Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-:2].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[C:17]1([S:23][C:24]2[CH:25]([CH3:48])[C@@H:26]3[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([C:24]2[CH:25]([CH3:48])[C@@H:26]3[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])=[O:2])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1C(Sc2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1C(S(=O)c2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
19 ml of saturated aqueous sodium bicarbonate solution and a solution of 350 mg of 3-chloroperbenzoic acid in 10 ml of methylene chloride were added to a solution of 360 mg of p-nitrobenzyl(1RS,5S,6S)-2-phenylthio-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate in 19 ml of methylene chloride, kept at 0° to 5° C. with ice-water cooling, and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was then diluted with methylene chloride and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by chromatography on a column of silica gel, using a 1/8 mixture of benzene and ethyl acetate as eluent, giving 200 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH2:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH:11]2[OH:14]
Reactant: COC(=O)CC1CC(=O)c2cc(F)ccc2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1Cc2ccc(F)cc2C(O)C1

Procedure:
To a mixture of 8 g. of sodium borohydride and 150 ml. of methanol, 23.5 g. of 7-fluoro-3-(methoxycarbonylmethyl)-1-tetralone are added. The mixture is diluted with 250 ml. of 2N hydrochloric acid after standing for four hours at 25° C; the aqueous mixture is then extracted with chloroform. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to yield methyl 6-fluoro-4-hydroxyl-1,2,3,4-tetrahydro-2-naphthylacetate. the latter compound is dehydrogenated by the process described in Part B of Example 2 to furnish methyl 6-fluoro-4-hydroxy-2-naphthylacetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[NH:12][C:11](=[S:15])[O:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]=[O:17].O>CO.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:16][OH:17])[C:11](=[S:15])[O:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: C=O
Reactant: N#Cc1ccc(-n2oc(=S)[nH]c2=S)cc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-n2oc(=S)n(CO)c2=S)cc1
Reaction time: 2 h

Procedure:
2-(4-Cyanophenyl)-1,2,4-oxadiazolidin-3,5-dithione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-cyanophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dithione.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>ClCCl.CCOC(C)=O>[OH:2][CH2:1][CH2:3][NH:4][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCCO)cc1
Yield: 55.8 %

Procedure:
To a solution of ethanolamine (0.68 g, 11 mmol) and triethylamine (1.10 g, 10.9 mmol) in dichloromethane (20 mL) was added 4-nitrobenzenesulfonyl chloride (2.20 g, 9.9 mmol) portionwise with stirring. The resulting clear yellow solution was stirred at room temperature for 15 min. The clear yellow solution was diluted with equal volume of EtOAc and washed with water and then with 5% HCl. The organic phase was evaporated to dryness to give 1.36 g of light yellow crystalline solid which was dried and used without further purification. δH (200 MHz, DMSO-d6) 2.90 [2H, m, NHCH2CH2OH], 3.36 [2H, m, NHCH2CH2OH], 4.75 [1H, t, OH], 8.00 [1H, m, NH], 8.02 and 8.38 [2×2H, q (A2B2), 2×Nosyl CH].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([NH:23][NH2:24])=[O:22])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:24]/[NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:19]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 68.6 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (40 mg, 0.234 mmol) and 3-morpholinobenzohydrazide (51.9 mg, 0.234 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (60 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H, J=2.4 Hz), 7.42-7.32 (m, 4H), 7.20 (m, 1H), 6.94 (d, 1H, J=8.8 Hz), 3.77 (m, 4H), 3.19 (m, 4H), 2.48 (s, 3H). ESI-MS: 374.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=2)[N:7]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=2)[N:7]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1nc(C#Cc2cccc(C(=O)OC)c2)ccc1O
Product: COC(=O)CCc1nc(CCc2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 57.4 %

Procedure:
Under the conditions of example 1 D, 1.24 g of 3-{3-hydroxy-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 970 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-7.5% ethyl acetate. 1.1 g of 3-{6-[2-(3-methoxycarbonylphenyl)-ethyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:27])=[C:24]([F:26])[F:25]>CN(C)C=O>[F:27][C:23](=[C:24]([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:3][C:2]([F:16])([F:1])[F:17])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Reactant: FC(F)=C(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(SC(F)(F)F)cc1
Yield: 16.9 %

Procedure:
Using 0.50 g of (4-(trifluoromethylthio)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 86 mg of sodium hydride (60% in oil), and 0.74 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethylthio)benzyl)malononitrile (the present compound (54)).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[CH2:10]([Li])CCC.IC.Cl>O1CCCC1.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:10])[S:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: [Li]CCCC
Reactant: Cc1ccsc1C(=O)O
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Methyl-2-thiophenecarboxylic acid (7.11 g) was dissolved in tetrahydrofuran (100 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 69 ml) was slowly added dropwise. The mixture was stirred at -78° C. for 1 hour, and iodomethane (6.2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred at room temperature for 15 hours, poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3,5-dimethyl-2-thiophenecarboxylic acid (4.97 g) as crystals.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH:13]=[C:12]([C:14](OCC)=[O:15])[CH2:11][CH2:10][N:5]12.[H-].C([Al+]CC(C)C)C(C)C.CO.O>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH:13]=[C:12]([CH2:14][OH:15])[CH2:11][CH2:10][N:5]12
Reactant: CCOC(=O)C1=Cc2cc3ccccc3n2CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCC1=Cc2cc3ccccc3n2CC1
Reaction time: 17 h
Yield: 92 %

