Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C@H:10]([CH2:21][OH:22])[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:21][OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCN1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN1CCNC[C@H]1CO
Temperature: 25 °C

Procedure:
A solution of Example 1 (e) (0.53 g) in dichloromethane (20m1) and trifluoroacetic acid was stirred at 0° C. for 30 minutes and allowed to warm to room temperature over 2 hours. It was evaporated to dryness and azeotroped with toluene to afford [2S]-1-heptyl-2-hydroxymethylpiperazine trifluoroacetate salt as a foam. The salt was dissolved in acetonitrile (3 ml), and treated with diusopropylethylamine (0.544 g) until pH 6. Example 1(f) (0.509 g) and lithium perchlorate (0.179 g) were added and the mixture was stirred at room temperature for 48 hours. [method of J. E. Chateauneuf et al. J. Org. Chem. 56, 5939-5942]. The reaction rriixture was evaporated and basified with sodium carbonate solution and extracted (x3) with dichloromethane. The organic fraction was dried and chromatographed on silica gel eluting with 50-100% ethyl acetate-hexane to afford the title compound as an oil (0.248 g).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[S:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:26]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:8][CH2:7][N:6]1[C:36]([C:34]1[N:35]=[C:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[S:32][CH:33]=1)=[O:37]
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl)piperazine hydrochloride obtained in Reference Example 6 (0.52 g), 2-(3-pyridyl)thiazol-4-carboxylic acid (0.3 g), triethylamine (0.46 g) and N,N-dimethylformamide (3 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.47 g). The reaction mixture is stirred at 0° C. for one hour, and then poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:AcOEt-CH2Cl2 --CH3OH=10:9:1) to give 2-methoxymethyl-1-[2-(3-pyridyl) thiazol-4-ylcarbonyl]-4-(3,4,5-trimethoxybenzoyl) piperazine. Recrystallization from ethanol gives colorless needles m.p. 149-150° C.
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[Cl:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C@@H:25]([NH:27][C:28]([C:30]3[N:31]=[C:32]([CH3:40])[N:33]([CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[CH:34]=3)=[O:29])[CH3:26])[N:20]=2)[CH:13]=[C:14]([F:18])[C:15]=1[C:16]#[N:17].[Cl-].[NH4+]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C@@H:25]([NH:27][C:28]([C:30]3[N:31]=[C:32]([CH3:40])[N:33]([CH2:35][CH2:36][C:37]([OH:39])([CH3:4])[CH3:38])[CH:34]=3)=[O:29])[CH3:26])[N:20]=2)[CH:13]=[C:14]([F:18])[C:15]=1[C:16]#[N:17]
Reactant: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)nc1C
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1CCC(C)(C)O
Temperature: 45 °C
Reaction time: 5 h
Yield: 19.32 %

