Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.C1C(=O)N([Cl:40])C(=O)C1>C(#N)C>[Cl:40][C:16]1[C:15]([O:18][CH2:19][C@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A mixture of (R)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (248 mg, 0.564 mmol) prepared as described in Example 19, Part A, NCS (151 mg, 1.128 mmol), and acetonitrile (5 mL) was heated at 90° C. for 1 h and then stirred at room temperature overnight. The crude material was concentrated under reduced pressure to afford (R)-tert-butyl (1-((9-chloro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (15 mg, 0.032 mmol, 6% crude yield). The mixture was carried on without further purification. LC/MS, (ESI) m/z 474.2 [(M+H)+, calcd for C25H33ClN3O4 474.2].
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:40][C:36]3[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3ccc(C)cn3)cc2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccc(C)cn3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (40.0 mg) obtained in Example 76-1 was dissolved in methanol (1.2 ml) and then added with 1-methylimidazol-2-aldehyde (11.9 mg) and sodium cyanoborohydride (11.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (42.5 mg) of the subject compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1)[CH3:9].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: COC(=O)c1ccc(C(C)N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc(CO)cc1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To 5 mL of tetrahydrofuran solution containing 177.8 mg of lithium aluminum hydride, 3 mL of tetrahydrofuran solution containing 245 mg of methyl 4-(1-aminoethyl)benzoate (synthesized according to a method disclosed in page 115 in Pamphlet of International Publication WO 03/024,955) was added, and then stirred for 1 hour. Thereto, sodium sulfate decahydrate was added until there are no bubbles, and stirred overnight at room temperature. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and 195 mg of [4-(1-aminoethyl)phenyl]methanol [115-1] was obtained as a colorless oily product.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[O:28]=[S:20]1(=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[N:19]1[CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1cccc(C(F)(F)F)c1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 3-trifluoromethyl benzyl bromide. MS: ESI (negative): 513 (M−H).
Reaction SMILES: NC1C=CC=CC=1C1N=C(CCCC(O)=O)OC=1.C[O:20][C:21](=[O:36])[CH2:22][CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])[N:28]=1>>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:27]1[N:28]=[C:24]([CH2:23][CH2:22][C:21]([OH:36])=[O:20])[O:25][CH:26]=1
Reactant: COC(=O)CCc1nc(-c2ccccc2N)co1
Agent: Nc1ccccc1-c1coc(CCCC(=O)O)n1
Product: Nc1ccccc1-c1coc(CCC(=O)O)n1
Yield: 84.8 %

Procedure:
Using a method similar to the procedure described for the preparation of 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid; hydrolysis of 3-[4-(2-amino-phenyl)-oxazol-2-yl]-propionic acid methyl ester (4.8 g, 19.5 mmol) gives 3-[4-(2-amino-phenyl)-oxazol-2-yl]-propionic acid (3.84 g, 85%) after chromatography over silica gel (MeOH/CH2Cl2). MS (ES): (M+1)+ 233.1 m/z.
Reaction SMILES: [C:1]([CH:3]=[C:4](OC)[O:5][CH3:6])#[N:2].[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19]>>[C:1]([CH:3]=[C:4]([O:5][CH3:6])[NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[NH:13][CH:12]=[N:11][C:10]=1[CH3:9])#[N:2]
Reactant: COC(=CC#N)OC
Reactant: Cc1nc[nH]c1CSCCN
Product: COC(=CC#N)NCCSCc1[nH]cnc1C

Procedure:
Reaction of 1-cyano-2,2-bis methoxyethylene (J.A.C.S., 1949, 71, 47) with 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure of Example 8(i) yields 1-cyano-2-methoxy-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([C:10]([OH:12])=O)=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3].S(Cl)([Cl:15])=O>>[NH2:1][S:2]([C:5]1[C:6]([C:10]([Cl:15])=[O:12])=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1cscc1C(=O)O
Reactant: O=S(Cl)Cl
Product: NS(=O)(=O)c1cscc1C(=O)Cl
Temperature: 90 °C

