Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[C:19]([C:21]1[CH:22]=[C:23]([CH:59]([CH3:61])[CH3:60])[C:24]2[O:28][C:27]([C:29]3[CH:57]=[CH:56][C:32]([C:33]([NH:35][CH2:36][CH:37]4[CH2:42][CH2:41][N:40]([C:43](OCC5C=CC([N+]([O-])=O)=CC=5)=[O:44])[CH2:39][CH2:38]4)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:58]=1)#[N:20]>O1CCCC1>[C:19]([C:21]1[CH:22]=[C:23]([CH:59]([CH3:61])[CH3:60])[C:24]2[O:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([NH:35][CH2:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:14][CH2:13][C:5]5[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=5)=[O:44])[CH2:41][CH2:42]4)=[O:34])=[CH:56][CH:57]=3)=[N:26][C:25]=2[CH:58]=1)#[N:20]
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)cc3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)cc3)oc12
Reaction time: 0.08 h
Yield: 21.6 %

Procedure:
To a solution of [3,5-bis(trifluoromethyl)phenyl]methanol (17 mg) in tetrahydrofuran (5 ml) was added sodium hydride (5 mg, 60% dispersion in mineral oil). The mixture was allowed to stir for 5 min, and then 4-nitrobenzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate (20 mg) was added. The reaction mixture was stirred overnight at room temperature, and then was concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column, eluting at 15 mL/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (5 mg, 21%). Mass spectrum (ESI) 673.1 (M+1). NMR signals are doubled and broadened because of restricted rotation about the amide C—N bond. 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8 Hz, 2H), 7.95 (m, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.80 (s, 2H), 7.52 (s, 1H), 6.316 (app t, 1H), 5.23 (s, 2H), 4.23 (m, 2H), 2.82-2.90 (m, 2H), 1.89-1.93 (m, 1H), 1.83 (m, 3H), 1.73 (m, 3H), 1.46 (d, J=7 Hz, 6H), 1.21-1.31 (m, 4H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 42 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 3-nitrobenzenesulfonyl chloride under the conditions used in example 2 giving 42% of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23]>C1COCC1>[S:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:25]([O:24][CH2:22][CH3:23])=[O:26]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 3.5 h

Procedure:
A solution of tert-butyl 4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate in dry THF was cooled to −78°, n-butyl lithium (1.5 eq.) was added slowly and reaction mixture stirred for 3-4 hrs. This reaction mixture was then added to the solution of ethylchloroformate (10 eq.) in dry THF at −78° C. Reaction mass wan then allowed to come at room temperature and stirred overnight. It was then cooled and quenched with ammonium chloride solution and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude was then purified using column chromatography to yield 6-tert-butyl 2-ethyl 4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16](=[O:18])[N:21]([O:22][CH3:23])[CH3:20])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 81 g (314.77 mmol) trans-4-[(tert-Butoxyformamido)methyl]cyclohexanecarboxylic acid in 4 l CH2Cl2 was treated with 50.13 g (503.63 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 55.37 ml (503.63 mmol) N-methylmorpholine and at 0° C. with 78.45 g (409.2 mmol) EDCI and 9.67 g (62.95 mmol) HOBT. The reaction mixture was stirred 16 h at room temperature, evaporated and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 100.03 g (quantitative) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester, MS: 301 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([CH2:20]O)[CH:15]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(Cl)(Cl)Cl>[Cl:3][CH2:20][C:16]1[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Solvent: ClC(Cl)Cl
Product: ClCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (0.184 mL, 2.52 mmol) was added dropwise to a stirred solution of (6-((3,4-dichlorophenyl)amino)pyrimidin-4-yl)methanol (0.17 g, 0.629 mmol) in chloroform at 0° C. The mixture was allowed to warm to room temperature and further stirred for 18 h. After concentration, the crude product 6-(chloromethyl)-N-(3,4-dichlorophenyl)pyrimidin-4-amine (0.08 g, 75%) was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (1H, br. s.), 8.81 (1H, s), 8.20 (1H, s), 7.64 (2H, s), 7.11 (1H, s), 4.76 (2H, s). LCMS: R.T.=3.48; [M+H]+=287.91.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:17])[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].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:66][CH2:67]I>O1CCOCC1>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:21][C:22]([CH3:26])([CH3:27])[C:23]([O:25][CH2:67][Cl:66])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCCl
Reaction time: 0.08 h
Yield: 64.5 %

