Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.Cl.O1CCOCC1>CO>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:17]1[C:2]([Br:1])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1cc2c(cc1Br)c1ccncc1c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 1.586 mmol) in anhydrous methanol (5 mL) was added a 4 M solution of HCl in 1,4-dioxane (2 mL, 8 mmol) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was then was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC (10 mM ammonium acetate in water; acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-bromo-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (20 mg, 0.049 mmol, 30% yield) as an off-white solid. LC/MS (ESI) m/e 404.1 [(M+H)+, calcd for C19H23BrN3O2 404.1]; LC/MS retention time (method A): tR=1.47 min; HPLC retention time (method A): tR=9.55 min; HPLC retention time (method B): tR=10.23 min; 1H NMR (400 MHz, CD3OD) δ ppm 9.48 (s, 1H), 8.80 (d, J=5.77 Hz, 1H), 8.67 (s, 1H), 8.26 (d, J=5.77 Hz, 1H), 7.15 (s, 1H), 4.37 (dd, J=9.54, 3.76 Hz, 1H), 4.18 (dd, J=9.66, 6.40 Hz, 1H), 3.83 (s, 3H), 3.48-3.56 (m, 1H), 1.89 (m, 1H), 1.51-1.72 (m, 2H), 1.05 (t, J=6.27 Hz, 6H).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([CH:11]3[CH2:13][CH2:12]3)=[N:6][C:5]=2[N:14]=1.N([O-])=O.[Na+].[ClH:19]>[OH-].[Na+]>[Cl:19][C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([CH:11]3[CH2:13][CH2:12]3)=[N:6][C:5]=2[N:14]=1
Reactant: Cl
Reactant: Nc1nc2nc(C3CC3)nc(O)c2s1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(C2CC2)nc2nc(Cl)sc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The compound (1.2 g) obtained in Step 3 was suspended in 2N aqueous sodium hydroxide solution (18 ml) and, under ice-cooling, sodium nitrite (1.2 g) was added in several portions. The obtained suspension was slowly added dropwise to a concentrated aqueous hydrochloric acid solution (18 ml) heated to 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.60 g). The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (0.34 g) containing the title compound as a main component. The obtained crude crystals were suspended in a mixed solvent of hexane and ethyl acetate, collected by filtration and dried to give the title compound (0.26 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]([CH3:26])[NH:7][C:6]=2[S:5][N:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>O1CCCC1>[CH3:34][S:35]([O:1][CH2:2][C:3]1[C:11]2[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]([CH3:26])[NH:7][C:6]=2[S:5][N:4]=1)(=[O:37])=[O:36]
Reactant: CCOC(=O)C1=C(C)Nc2snc(CO)c2C1c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)Nc2snc(COS(C)(=O)=O)c2C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
In an argon stream, 630 mg (1.68 mM) of ethyl 3-hydroxymethyl-6-methyl-4-(3-nitrophenyl)-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate obtained in Example 2 was dissolved in 6 ml of anhydrous tetrahydrofuran, and under ice cooling, 0.62 ml (4.45 mM) of triethylamine was added. A solution of 0.26 ml (3.36 mM) of methanesulfonyl chloride in 2 ml of anhydrous tetrahydrofuran was added dropwise, and reacted at the above temperature for 45 minutes. Water (6 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was then poured into 10% HCl-ice, and extracted with methylene chloride. The methylene chloride layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 927 mg of crude ethyl 3-methanesulfonyloxymethyl-6-methyl-4-(3-nitrophenyl)-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate as a pale yellow jelly-like product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH:15]1([C:18]2[CH:19]=[C:20]([NH2:23])[NH:21][N:22]=2)[CH2:17][CH2:16]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][C:20]2[NH:21][N:22]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[CH:19]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(-c2ccccc2)c(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCO
Product: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Yield: 60 %