Procedure:
A solution of 1.0 g of 4-aminosulfonylthiophene-3-carboxylic acid in 20 ml of thionyl chloride is heated in an oil bath maintained at 90° C. for 2 hours. Rotoevaporation gives 1.0 g of the title compound, m.p. 236°-238° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[CH2:29][OH:30].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:31]3[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH2:29][OH:30])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: N[C@H](CO)c1cc(F)cc(I)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(I)c2)c(F)c1
Reaction time: 15 h
Yield: 49.6 %

Procedure:
To a solution of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (18 mg, 0.052 mmol) in DMF (0.52 mL) was added (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol hydrochloride (19.6 mg, 0.062 mmol), HOAt (10.52 mg, 0.077 mmol), EDC (19.76 mg, 0.103 mmol), and DIEA (27 μl, 0.155 mmol). The reaction mixture was stirred for 15 h. After water was added, the reaction mixture was extracted with EtOAc and the organic layer was washed with water twice. The organic layer was separated and dried over Na2SO4, filtered off and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 0-100% EtOAc/heptane to provide 15.8 mg of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluoro-N—((S)-1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)benzamide as a free base (50%). LCMS (m/z): 613.1 (MH+), 0.74 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.89-7.69 (m, 2H), 7.66-7.47 (m, 3H), 7.39-7.26 (m, 1H), 7.12 (d, J=9.4 Hz, 1H), 5.05 (t, J=5.9 Hz, 1H), 4.43-4.14 (m, 1H), 3.84-3.66 (m, 2H), 3.64-3.45 (m, 1H), 2.74 (t, J=11.7 Hz, 1H), 2.17 (td, J=3.1, 6.0 Hz, 1H), 2.05-1.87 (m, 1H), 1.84-1.66 (m, 2H), 1.65-1.47 (m, 1H), 1.47-1.27 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[C:24]2[C:3]=1[C:4](=[O:31])[O:5][C:6]12[C:19]2[CH:18]=[C:17]([F:20])[C:16]([OH:21])=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][C:9]([F:23])=[C:10]([OH:22])[CH:11]=2.Cl>>[NH2:1][C:2]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:3]=1[C:4](=[O:31])[O:5][C:6]12[C:7]2[CH:8]=[C:9]([F:23])[C:10]([OH:22])=[CH:11][C:12]=2[O:13][C:14]2[C:19]1=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=2
Reactant: Nc1c([N+](=O)[O-])ccc2c1C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Agent: Cl
Product: Nc1ccc2c(c1N)C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Yield: 78.7 %

Procedure:
4-Amino-5-nitro-2′,7′-difluoro-3′,6′-dihydroxy-spiro[isobenzofuran-1(3H),9′-[9H]xanthen]-3-one (1.3 g, 3.0 mmol) was added to an aqueous solution of Na2S and NaSH, and the mixture was refluxed for 24 hours. The reaction mixture was cooled, and adjusted to pH 3 with hydrochloric acid, and precipitates were collected by filtration. The obtained product was dried and purified by silica gel chromatography to obtain the title compound (0.94 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12](Cl)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH2:12][C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)C(F)(F)C3
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)CC(F)(F)C3
Yield: 106.3 %

Procedure:
The product from step (b) (21 mg) was dissolved in EtOAc (40 ml) and placed in a parr hydrogenation bottle. To this solution was added 5% Pd—C (10 mg). The mixture was shaken under 50 psi of hydrogen for 2 hours after which LCMS indicated no starting material. The mixture was purged with Nitrogen and filtered thru a bed of celite. The solvent was evaporated in vacuo to give the sub-titled compound (20 mg) as a yellow oil. MS: ESI (positive): 296 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN1C(=O)CCC1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1ccccc1
Solvent: CN1CCCC1=O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
To a solution of 3,5-dibromopyridine (XXXVII) (1.00 g, 4.24 mmol) in NMP (11 mL) was added phenol (XXXVIII) (398 mg, 4.24 mmol) and CsCO3 (1.38 g, 4.24 mmol). The reaction was heated at 100° C. over the weekend. The reaction was then partitioned between Et2O/water. The Et2O was separated, washed with 2× water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes→2:98 EtOAc:hexanes) to afford 3-bromo-5-phenoxypyridine (XXXIX) (535 mg, 2.14 mmol, 50% yield) as a clear oil. 1H NMR (DMSO-d6) δ ppm 7.13-7.15 (m, 2H), 7.23-7.26 (m, 1H), 7.43-7.46 (m, 2H), 7.69-7.70 (m, 1H), 8.37 (d, J=3 Hz, 1H), 8.49 (d, J=2 Hz, 1H); ESIMS found for C11H8BrNO m/z 250 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>O1CCCC1>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: Clc1ccccc1CBr
Reactant: COc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)CC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(n2Cc2ccccc2Cl)CCC(NC(=O)C(C)C)C1
Reaction time: 0.42 h
Yield: 68.8 %