Procedure:
To a solution of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid (16.0 g, 24 mmol) in dioxane (500 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (14.3 mL). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (500 mL) and then chloroiodomethane (17.5 mL, 240 mmol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 400 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 11.0 g of chloromethyl 5-(N-CBz-L-valyloxy)4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: [CH3:1][C@@H:2]([N:24]([CH2:32][C@@H:33]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[O:34][Si](CC)(CC)CC)C(=O)OC(C)(C)C)[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C@@H:2]([NH:24][CH2:32][C@@H:33]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[OH:34])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@H:14]([CH3:23])[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: C[C@H](Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)NC[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
Further, to a solution of tert-butyl (1R)-1-methyl-2-(7-(((1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl)oxy)-1H-indol-3-yl)ethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)carbamate (190 mg, 0.285 mmol) in ethanol (2.0 mL) is added a 4N hydrochloric acid/dioxane (2.0 mL, 8.0 mmol), and the mixture is stirred at room temperature for 14 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and the mixture is extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform/methanol=100/1→100/4) to give the title compound (107 mg, yield: 83%).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH2:23]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(OCc4ccccc4)cc3)n2)c1

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.51 g of 4-phenylmethoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was boiled with 30 ml of ethyl acetate, insoluble constituents were filtered off and the solution was treated at boiling with 20 ml of hexane. 0.5 g of 4-benzyloxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide separated as beige crystals upon cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14](O)[CH:13]=[C:12]([CH3:17])[N:11]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([S:9][CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:18])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(SCc2c(Cl)cncc2Cl)n1
Product: Cc1cc(Cl)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 75 °C
Yield: 47.1 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.0 g, 6.62 mmol) and phosphoryl trichloride (20 mL) was heated at 75° C. for 1 hour. The solvent was evaporated, and the crude residue was extracted into ethyl acetate (2×100 mL). The organic layer was washed with 10% sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated, and the residue was purified by CombiFlash using 0-5% methanol in dichloromethane to provide 4-chloro-2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidine as a white solid (1.01 g, 47.1% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 4.70 s, 2H), 7.40 (s, 1H), 8.66 (d, 2H); M+1 321.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][N:28]([CH2:30][CH:31]1[CH:36]([NH2:37])[CH:35]2[CH2:38][CH2:39][N:32]1[CH2:33][CH2:34]2)[CH3:29]>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:37][CH:36]2[CH:35]3[CH2:38][CH2:39][N:32]([CH2:33][CH2:34]3)[CH:31]2[CH2:30][N:28]([CH3:29])[CH3:27])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CN(C)CC1C(N)C2CCN1CC2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1C2CCN(CC2)C1CN(C)C
Temperature: -55 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.22 g, 11 mmoles) and triethylamine (1.12 g, 11 mmoles) in anhydrous methylene chloride (35 ml) under nitrogen was cooled (0° C.) and treated dropwise with ethyl chloroformate (1.2 g, 11 mmoles). After 45 minutes at 0° C., the solution was cooled (-55° C.) and treated dropwise with 2-(dimethylaminomethyl)-1-azabicyclo[2.2.2]octan-3-amine (2.11 g, 11.5 mmoles) in 7 ml of methylene chloride. The solution was warmed to 25° C. over one hour, stirred for one hour, and diluted with methylene chloride to a total volume of 100 ml. The organic solution was washed with 1.0N sodium hydroxide (2×35 ml), saturated aqueous sodium bicarbonate (35 ml), and brine (35 ml), dried (Na2SO4), and concentrated in vacuo to provide 2.94 g (73%) of an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:12]([O:14][CH3:15])=[O:13])[C@H:3]1[OH:24].[CH3:25][C:26]([CH3:28])=O>C1C=CC=CC=1>[CH2:17]([O:16][C:7]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[C@@H:3]([OH:24])[C@H:2]([NH:1][CH:26]([CH3:28])[CH3:25])[CH2:11][CH2:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Reactant: CC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](NC(C)C)[C@@H]2O

Procedure:
500 mg. of trans-2-amino-6-benzyloxy-1hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene is dissolved in a mixture of 3 ml. of acetone and 10 ml. of anhydrous benzene and the solution is heated on reflux for 5 hours. The reaction mixture is concentrated under reduced pressure and 10 ml. of ethanol is added to the residue. After the addition of 100 mg. of sodium borohydride with stirring, the mixture is stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure, and water and ethyl acetate are added to the residue. The mixture is extracted with ethyl acetate. The organic solvent layers are pooled, washed with water, dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-n-hexane to obtain trans-6-benzyloxy-2isopropylamino-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene as colorless needles melting at 91°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:16][CH2:17][C:18](Br)=[O:19]>C(#N)C>[Br:16][CH2:17][C:18]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]3[C:14](=[CH:15][C:2]=2[NH2:1])[CH:13]=[CH:12][CH:11]=[N:10]3)[N:7]=1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1cc2cccnc2c2ncccc12
Solvent: CC#N
Product: Nc1cc2cccnc2c2nc(C(=O)CBr)ccc12

