([N:39]2[CH2:45][CH2:44][CH2:43][N:42]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([B:4]4[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]4)=[CH:17][CH:16]=3)=[O:15])[CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(C(=O)N3CCCN(C4CCC4)CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.24 g) in dry DMF (30 ml) was treated with EDC (1.48 g) and HOBT (0.67 g). The reaction mixture was stirred at rt for 5 min, followed by the addition of 1-(cyclobutyl)hexahydro-1H-1,4-diazepine dihydrochloride (D4) (1.13 g) and triethylamine (2.7 ml). The mixture was stirred at rt overnight. The reaction mixture was then poured into water (250 ml) and extracted with EtOAc (2×35 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate (2×30 ml) followed by water (5×30 ml). After drying (magnesium sulphate) the solution was evaporated to give the title compound (D7) as an oil (0.84 g).MS electrospray (+ve ion) 385 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:21])[C:6]=2[CH:22]=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[CH3:23])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 7-chloro-5-oxo-1-(6-aminonicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in pyridine (2 ml) is added with stirring 2-methylbenzoyl chloride (0.18 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid solution and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) as colorless amorphous.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)[CH2:14][CH2:13][CH2:12]2.[C:25](O)([CH3:28])([CH3:27])[CH3:26].[OH-].[Na+]>O>[C:25]([C:18]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:19][C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)=[CH:10][C:9]=1[O:8][CH3:7])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc2c(c1)CCCC2Cc1c[nH]cn1
Reactant: CC(C)(C)O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1C(C)(C)C)C(Cc1c[nH]cn1)CCC2
Temperature: 37.5 °C
Reaction time: 15 h

Procedure:
Sulfuric acid (0.75 ml) is added into the mixture of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole hydrochloride (75 mg) and tert-butanol (3 ml). The mixture is stirred at 35-40° C. for 15 hours. The reaction mixture is poured into water and is made alkaline with sodium hydroxide. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated to dryness. The residue consisting of crude product is coverted to its hydrochloride salt in ethyl acetate. The yield is 40 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].C(Cl)Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)Nc1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Added 3′-fluoroacetanilide (3.06 g, 20 mmol) cautiously to concentrated sulfuric acid (6 mL) at 5° C. To the resulting solution, added fuming nitric acid (1.05 mL, 25 mmol) dropwise while maintaining temperature at 5–10° C. After 30 min, added ice (50 g), later diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated to give the crude product (4.0 g) as a mixture of isomers (1:1.4 ratio of 4′-nitro/2′-nitro). The desired isomer, 3′-flouro-4′-nitroacetanilide, was isolated by flash chromatography (DCM-5% MeOH/DCM) in low yield (1.2 g, 30%) as a yellow solid. 1H-NMR (CDCl3): δ 8.08 (1H, app t), 7.82 (1H, dd), 7.41 (1H, br s), 7.21 (1H, m), 2.25 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20](=[O:23])(=[O:22])[NH2:21])[CH:17]=2)[O:12][CH2:11]1)=[O:8].[OH-].[Na+].[CH3:31][NH:32][C:33](=[O:38])C(Cl)(Cl)Cl.C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20]([NH:21][C:33]([NH:32][CH3:31])=[O:38])(=[O:22])=[O:23])[CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NC1COc2cc(OC)c(S(N)(=O)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 0 °C

Procedure:
1.71 g (4 mmol) of 3-(5-chloro-2-methoxybenzamido)-6-sulfamoyl-7-methoxychroman were heated at 80° C. for 30 minutes in 10 ml of dry DMSO after addition of 0.4 g (10 mmol) of freshly powdered sodium hydroxide and 1.05 g (6 mmol) of N-methyltrichloroacetamide. The cooled reaction mixture was introduced into ice-water, clarified with active charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized twice from ethanol. The product had a melting point of 256°-257° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[C:17](P(C(C)(C)C)C(C)(C)C)(C)([CH3:19])[CH3:18].C1(C)C=CC=CC=1.[Br-].C([Zn+])(C)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)([CH3:19])[CH3:18]
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Zn+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1cccc2c1CCOC2C1=NCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (0.25 g, synthesis method A), palladium(II) acetate (0.01 g), tri-tert-butylphosphine (0.044 ml) and toluene (3 ml) in ice bath temperature was added 6.22 ml of 0.5M isopropyl zinc bromide in THF, and stirred at ambient temperature for 3 hrs. The reaction was quenched with dilute hydrochloric acid, and the organic phase was separated. The aqueous phase was made alkaline with 1M NaOH, and purified with separation methods A and G to yield the title compound. (Yield 2 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:11]=1[CH2:12][CH2:13][C:14](OC)=[O:15])=[O:9])(=[O:3])[CH3:2].[NH3:23]>CO>[CH3:2][C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:11]=1[CH2:12][CH2:13][C:14]([NH2:23])=[O:15])=[O:9])=[O:3]
Reactant: COC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Reactant: N
Solvent: CO
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(N)=O