Procedure:
To 2,4-Dichloro-5-phenyl-pyrimidine (187 mg, 0.83 mmol) and trethylamine (255 μL, 1.83 mmol) in ethanol (25 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (142 mg, 1.16 mmol) and the solution was heated to 80 C for 14 h. The solvent was removed in vacuum, and the title compound was obtained by flash chromatography (0–2% methanol in dichloromethane) to give: 150 mg (60% yield). HPLC tr=6.68 min (87%), LCMS m/e 312.1 (M+H), 310.0 (M−H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.320 g; 0.86 mmol), LHMDS 1N in THF (1.29 mL; 1.29 mmol), 1-iodopropane (0.168 mL; 1.72 mmol) in DMF (4.3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.266 g (75%) of the title compound as a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([O:27][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:28]
Reactant: Cc1nc2cc(O)ccc2n1C
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2n1C
Yield: 28.2 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (254 mg, 0.774 mmol), 1,2-dimethyl-1H-benzimidazole-5-ol (163 mg, 1.06 mmol), potassium carbonate (267 mg, 1.94 mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and in the same manner as in Example 95, the title compound (79 mg, 28%) was obtained as a white powder.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:7][CH2:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)([CH3:6])[CH3:5].[H-].[Na+]>CS(C)=O.O>[Br:15][C:13]1[CH:12]=[N:11][C:10]2[NH:16][C:3](=[O:2])[C:4]([CH3:6])([CH3:5])[NH:7][CH2:8][C:9]=2[CH:14]=1
Reactant: COC(=O)C(C)(C)NCc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)NCc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(2-amino-5-bromo-pyridin-3-ylmethyl)amino]-2-methylpropionic acid methyl ester (2.63 g, 8.71 mmol) in DMSO (100 mL) was treated with NaH (60% dispersion in mineral oil, 0.35 g, 8.7 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (200 mL) and then extracted with EtOAc (5×150 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2,/MeOH, 99:1 to 98:2) gave (0.79 g, 33%) as an off-white solid: MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)C(O)=O.O[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=1S(O)(=O)=O.ClC1C([N+]([O-])=O)=C(C=CC=1)C(O)=O.ClC1C=CC([N+]([O-])=O)=CC=1C(O)=O.[OH-].[Na+]>[C].[Pd]>[CH:17]1[C:18]([NH2:21])=[CH:19][CH:20]=[C:15]([O:1][C:2]2[CH:10]=[CH:6][C:5]([NH2:11])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(O)c(S(=O)(=O)O)c1
Agent: [Pd]
Agent: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Product: Nc1ccc(Oc2ccc(N)cc2)cc1

Procedure:
A 5-hydroxy-2-nitrobenzoic acid derivative (e.g. sodium 5-hydroxy-2-nitrobenzoate) or a 2-hydroxy-5-nitrobenzenesulfonic acid derivative (e.g. sodium 2-hydroxy-5-nitrobenzoate) is reacted with a 5 chloro-2-nitrobenzoic acid derivative or a 2-chloro-5-nitrobenzoic acid derivative in the presence of an alkali (e.g. sodium hydroxide), followed by hydrogenation using palladium-carbon, to give the corresponding 4,4′-diaminodiphenyl ether derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([CH3:6])=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]#[N:23].C(N(CC)CC)C>C(O)C>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]1[NH:2][C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([CH3:6])[N:23]=1
Reactant: CC(=O)C(N)c1ccccc1
Reactant: N#CNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(Nc2c(Cl)cccc2Cl)[nH]c1-c1ccccc1
Yield: 14.7 %

Procedure:
1-Amino-1-phenylacetone hydrochloride (189 mg), 2,6-dichlorophenylcyanamide (187 mg, prepared as described in J. Med. Chem., 1975, 18, 90-99) and triethylamine (101 mg) were kept at the reflux temperature in ethanol (10 ml) for 3 hours. Cooling was followed by drying in vacuo and purification by preparative HPLC. The product-containing fractions were combined, the acetonitrile was stripped in a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. Drying over magnesium sulfate was followed by evaporation to dryness and, after addition of hydrochloric acid, freeze drying. 26 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[C:17]([CH2:23][OH:24])[CH:16]=3)=[CH:10][CH:9]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:24][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:11]2[S:12][C:8]([C:3](=[O:4])[CH2:1][CH3:2])=[CH:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][OH:22]
Reactant: CCC1(c2ccc(CCc3ccc(CO)c(CO)c3)s2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(CCc2ccc(CO)c(CO)c2)s1

Procedure:
In a manner similar to that of Example 6(g), by reaction of 8.7 g (23 mmol) of (4-{2-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]ethyl}-2-hydroxymethylphenyl)methanol with a solution of para-toluenesulphonic acid in an acetone/water mixture, the desired product is obtained in the form of a white powder (m=5.41 g; Y=71%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[C:18]([F:27])=[CH:19][C:20]([F:26])=[C:21](B(O)O)[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:16][C:17]1[C:18]([F:27])=[CH:19][C:20]([F:26])=[C:21]([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:22]=1
Reactant: OB(O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccnc(-c2cc(Cl)c(F)cc2F)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 21.5 %

