Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:22]3[C:23](=[O:27])[C:24]=2[CH2:25][CH3:26])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[CH:31]=[CH:30][C:29]4([CH2:2][CH:28]4[N:22]3[C:23](=[O:27])[C:24]=2[CH2:25][CH3:26])[C:32]([O:34][CH3:35])=[O:33])[CH:14]=[CH:15][CH:16]=1
Reactant: C[S+](C)(C)=O
Reactant: CCc1c(/C=C/c2cccc(OC)c2)nc2ccc(C(=O)OC)cn2c1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(/C=C/c2cccc(OC)c2)nc2n(c1=O)C1CC1(C(=O)OC)C=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyl-sulphoxonium iodide (1 g) was reacted with 50% sodium hydride (0.22 g) in dimethylformamide (30 ml) under stirring at room temperature for 30 minutes, then a solution of 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 177°-179° C., (1.27 g) in dimethylformamide (20 ml) was added. The mixture was allowed to react under stirring at room temperature for 2 hours, then it was diluted with ice water and the precipitate was filtered, so obtaining 1.19 g of 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester (m.p. 184°-188° C.), which was treated with 0.5% KOH in 95% ethanol solution (40 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was diluted with water and acidified with acetic acid and the precipitate was filtered: crystallization from CH 2 Cl2 /methanol gave 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.65 g), m.p. 184°-188° C. NMR (CF3COOD) δ: 1.22(d.d) (one of 6,7-methylen protons), 1.36(t) (--CH2 --CH3), 2,96(m)(--CH2CH3 and 6,7-methylen proton), 4.12(s) (OCH3), 5.50(d.d) (c-6 proton), 7.03(d) (c-9 proton), 7.36(d) (Hβ -vinyl proton), 7.68(d) (Hα -vinyl proton), 7.18-7.70(m) (4-phenyl protons), 8.26(d) (c-8 proton), JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][C:4]=1/[CH:17]=[CH:18]/[C:19](=O)[CH2:20][C:21](=O)/[CH:22]=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1.C1COCC1.O.[NH2:37][NH2:38].C([O-])(O)=O.[Na+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[C:21](/[CH:22]=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][CH:28]=2)[NH:38][N:37]=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: NN
Reactant: COc1cc(OCc2ccccn2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCc2ccccn2)ccc1/C=C/c1cc(/C=C/c2ccc[nH]2)[nH]n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To 30 mg of (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1H-pyrrol-2-yl)hepta-1,6-diene-3,5-dione were added 1 mL of THF, 3 μL of AcOH and 4 μL of hydrazine monohydrate, and the mixture was stirred at 60° C. for 4 hours. To this, 500 μL of AcOH was added and the mixture was stirred at 80° C. for 1 hour. To this, 4 μL of hydrazine monohydrate was added and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was allowed to cool back to room temperature, and a saturated aqueous NaHCO3 solution was added. After extraction with AcOEt, the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by PTLC (CHCl3/methanol or AcOEt system) to give 8 mg of the title compound (27% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2cccc(C(F)(F)F)c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 3-trifluoromethylaniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 25.88 min.; purity: 89%; MS (m/e): 407 (MH+).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[O:13]=[C:14]1[N:21]2[C:16]([CH3:24])([CH2:17][CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH2:15]1.C(I)(C)C>CCOC(C)=O.CN(C)P(N(C)C)(N(C)C)=O.C1COCC1>[O:13]=[C:14]1[N:21]2[C:16]([CH3:24])([CH2:17][CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH:15]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CC12CCOC(C)(C)N1C(=O)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)C1C(=O)N2C(C)(C)OCCC12C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
THF, 20 ml is placed under N2, treated with 1.54 ml diisopropylamine and cooled to -78° C. A solution of n-butyl lithium (1.97 M in hexane; 5.6 ml) is added dropwise over 5 min. The reaction mixture is stirred at -78° C. for 10 min. and then treated with 8-oxo-2,2,6-trimethyl-3-oxa-1-azabicyclo[4.2.0]octane (0.0079 mmole) ml THF added dropwise over 5 min. After another 10 min. hexamethylphosphoramide 1.97 ml is added. The mixture is stirred another 10 min., then treated with 2 ml of isopropyl iodide. The reaction mixture is stirred at -78° C. for 15 min. and allowed to warm to 25° C. and stirred for 15 min. The reaction mixture is diluted with EtOAc, washed once with pH 7 phosphate buffer then dried and evaporated. The residue is chromatographed on silica gel using 25% EtOAc/C6H6 as eluant to give 8-oxo-2,2,6-trimethyl-7-isopropyl-3-oxa-1-azabicyclo[4.2.0]-octane.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7](C(O)=O)=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:22][CH2:21]1.C([N:38](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(O)(C)(C)C>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([NH2:38])=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:22][CH2:21]1
Reactant: Nn1c(SCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2cc(C(=O)O)ccc2c1=O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1ccc2c(=O)n(N)c(SCCCN3CCN(c4ccc5ccccc5n4)CC3)nc2c1
Yield: 8.5 %