Procedure:
5-Amino-1,10-phenanthroline (2) (Preparation 1; 1.28 g; 6.54 mmol) was dissolved with heating in 200 ml anhydrous acetonitrile. Into this solution, was added bromoacetyl bromide (Aldrich; 6.60 g; 32.7 mmol) in 7.2 ml anhydrous acetonitrile.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (80 mg, 0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in 2ml of dry THF was added potassium tert-butoxide (35 mg, 0.31 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 91 mg (83%) of the title compound as yellow solid, mp 16-162° C. 1H NMR (CDCl3) δ7.62 (d, 1H), 6.87 (s, 2H), 6.18 (s, 1H), 3.40 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[C:15]=2[CH3:24])(=[O:13])=[O:12])=[C:6]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=1)(=[O:3])[CH3:2].[Br-:29].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:29][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[C:15]=2[CH3:24])(=[O:12])=[O:13])=[C:6]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(F)cc3c2C)c(S(C)(=O)=O)c1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1c(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.5 %

Procedure:
Into 4.0 mL of chloroform was dissolved 200 mg of Compound 19, and 194 mg of benzyltrimethylammonium tribromide was added, followed by 1 hour of stirring at room temperature. The reaction was terminated by adding water to the reaction solution and then the solvent was once removed by evaporation. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was washed with methanol to obtain 201 mg of N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide as a colorless solid. The thus obtained N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide (150 mg) was dissolved into a mixed solution of 1.5 mL of dioxane and 1.5 mL of ethanol, and 53 mg of sodium hydrogen carbonate and 26 mg of thioacetamide were successively added, followed by 2 hours of stirring under heating and refluxing. The reaction was terminated by adding water to the reaction solution and then the solvent was removed by evaporation under reduced pressure. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 61 mg of the title compound as light yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[OH:21][C:3]1[CH:4]=[C:5]([C:8]2([CH3:20])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: COc1cc(C2(C)C(=O)Nc3ccccc3C2=O)ccc1O
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(c2ccc(O)c(O)c2)C(=O)Nc2ccccc2C1=O
Yield: 62.7 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(4-hydroxy-3-methoxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (120 mg, 0.40 mmol) and BBr3 (1.60 mL, 1.0 M solution in dichloromethane). After normal workup, the pure objective compound (71 mg, 62%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=3:1): 1H NMR (200 MHz, DMSO-d6) δ 1.57 (s, 3H, CH3), 6.42 (dd, J=8.14, 2.03 Hz, 1H, ArH), 6.59-6.63 (m, 2H, ArH), 7.07 (t, J=7.73 Hz, 2H, ArH), 7.55 (t, J=7.32 Hz, 1H, ArH), 7.68 (d, J=7.32 Hz, 1H, ArH), 9.00 (br s, 1H, OH), 10.93 (br s, 1H, NH); m.p. 259-261° C.; MS(EI) m/e 283 [M+], 268, 255, 237; HRMS m/e cacld. for C16H13N1O4 283.0845, found 283.0849.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([OH:9])=O.[NH2:24][CH2:25][C:26]1[C:27]([F:43])=[C:28]([O:33][C:34]2[CH:35]=[C:36]([CH:39]=[C:40]([Cl:42])[CH:41]=2)[C:37]#[N:38])[C:29]([Cl:32])=[CH:30][CH:31]=1>>[Cl:1][C:2]1[N:3]=[C:4]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[NH:5][C:6]=1[C:7]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][C:34]2[CH:35]=[C:36]([C:37]#[N:38])[CH:39]=[C:40]([Cl:42])[CH:41]=2)[C:27]=1[F:43])=[O:9]
Reactant: CN(C)S(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Product: CN(C)S(=O)(=O)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 59.4 %

Procedure:
4-chloro-2-[(dimethylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.12 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.045 g, 0.14 mmol) were employed using a procedure similar to that described herein to provide the title compound (0.039 g, 59%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% formic acid). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54 (s, 1H), 7.34-7.42 (m, 2H), 7.26 (s, 1H), 7.22 (s, 1H), 4.64 (s, 2H), 2.86 (s, 6H). ES-LCMS: m/z 546.1, 547.9, 550.0 (M+1).