Procedure:
tert-Butyl 2-bromopyridin-4-ylcarbamate (258 mg, 0.945 mmol), 5-chloro-2,4-difluorophenylboronic acid (236 mg, 1.228 mmol) and bis(triphenylphosphine) palladium chloride (133 mg, 0.189 mmol) were combined in dioxane (5 mL) and saturated Na2CO3 (0.472 ml, 0.945 mmol). The reaction mixture was heated at 90° C. in an oil bath. After 12 hours, the reaction mixture was cooled, water (10 mL) was added and the reaction mixture was extracted with EtOAc (100 mL, 2×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid was added (4 mL). The reaction was stirred at room temperature for 20 minutes then the solvent was removed on a rotavap and the residue was further dried under high vacuum overnight. This residue was purified by NH column chromatography, eluted with EtOAc in Hexanes (0-100%) to give the title compound (49 mg) as white solid. ESI-MS: m/z 242.0 (M+H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+].Cl>CS(C)=O>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (1.63 mL) was added to a solution of 4-(4'-hydroxyphenyl)benzoic acid (2.02 g) and 5N sodium hydroxide (3.77 mL) in dimethylsulfoxide (25 mL) and the mixture was stirred at 60°-70° C. for a period of 18 hours. The reaction mixture was cooled to room temperature and then acidified with approximately 6 mL of 2N HCl and partitioned between ethyl acetate and water. The organic phase was washed with 3×250 mL of water and 1×250 mL brine and filtered. The filter cake was saved. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain the 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylic acid (1.54 g). The filter cake from above was washed with dichloromethane and traces of the organic solvent were removed under reduced pressure to yield 1.53 g of product. The material was combined to yield a total of 3.07 g of 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 0.87 (t, 3H), 1.29 (m, 8H), 1.41 (m, 2H), 1.72 (m, 2H), 4.01 (t, 2H), 7.03 (d, 2H), 7.68 (d, 2H), 7.73 (d, 2H), 7.98 (d, 2H).
Reaction SMILES: ClC(OCC)=O.[C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(O)=[O:8].C(N(CC)CC)C.Cl.[CH2:53]([O:60][C:61](=[O:67])[C@@H:62]1[CH2:66][CH2:65][CH2:64][NH:63]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([CH2:53][O:60][C:61]([CH:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:7]([C@@H:10]2[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]2[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:8])=[O:67])[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)N1CCCC1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a -5° C. methylene chloride (1 mL) solution of ethyl chloroformate (0.12 g, 1.1 mmol) was added a methylene chloride solution of compound 29 (0.35 g, 0.7 mmol), followed by the addition of triethylamine (0.112 g, 1.1 mmol). The resultant reaction mixture was stirred for 1 h between -5° C. and 5° C. Triethylamine (0.11 g, 1.1 mmol) and proline benzylester hydrochloride (260 mg, 1.1 mmol) was added, and the solution was stirred between -5° C. to 5° C. for an additional 15 min and for 16 h at room temperature. The solution was washed with saturated aqueous NaHCO3 solution, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:EtOAc/8:2) to afford 70 mg (14%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)cc2c1NC(=O)CC2
Yield: 98.3 %

Procedure:
6-Nitro-8-methoxy-3,4-dihydrocarbostyril (2 g) and 5% palladium-carbon (0.2 g) were added in ethanol (50 ml) and catalytic reduction was conducted at a hydrogen gas pressure of 3 kg/cm2 for 1 hour. Then, the reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from benzene to give 1.7 g of 6-amino-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CNCCNC1
Product: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure C.
Reaction SMILES: [OH-:1].[Li+].OO.C([C@@H]1COC(=O)N1[C:18](=[O:38])[C@@H:19]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[CH2:20][N:21]([CH:29]([CH3:31])[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])C1C=CC=CC=1>O.C1COCC1>[C:24]([O:23][C:22]([N:21]([CH:29]([CH3:30])[CH3:31])[CH2:20][C@H:19]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:18]([OH:38])=[O:1])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A mixture solution of lithium hydroxide (374 mg, 15.6 mmol) in H2O (60 mL) and 30% hydrogen peroxide (1.60 mL, 15.6 mmol) was added dropwise to a solution of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate (7.54 g, 14.9 mmol) in THF (150 mL) at −5° C. The mixture was stirred at −5° C. After 10 minutes, the reaction was quenched with 10% Na2SO3 (16 mL) at −5° C. and stirred at room temperature for 30 minutes. The THF was removed in vacuo. The aqueous layer was acidified with 1M NaH2PO4 and extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated to give (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(5-chlorothiophen-2-yl)propanoic acid which was used in the next step without purification. MS (APCI+) [M+H]+ 348.2.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][N:12]([CH3:22])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
To a mixture of tert-butyl 3-phenylpiperazine-1-carboxylate (288 mg, 1.1 mmol), and formaldehyde (185 mg, 6.16 mmol) in methanol (7 mL) was added sodium triacetoxyborohydride (949 mg, 4.48 mmol) at 0° C. After stirring for 3 h at room temperature, the reaction mixture was diluted with 10% sodium bicarbonate solution and ethyl acetate. The aqueous part was extracted with ethyl acetate and the combined organic part was dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by flash chromatography (20/1 dichloromethane/methanol) to provide 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 101%). (M+H)+=277 m/e. To a solution of 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 1.11 mmol) in THF (3 mL) at 0° C. was added 4M HCl in dioxane (0.9 mL). The reaction mixture was stirred overnight and concentrated in vacuo. The residue was triturated with dichloromethane and filtered to provide 1-methyl-2-phenyl-piperazine dihydrochloride (290 mg), which was used as is for the next step.