Procedure:
In 10 ml of tert-butanol, 250 mg of 3-amino-4-oxo-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4-dihydroquinazolin-7-carboxylic acid as synthesized in Example 1-57 was dissolved, to which 52 mg of triethylamine, and further 147 mg of DPPA, were added by the order stated. This mixture was heated under reflux for an overnight. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1). The purified product was added to 8 ml of 4N hydrochloric acid-dioxane solution, stirred for an hour, and an excessive amount of triethylamine was added. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 20 mg (8%) of 3,7-diamino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3H-quinazolin-4-one.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:44])[CH2:42]Br)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:41](=[O:44])[CH2:42][N:11]2[CH2:10][CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To 90 ml of an ethyl acetate solution containing 7.56 g (30 mmol) of 1-diphenylmethylpiperazine and 3.33 g (33 mmol) of triethylamine was added 9.15 g (30 mmol) of p-benzyloxy-α-bromoacetophenone. The resultant mixture was stirred at room temperature for 45 minutes. After addition of 100 ml of ice water, the thus obtained mixture was stirred for about 10 minutes. Precipitated crystals were collected by filtration and then washed successively with water, ethanol and ethyl acetate and thereafter dried to give 12.5 g of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanone (yield: 87.4%).
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].[H][H]>CO.[Ni]>[NH2:1][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 99.9 %

Procedure:
A solution of 14.7 g (60 mmol) of (S)-3-azido-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 200 ml of methanol was treated with 1.0 g of Raney-nickel and shaken in a hydrogen atmosphere at pressures of 49.5-51 psi and temperatures of 25.3-29.5° for nine hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 13.2 g of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Product: COc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
0.16 g of 3-fluoro-4-nitrophenol and 0.37 g of p-anisidine were mixed and stirred for 1.5 hours at 150° C. After cooling, it was dissolved in dichloromethane, and extracted twice with 1N aqueous hydrochloric acid and once with saturated sodium chloride solution. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[OH:24][CH:16]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:15][N:14]1[CH2:13][CH2:12][CH2:11][C:10]2[NH:9][CH:8]=[C:7]([CH3:32])[C:6]=2[C:4]1=[O:3]
Reactant: CCOC(=O)c1c(CCCNCC(O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Yield: 76.2 %

Procedure:
5-[3-(2-hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 53d (580 mg, 1.28 mmol) was dissolved in 6 ml of toluene under stirring, and trimethyl aluminum in toluene (1.9 ml, 2 mol/L, 3.84 mmol) was added dropwise in an ice-water bath under an argon atmosphere. Upon completion of the addition, the ice-water bath was removed, and the reaction mixture was heated to reflux for 24 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, added with hydrochloric acid solution (20 ml, 6 mol/L) and stirred for 20 minutes at room temperature. The mixture was adjusted to about pH 12 with aqueous sodium hydroxide solution (12 mol/L) in an ice-water bath and extracted with dichloromethane (50 ml×2). The combined organic extracts were concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 53e (300 mg, yield 57.6%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][C:3]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(CBr)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of bromoacetyl chloride (5.50 mL, 66.9 mmol) in tetrahydrofuran (120 mL) at 0° C. was added a mixture of 4-dimethylaminepyridine (2.80 g, 22.9 mmol) and cyclohexylamine (5.00 mL, 43.7 mmol) in tetrahydrofuran (60 mL). The mixture was warmed to room temperature and stirred an additional 18 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 10% ethyl acetate:hexanes) to provide of the title compound (25% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.18 (m, 5H), 1.64 (m, 5H), 3.52 (m, 1H), 3.99 (s, 2H), 8.04 (br d, 1H, J=7.1 Hz); MS (DCI/NH3) m/e 237/239 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:43](=O)[CH2:44]Cl)[CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:43][CH2:44][O:1][C:2]2[CH:38]=[CH:37][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:4][CH:3]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 8.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (27 mg) and 1-azetidin-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.3 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1cccc(C(F)(F)F)c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 3-(trifluoromethyl)benzaldehyde (85 ul, 0.633 mmol) similar to Example 6 and isolated as a yellow solid (88 mg, 30%). 1H NMR (CDCl3): 7.86 (s, 1H), 7.76-7.50 (m, 5H), 7.35 (d, J=3.0 Hz, 1H), 7.14 (dd, J=3.3, 9.3 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 4.47-4.32 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46]>ClCCCl.C(O)C>[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1
Reactant: O=Cc1ccco1
Reactant: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCCl
Product: N#Cc1ccc2[nH]cc(CC3CCN(Cc4ccco4)C3)c2c1
Reaction time: 0.17 h