Procedure:
Methylmagnesium bromide 3M in Et2O-solution (0.128 ml, 0.383 mmol) and dry THF (1 ml) were added into a flask and heated to 30° C. (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (35 mg, 0.077 mmol) of Example 286(b) dissolved in THF (5 ml) was added very slowly. The reaction mixture was heated to 45° C. and stirred for 5 h. Another batch of methylmagnesium bromide 3M in EtO2-solution (0.128 ml, 0.383 mmol) was added and the mixture was stirred at RT overnight. Next day the reaction mixture was poured into 10 ml of saturated ammonium chloride, THF was evaporated and the remaining water phase was extracted with ethyl acetate. The ethyl acetate phases were combined, dried and evaporated. The product was purified by flash-chromatography. Yield 19.32%. 1H-NMR (400 MHz; DMSO-d6): δ 1.06 (d, 3H), 1.12 (s, 6H), 1.69-1.77 (m, 2H), 2.34 (s, 3H), 3.92-3.98 (m, 2H), 4.25-4.46 (m, 4H), 7.01 (d, 1H), 7.50 (s, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 8.00 (s, 1H), 8.03 (d, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl.O>CCOC(C)=O>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114, 1624-35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ 7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s, 1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s, 1H); APCI−MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46 H2O.0.2 EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1NC(CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc([N+](=O)[O-])c3N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(5-Nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-methanol (6.5 g, 31.0 mmole) was dissolved in methylene chloride (200 mL), N, N-diisopropylethylamine (10.8 mL, 62 mmole) and 4-DMAP (1.18 g) were added, followed by p-toluenesulfonyl chloride (12.85 g, 67.4 mmole) and the mixture stirred at room temperature under nitrogen overnight. The mixture was diluted with methylene chloride (100 mL), washed with HCl (1N, 200 mL), saturated sodium bicarbonate (200 mL), saturated sodium chloride (200 mL) and dried (Na2SO4). Filtration, evaporation in vacuum and column chromatography on silica gel with 1:1 hexane/methylene chloride as eluent gave 10.5 g (93%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 8.20 (d, 1H); 7.70 (d, 1H); 7.65 (dd, 1H); 7.40 (d, 2H); 7.05 (dd, 1H); 6.55 (dd, 1H); 4.10 (m, 5H); 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[N:40][CH:39]=2)O1>>[CH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cncc5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure A for Suzuki coupling, 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline were reacted to give 160. LCMS: M+H+=532.2.
Reaction SMILES: CO.C([NH:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[N:12]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[N:12]=1
Reactant: Fc1cc(F)c(NCc2ccccc2)nc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(F)c(F)cc1F
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To 40 ml of methanol were added 7.60 g of the crude 2-benzylamino-3,5,6-trifluoropyridine as described above together with 0.55 g of 10% palladium on carbon and 2 ml acetic acid, and the mixture was hydrogenated at 50° C. for one day. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. The precipitate was dispersed in n-hexane, and collected by filtration to obtain 3.85 g of the title compound as a colorless solid.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=O)[N:5]=[N:4][N:3]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CN
Reactant: CCOC(=O)Cn1nnnc1S
Solvent: CCO
Product: CNC(=O)Cn1nnnc1S
Reaction time: 8 h

Procedure:
Ethyl 5-mercapto-1H-tetrazol-1-ylacetate (2.0 g) was dissolved in 33% methylamine in ethanol (20 ml) and stood overnight at R.T. The solution was evaporated to dryness in vacuo, the residue dissolved in water (20 ml), adicified and ether extracted (6×50 ml). The extracts were dried and evaporated to give a crystalline solid which was crystallised from ethyl acetate, 0.59 g (32.0%) m.p. 167°-168°; δ[(CD3)2CO] 2.88 (3H,d, J 5 Hz, --NHCH3), 5.15 (2H,s, --CH2CO--), 6.70 (1H,m, --NH--), 12.9 (1H,bs, --SH). Found: C, 27.53; H, 4.17; N, 40.07; S, 18138. C4H7N5OS requires: C, 27.74; H, 4.07; N, 40.44; S, 18.51%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.O.[CH2:14](OCC)C>>[OH:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCOCC
Solvent: O
Product: CCOC(=O)C1CCC(C)(O)CC1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 25.0 g of ethyl 4-oxocyclohexanecarboxylate in 500 ml of diethyl ether, 150 ml of 1.6N methyl lithium-ether solution was added at −60° C. in nitrogen atmosphere, followed by 30 minutes' stirring at −60° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/4) to provide 22.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.Cl>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: NCCN1CCCC1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1NCCN1CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.86 mL (5.05 mmol) ethyldiiopropylamine are added to a solution of 600 mg (2.53 mmol) 5-bromo-2-chloro-3-nitropyridine and 0.32 mL (2.53 mmol) 1-(2-aminoethyl)-pyrrolidine in 3 mL n-butanol. The reaction is heated to 50° C. and stirred for one hour at this temperature. The solvent is eliminated i.vac. and the residue is combined with 40 mL water and acidified with 1 M HCl. The aqueous phase is extracted with 20 mL EtOAc and the aqueous phase is then made alkaline with saturated K2CO3 solution. The aqueous phase is extracted with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([NH2:15])=[S:14])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]I>CC(C)=O>[C:1]1([CH:7]([NH:12][C:13](=[NH:15])[S:14][CH3:16])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: NC(=S)NC(c1ccccc1)C(F)(F)F
Solvent: CC(C)=O
Product: CSC(=N)NC(c1ccccc1)C(F)(F)F