Procedure:
Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 6) (100 mg, 0.35 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen. Add dropwise potassium bis(trimethylsilyl)amide (0.77 mL, 0.385 mmol, 0.5N in toluene) and stir 25 min. Add slowly 2-chlorobenzylbromide (0.050 mL, 0.385 mmol) and stir at ambient temperature for 18 h. Quench with saturated ammonium chloride solution (0.5 mL) and dilute with a volume of dichloromethane and water (1 mL). Pass over a Varian Chem Elut column to remove aqueous portion and concentrate in vacuo. Alternatively, workup with ethyl acetate/water and dry over MgSO4. Purify the resulting residue by flash chromatography, eluting with dichloromethane with a gradient up to 10% ethyl acetate/dichloromethane to obtain 99 mg (69%) of a white solid. MS (ES): m/z 411, 413 (M+1); 1H NMR(DMSO-d6): δ 7.86 (d, 1H, J=7.5 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.28 (t, 1H, J=7.7 Hz), 7.17 (m, 2H), 6.97 (d, 1H, J=2.2 Hz), 6.68 (dd, 1H, J=8.8, 2.2 Hz), 6.24 (d, 1H, J=7.9 Hz), 5.36 (s, 2H), 4.02 (m, 1H), 3.77 (s, 3H), 2.98 (dd, 1H, J=15.2, 5.1 Hz), 2.75-2.61 (m, 2H), 2.41 (m, 1H), 1.96 (m, 1H), 1.81 (m, 1H), 2.52 (m, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14].O=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[F:14][C:8]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[C:16]1[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=1
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)ccc1F
Reaction time: 1 h
Yield: 83.3 %

Procedure:
2.0 M Isopropyl magnesium chloride solution in THF (163 mL, 324.3 mmol) was added to a solution of 2-bromo-1,4-difluorobenzene (62.5 g, 324.3 mmol) in THF (350 mL) at −40° C. and stirring was continued at 5° C. for 1 h. tert-Butyl 2-oxopyrrolidine-1-carboxylate (Step-1)(73 g, 392 mmol) in THF (150 mL) was added dropwise to above reaction mixture at −40° C. and stirring was continued at 10° C. for 2 h. Reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 76 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][CH3:17])[C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:21]
Reactant: CNc1ccc(C(=O)Nc2cccc(Cl)n2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CNc1ccc(C(=O)Nc2cccc(Cl)n2)cc1N

Procedure:
Prepared analogously to example 323c from N-(6-chloro-pyridin-2-yl)-4-methylamino-3-nitro-benzamide, iron powder and sat. NH4Cl solution in ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20]([CH2:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([O:29]C(=O)C)[CH2:25][CH2:24]1)=[O:21].C(O[C@@H]1CC[C@H](CC(NC2SC3C(N4CCOCC4)=CC=C(OC)C=3N=2)=O)C1)(=O)C>>[OH:29][C@@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][C:20]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:21])[CH2:24][CH2:25]1
Reactant: CC(=O)O[C@H]1CC[C@@H](CC(=O)Cl)CC1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Agent: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](O)CC3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and (cis)-acetic acid 4-chlorocarbonylmethyl-cyclohexyl ester, the tide compound was synthesized in exact the same manner as (cis)-2-(3-acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide and obtained as light yellow crystals (33% yield). MS: m/e=406(M+H+), mp 212-216° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:13])[N:8]([CH2:10][CH2:11][CH3:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>C(OCC)(=O)C.O>[Cl:22][C:21]([Cl:24])([Cl:23])[CH2:20][O:19][C:17](=[O:18])[NH:13][C:7]1[N:8]([CH2:10][CH2:11][CH3:12])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCCn1nc(C(C)(C)C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.1 %