Procedure:
8.15 g (0.025 mol) of methyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate are stirred at room temperature for 30 hours in 200 ml of a solution of ammonia in methanol. After concentration of the solution the residue is extracted with methylene chloride/water, dried with magnesium sulfate, the solvent is distilled in a vacuum. The residue is chromatographed on silica gel with chloroform-methanol (9:1). Recrystallization from methanol/ether yields 2-(4-acetamidobutyryl)-5-chlorohydrocinnamide as white crystals with melting point 149°-151°.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]1.[Cl-].[CH:20]1([CH2:26][CH2:27][CH2:28][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][CH2:27][CH:28]=[C:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=3[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOc1c(NC2CCC(=O)CC2)ccnc1C
Reactant: c1ccc([P+](CCCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: CCOc1c(NC2CCC(=CCCC3CCCCC3)CC2)ccnc1C
Yield: 42 %

Procedure:
Preparation was carried out analogously to Example 27 from 4-(4-oxocyclohexylamino)-3-ethoxy-2-methylpyridine and 3-cyclohexylpropyltriphenylphosphonium chloride. Yield: 42%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20](Br)=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14].[CH3:27][O-:28].[Na+]>C(#N)C.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20]([O:28][CH3:27])=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(OC)ncc(Br)n2n1

Procedure:
A solution of 686 mg (1.35 mmol) of N-(2-fluoro-6-methoxycarbonylphenyl)-5,8-dibromo[1,2,4]triazolo-[1,5-a]pyrazine-2-sulfonamide in 10 mL dry acetonitrile was treated with 3.0 mL (3.0 mmol) of a 1M solution of 15 sodium methoxide in dry methanol at 0° C. with stirring. The reaction was quenched after 5min with 0.5mL of glacial acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was triturated with water and the resulting light brown solid was collected by filtration and dried in a vacuum oven. This crude material was purified by flash column chromatography on silica gel using a 0.5 to 2percent ethanol/dichloromethane gradient as eluent to obtain 538 mg (87 percent of theory) of the title compound as a white glassy foam solid melting at 201°-202° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])=O)(C)(C)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl-].[NH4+]>C(#N)C.C(OCC)(=O)C>[CH2:19]([N:10]1[C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[NH:8][C:9]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1[nH]c2ccc(Br)cc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A mixture of 5-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (2.5 g, 8 mmol), benzyl bromide (1.2 mL, 10 mmol), potassium carbonate (1.38 g, 10 mmol), and potassium iodide (50 mg) in anhydrous acetonitrile was heated at 80° C. under nitrogen for 1 hour. The reaction mixture was cooled to room temperature and treated with a saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL) and dried (MgSO4). After removal of the solvent, the residue was taken up in trifluoroacetic acid (10 mL, neat) and the solution was stirred at room temperature under nitrogen for 10 minutes. The reaction solution was then treated with brine (30 mL) and ethyl acetate (50 mL). The organic layer was separated and dried (MgSO4). After removal of the solvent, the residue was applied to a pad of silica gel to afford the title compound as white solid (1.89, 78%): mp 245-246° C.; 1H-NMR (DMSO-d6) δ 11.2. (s, 1H), 7.37-7.27 (m, 6H), 7.13 (dd, 1H, J=8.25, 2.25 Hz), 6.95 (d, 1H, J=8.25 Hz), 5.0 (s, 2H); MS (ES) m/z 301([M−H]−, 50%), 303([M−H]−, 50%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2nc(Cl)sc2c1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Temperature: 125 °C
Reaction time: 12 h