Procedure:
Under an inert atmosphere and at ambient temperature, 47.3 mmol (10 g) of 3-[3-pyrrolidinylmethyl]-1H-indole-5-carbonitrile (described in Preparation A) are dissolved in 650 ml of 1,2-dichloroethane, and then 47.3 mmol (4.26 g) of furaldehyde are added. Stirring is carried out for 10 minutes, and 66.2 mmol (13.79 g) of sodium triacetoxyborohydride are added. After 30 minutes at ambient temperature, 350 ml of saturated sodium hydrogen carbonate solution are added. The organic phase is separated off, washed with water and dried over magnesium sulphate. Purification is carried out by chromatography on silica using a mixture of dichloromethane/methanol/ammonia 98/2/0.2 as eluant. The compound obtained is converted into the salt by one equivalent of oxalic acid in ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42].Cl>ClCCl.CO>[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-(6-bromo-4-(trans-4-(dimethylamino)cyclohexylamino)quinolin-3-yl)ethanone (4.48 g, 11.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.65 g, 13.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (2:1, 325 mL) after which HCl (115 mL, 1.25 M in methanol) was added to from a solution. The solution was concentrated to ˜100 mL and the resultant solid was filtered, washed with dichloromethane, and dried to obtain desired product (4.2 g, 70% over two steps) as a yellow solid: 1H NMR (500 MHz, MeOD) δ 9.13 (s, 1H), 8.48 (br s, 1H), 8.30 (dd, J=8.8, 1.8 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.77 (s, 2H), 4.62 (br s, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.58-2.54 (m, 2H), 2.35-2.29 (m, 2H), 1.92-1.82 (m, 4H); ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=6.41 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22].Cl.[NH2:28][OH:29].C(N(CC)CC)C.O>O1CCOCC1.C(OCC)(=O)C.CCCCCC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19](=[N:28][OH:29])[NH2:20])[C:3]=1[S:21]([C:23]([F:25])([F:24])[F:26])=[O:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole (500 mg, 1.1 mmol) and hydroxylamine hydrochloride (79 mg, 1.1 mmol) were dissolved in 5 ml of dioxane, and then triethylamine (115 mg, 1.1 mmol) was added at room temperature. After the mixture was stirred at room temperature for 6 hours, hydroxylamine hydrochloride (79 mg, 1.1 mmol) and triethylamine (115 mg, 1.1 mmol) were further added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into 100 ml of iced water and extracted with 100 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain a brown oily substance. This oily substance was subjected to silica gel column chromatography [eluent: mixed solvent of n-hexane and ethyl acetate (volume ratio=3:1)] to obtain 340 mg (0.72 mmol) of the title compound as a colorless crystal. Yield 63%.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][C:6]([C:13]([O:15]C)=[O:14])([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].Cl>O>[CH3:1][O:2][CH:3]1[O:8][CH2:7][C:6]([C:9]([OH:11])=[O:10])([C:13]([OH:15])=[O:14])[CH2:5][CH2:4]1
Reactant: COC(=O)C1(C(=O)OC)CCC(OC)OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1CCC(C(=O)O)(C(=O)O)CO1
Temperature: 90 °C

Procedure:
Dimethyl 6-methoxytetrahydropyran-3,3-dicarboxylate (6.6 g, 0.028 mol) was added to a solution of sodium hydroxide (2.8 g, 0.07 mol) in water (10 ml), and the mixture was heated at 90° C. for 3 hours. After the reaction mixture was cooled to 0° C., 6N hydrochloric acid (12 ml, 0.07 mol) was added to neutralize the solution. After salting out, the mixture was extracted with five 30 ml portions of ethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and subjected to rotary evaporation. The residual white powder was recystallized from a mixture of diethyl ether and acetone (3:1). Yield of the product, which decomposed at 136° to 140° C., was 94%.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[S:16][C:15]4[N:17]=[CH:18][CH:19]=[N:20][C:14]=4[N:13]([CH2:21][O:22][CH3:23])[C:12]=3[CH:24]=2)=[CH:6][NH:5][N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.Cl>O1CCCC1>[NH:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[S:16][C:15]4[N:17]=[CH:18][CH:19]=[N:20][C:14]=4[N:13]([CH2:21][O:22][CH3:23])[C:12]=3[CH:24]=2)[CH:3]=[N:4]1
Reactant: COCN1c2cc(-c3c[nH]nc3[Si](C)(C)C)ccc2Sc2nccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCN1c2cc(-c3cn[nH]c3)ccc2Sc2nccnc21
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
5 ml of a solution of 130 mg of 8-(3-trimethylsilyl-pyrazol-4-yl)-10-methoxymethyl-10H-pyrazino(2,3-b][1,4]-benzothiazine in tetrahydrofuran was stirred at room temperature and 1.1 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added thereto. After stirring for 5 minutes, the reaction mixture was distributed into ethyl acetate and 1 N hydrochloric acid. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 42 mg of the title compound as yellow crystals.
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Cl:21][C:22]1[C:28](Cl)=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 13.1 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.40 g, 1.44 mmol) and 2,3-dichloroaniline (0.34 g, 2.10 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, a precipitate formed. The filter cake was collected. Titration from acetone and hexanes gave 68 mg (11%) of 3-(2-chloroanilino)-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione. LCMS(H+) 394.