Procedure:
To a stirred mixture of Intermediate 23a (0.774 g, 4.27 mmol) in ethyl acetate (4 mL) and 1 M aqueous NaOH (7.7 mL, 7.7 mmol) was added 2,2,2-trichloroethyl chloroformate (0.62 mL, 4.50 mmol) and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water and saturated aqueous NaCl, then evaporated to give the title compound (1.57 g) as an oil. LCMS (Method 3): Rt 4.28 min, m/z 356/358/360 [MH+]. 1H NMR (300 MHz, CDCl3): 0.90 (3H, t, J 7.5 Hz), 1.28 (9H, s), 1.78-1.87 (2H, m), 3.92 (2H, t, J 7.4 Hz), 4.83 (2H, s), 6.08 (1H, s), 6.46 (1H, s).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:20]=3[CH3:19])[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
86 mg (96%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(2,3-dimethylphenyl)piperazine (36 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CN(C)C=O>[C:15]([S:17][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1)(=[O:18])[CH3:16]
Reactant: C=CCOC(=O)c1ccc(CBr)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Allyl 4-(bromomethyl)benzoate (98 g, 0.4 moles) in dry dimethylformamide (100 ml) was added dropwise to a cooled suspension of potassium thioacetate (46 g, 0.4 moles) in dry dimethylformamide (200 ml). The cooling bath was removed and the mixture was stirred overnight. The reaction was poured into water and extracted with ethyl acetate (×3). The combined extracts were washed with water and brine. The mixture was dried and evaporated to give allyl 4-(acetylthiomethyl)benzoate as an orange oil (100 g, 100% yield). 1H NMR δ (CDCl3) 2.36 (3H, s, COCH3), 4.13 (2H, s, CH2), 4.82 (2H, m, CH2O), 5.32 (2H, m, CH2CH--), 6.05 (1H, m, CHCH2), 7.35 (2H, d, Ph-H), 7.98 (2H, d, Ph-H).
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C/C=C\CCCCCCCC.[Na+:21].P([O-])(O)(O)=O.[Na+]>C(O)C>[C:1]([O-:20])(=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:21]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCO
Product: O=C([O-])c1ccccc1

Procedure:
A liquefied composition containing 5 weight percent of sodium oleate, 5 weight percent of ethanol, enough sodium dihydrogen phosphate to obtain a pH of 9.8, 0.1 weight percent of sodium benzoate, and the remainder sterile distilled water (q.s.). The liquefied composition (termed GHT 7701) was placed in amber glass bottles.
Reaction SMILES: [C:1]([CH:6]([NH:15][C@H:16]([C:18]([CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]([C:30]([OH:32])=[O:31])[NH:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([CH:6]([NH:15][C@H:16]([C:18]([CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]([C:30]([OH:32])=[O:31])[NH:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)C1NC(C(=O)O)Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)C1NC(C(=O)O)Cc2ccccc21
Reaction time: 1 h

Procedure:
880 mg of N-(1-carboethoxy-3-phenylpropyl)-L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are dissolved in 20 ml of dioxane/water (9:1) and are hydrolyzed at room temperature with 4.5 ml of 1N sodium hydroxide solution. After one hour, the solution is acidified with the equivalent quantity of 1N hydrochloric acid, and the dioxane is largely evaporated off. The residue is extracted several times with ethyl acetate, and, after the solvent has been stripped off, the organic phase is subjected to chromatography over a cation exchanger (DOWEX 50).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=O.Cl.[CH3:12][O:13][NH2:14].Cl>C(O)C>[CH3:12][O:13][N:14]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CON
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CON=C(C)c1ccc(N)cc1
Yield: 88.8 %

Procedure:
To a solution of 4-amino acetophenone (650 mg, 4.8 mmol) and O-methyl-hydroxylamine hydrochloride (800 mg, 9.6 mmol) in ethanol (10 ml) was added a drop of conc. hydrochloric acid and the reaction was heated to reflux for 2 hr. The solvent was evaporated under reduced pressure and ethyl acetate was added, washed with water, dried over anhydrous sodium sulphate, and then filtered. Evaporation yielded 1-(4-aminophenyl)-ethanone-O-methyl-oxime (700 mg, 89%) as a solid.