Procedure:
To the solution of 7-bromo-2-chloro-6-methoxybenzo[d]thiazole (150 mg, 0.539 mmol, 1.0 eq) in 1 mL of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (0.123 mg, 0.809 mmol, 1.5 eq) and DIPEA (263 μL, 1.503 mmol, 2.8 eq) at room temperature. The reaction mixture was stirred at 125° C. for 12 hours, thereafter the mixture was diluted with saturated sodium bicarbonate solution (ca. 100 mL) and aqueous layer extracted with ethyl acetate (ca. 200 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give crude product as brown oil which was sufficiently pure and was carried to next step without further purification. LC/MS (m/z) [359.0] (MH+)
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1([CH2:6][O:7][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:5][O:4][CH2:3]1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a mixture of (3-methyl-oxetan-3-yl)-methanol (10.2 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 mL) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (18 g).
Reaction SMILES: [C:1]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:20]([CH3:38])[C@H:21]([C:34]([O:36][CH3:37])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C.CC(C)N=C=NC(C)C.CCOCC>[C:1]([N:11]([CH3:19])[C@H:12]([C:16]([N:20]([CH3:38])[C@H:21]([C:34]([O:36][CH3:37])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)OC
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 3.25 g of Z-N-Me-Val-OH, 2.2 g of N-Me-Tyr(3-tBu)-OMe and 1.88 g of HOBT in DMF (30 ml), DIC (1.9 ml) was added under cooling with ice and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture and extraction was effected with ether. The extract was washed with saturated brine and the organic layer was dried with sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe in the amount of 1.96 g (47%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:52][C@H:51]([CH2:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=1)[CH2:53][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:13][CH2:14]2)=[CH:23][CH:24]=1
Reactant: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 21.9 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methyl-2-thienyl)methanone (0.174, 0.507 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.206 g, 0.51 mmol) according to Procedure G to give the title compound (0.083 g, 0.111 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:43])[C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([N:25]2[C:36](=[O:37])[C:35]4[C:34](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:33]2=[O:43])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N)nccc3c2)C1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N4C(=O)c5ccccc5C4=O)nccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of (S)-3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid tert-butyl ester (380 mg, 1.11 mmol) and triethylamine (1.5 ml, 11.1 mmol) in anhydrous tetraydrofuran (1.5 ml) was added phthaloyl dichloride (170 μL, 1.16 mmol). The mixture was stirred at ambient temperature for 2 h and then poured into quickly stirring water. The mixture was extracted with dichloromethane (3×50 ml) and concentrated in vacuo to give a residue. Flash chromatography of the residue on silica (eluent: 0-100% ethyl acetate in heptane) gave (S)-3-[1-(1,3-dioxo-1,3-dihydroisoindol-2-yl)isoquinolin-6-yloxy]piperidine-1-carboxylic acid tert-butyl ester (390 mg) E1l-MS: m/z=474.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:24][C:25](=[O:27])[CH3:26])=[N:10][C:11]2[CH:12]=[CH:13][C:14]3[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:15]=3[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C:8]1[C:9]([NH:24][C:25](=[O:27])[CH3:26])=[N:10][C:11]2[CH:12]=[CH:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(ccc3nc(NC(C)=O)c(Cc4ccccc4)nc32)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Reaction time: 3 h

Procedure:
Under an argon atmosphere, to a suspension of N-(2-benzyl-8-methoxybenzo[f]quinoxalin-3-yl)acetamide (60.0 mg, 168 μmol) in anhydrous dichloromethane (2 mL) was added boron trifluoride (1.0 M in dichloromethane) (840 μL, 840 μmol) at 0° C. After elevating to room temperature, the mixture was stirred for 3 hours. To the mixture was then added a solution of saturated sodium hydrogencarbonate, and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave N-(2-benzyl-8-hydroxybenzo[f]quinoxalin-3-yl)acetamide (13) as a crude yellow solid product. The product was used for the subsequent reaction without any further purification. TLC Rf=0.36 (n-hexane/ethyl acetate=1/2); 1H NMR (500 MHz, CD3OD) δ 2.17 (s, 3H), 4.50 (s, 2H), 7.20-7.32 (m, 9H), 7.78 (d, 1H, J=9.0 Hz), 7.96 (d, 1H, J=9.0 Hz), 9.44 (d, 1H, J=7.5 Hz).