Procedure:
14.5 g N-(α-phenyltrifluoroethyl) thio Urea are dissolved in 270 ml acetone and this solution is heated to reflux. A solution of 17.6 g methyl iodide in 7.75 ml acetone is added thereto while keeping the heating at reflux during the addition and for a further period of three hours. The solvent is thereafter evaporated off and 25 of an oily product is obtained. The crystallisation thereof is initiated by scraping in the presence of benzene. The crystals melt at 138°-144°. A further crystallisation supplies 18.5 g of pure N-(α-phenyl trifluoroethyl) S-methylisothiourea in the form of its hydriodide melting at 142°-144°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H). (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H). (3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+MeOH—H2O).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:23]=3)[CH:14]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:22]2[N:21]=[N:20][C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[C:12]([NH:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)=[O:33])=[N:23]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cccc(-c3nnn(Cc4ccc(OC)cc4)n3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(-c3cccc(C(=O)NCc4ccc(C(=O)O)cc4)c3)n2)cc1
Yield: 72.5 %

Procedure:
The ester (0.065 g, 0.14 mmol) prepared in Example 1, Step (e) was diluted with aqueous tetrahydrofuran followed by the addition of lithium hydroxide monohydrate (0.018 g, 0.4 mmol). Following the experimental conditions described in (d) yielded the free acid (0.045 g, 71%)as a white solid. 1H NMR (DMSO-d6) δ 12.8 (bs, 1H), 9.4 (t, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.9 (d, 2H), 7.7 (t, 1H), 7.4 (dd, 4H), 6.9 (d, 2H), 5.9 (s, 2H), 4.5 (d, 2H), 3.7 s, 3H) ppm. Mp 202–205° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=O)[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[N:20][OH:21])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1
Reactant: CN1CC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CC(=NO)c2c(ccn2CCCCCl)S1(=O)=O
Yield: 45.1 %

Procedure:
A suspension of 145 mg (0.5 mmol) of Compound 17, 104 mg (1.5 mmol) of hydroxylamine hydrochloride and 123 mg (1.5 mmol) of sodium acetate in 15 ml of methanol was refluxed for 166 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of a half-saturated aqueous solution of potassium carbonate to the residue. The resulting mixture was extracted with chloroform (twice). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent:chloroform), whereby 69 mg of the title compound were obtained (yield: 45%).
Reaction SMILES: [P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:2].Br[CH2:26][C:27](=[O:33])[C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30]>>[P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:26][C:27](=[O:33])[C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[N:6]=1)=[O:2]
Reactant: CCC(C)(C)C(=O)CBr
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)n[nH]c2c1
Product: CCC(C)(C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C2CCCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared from cyclopentylidene(6-methoxy-1H-indazol-3-yl)methyl dimethyl phosphate from Step B Example 6 and 1-Bromo-3,3-dimethylpentan-2-one from Step A Example 4 using the procedure described in Method I Step C of Example 1 followed by RP-HPLC purification using 35˜100% MeCN gradient without TFA. It was obtained as a colorless solid after lyophilization. LC-MS: 3.70 min. (m/Z=339.2, 465.2, 487.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[CH2:12]1[NH:19][CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][N:19]2[CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]2)=[C:6]([F:8])[CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Fc1cc(Br)cc(F)c1CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1(=O)CCN(Cc2c(F)cc(Br)cc2F)CC1

Procedure:
A solution of 3.8 g (11.3 mmol) 5-bromo-2-bromomethyl-1,3-difluoro-benzene, 1.83 g (13.6 mmol) thiomorpholine dioxide and 1.88 ml (13.6 mmol) triethylamine in 40 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is taken up in diethylether, vigorously stirred, and the title compound is obtained after filtration as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Product: C[Sn](C)(C)c1cccnc1

Procedure:
The 3-trimethylstannylpyridine reagent was prepared from 3-bromopyridine by reacting the latter with n-butyllithium under nitrogen at -78° C., followed by addition of one equivalent of trimethylstannyl chloride. Aqueous work-up and concentration in vacuo gave 3-trimethylstannylpyridine in 79% yield.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:36][C@H:35]2[NH:37][CH2:38][C@@H:30]1[CH2:31][CH:32]=[CH:33][CH2:34]2.CCN(C(C)C)C(C)C>C(O)C>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:37]2[CH2:38][CH:30]3[N:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)[CH2:36][CH:35]2[CH2:34][CH:33]=[CH:32][CH2:31]3)=[CH:7][CH:8]=1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: O[C@H](COc1cccc2[nH]c3ccccc3c12)CN1CC2C/C=C\CC1CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H](COc1cccc2[nH]c3ccccc3c12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
(S)-4-Oxiranylmethoxy-9H-carbazole (18.5 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.