Procedure:
A solution of 26 g (0.108 mol) of ethyl 6,7-dihydropyrido[1,2-a]indole-8-carboxylate in 850 ml of dry tetrahydrofuran is treated dropwise within 1 hour under a nitrogen atmosphere with a 1M solution of diisobutylaluminium hydride in tetrahydrofuran (220 ml, 0.22 mol). The reaction mixture is stirred for 17 hours and 50 ml of methanol are subsequently added dropwise. After the addition of 1000 ml of water and 500 ml of toluene, the mixture is filtered and the aqueous part of the filtrate is separated and extracted with 250 ml of toluene. The combined organic phases are then dried over anhydrous sodium sulfate and evaporated to dryness. There are obtained 19.8 g (92%) of 6,7-dihydropyrido[1,2-a]indole-8-methanol as a beige solid, m.p. 139°-142° C.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH:10]([C:11]([OH:13])=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]1([S:7][CH:8]2[CH:10]([C:11]([O:13][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[C:18]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:19]=3)=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)C(Sc2ccccc2)C1C(=O)O
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Product: CC1(C)C(Sc2ccccc2)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1

Procedure:
Using the method of Example 3, 3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid is reacted with 4-fluoro-3-phenoxybenzyl bromide to yield 4-fluoro-3-phenoxybenzyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>C1COCC1>[Cl:10][CH2:11][CH2:12][NH:13][C:14]([NH:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[CH:7]=1)=[O:15]
Reactant: O=C=NCCCl
Reactant: Cc1cc(N)cc(C)n1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCCl)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,6-Dimethyl-pyridin-4-ylamine (Example C1.2., 1.22 g, 10 mmol) is dissolved in dry THF (30 mL) and 1-chloro-2-isocyanato-ethane (1.06 g, 10 mmol) is added. The mixture is stirred at r.t. for 15 h. The mixture is evaporated and the residue purified by MPLC to provide the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.N1C=CC=CC=1.[CH3:30][C:31]([CH3:37])([CH3:36])[CH2:32][C:33](Cl)=[O:34]>C(Cl)(Cl)Cl.CO.CO.C(Cl)(Cl)Cl>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:33](=[O:34])[CH2:32][C:31]([CH3:37])([CH3:36])[CH3:30])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1ccc2ncnc(N)c2c1
Reactant: CC(C)(C)CC(=O)Cl
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2ncnc(N)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a mixture of 4,6-diaminoquinazoline hydrochloride (10.0 g), tripropylamine (17.61 g) and dry pyridine (100 ml) was added dropwise during 35 minutes 3,3-dimethylbutyryl chloride (10.34 g) under ice-cooling. the reaction mixture was stirred for 2 hours at the same temperature. To the resultant mixture was added ice-water. The mixture was stirred for 5 minutes and then concentrated under reduced pressure. To the residue was added water and sodium hydrogen carbonate (13.0 g) little by little to give precipitates, which were separated by filtration, washed with water and dried. Thus obtained crude crystals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give a residue, which was suspended in 5% methanol-chloroform solution (70 ml). After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][O:38][CH2:39][Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:37][O:38][CH3:39])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added methoxymethyltributyl-stannane (220 mg, 0.66 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (35 mg). The mixture was heated to reflux for 16 hours, and then cooled. An additional portion of tetrakis(triphenylphosphine)palladium(O) (30 mg) was added, and reflux was continued for a further 8 hours. The solvent was removed in vacuo, and the residue was flash chromatographed using a gradient elution of a mixture of 1% methanol and 99% dichloromethane, through to 5% methanol and 95% dichloromethane, to give the title compound (33 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>>[CH2:12]([S:15]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)(=[O:17])=[O:16])[CH2:13][CH3:14]
Reactant: Cc1ccc(C(Cl)=NO)cc1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)ON=C(Cl)c1ccc(C)cc1

Procedure:
Eight and one-half grams of 4-methylbenzohydroximoyl chloride, prepared as in Example VI-A, was treated with 7.1 g of propanesulfonyl chloride in the same manner as described in Example VI-B. Recrystallization of the oil from ethanol gave 8.1 g of N-(propanesulfonyloxy)-4-methylbenzimidoyl chloride, m.p. 57.5°-60.5°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Na].[CH3:12][O:13][C:14](=[O:23])[C:15]([CH:18](OC)OC)=[CH:16]O.O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]1[CH:16]=[N:9][C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:10][CH:18]=1)=[O:23]
Reactant: N=C(N)c1cccnc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2cccnc2)nc1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
To a solution of nicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylic acid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100° C. under N2 for 3 hours. After this time the reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.7 g, 51%). MS: 216 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]#[C:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[S:8][CH:9]=1)([O:3]C)=[O:2].[OH-].[K+].O.Cl>O1CCCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]#[C:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)[S:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1csc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC(=O)CC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C#Cc3cc(C(=O)O)cs3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 58.7 %

Procedure:
A solution of 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.12 g, 0.427 mmol) and coarsely ground potassium hydroxide (0.045 g, 0.81 mmol) in tetrahydrofuran (2.5 mL), methanol (2.5 mL), and water (0.5 mL) was stirre at room temperature under an argon atmosphere for three days. The reaction was acidified (10% HCl), was extracted three times with 5:95 methanol:dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.25:2.5:97.5 acetic acid:methanol:dichloromethane, provided 4-(4-carboxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as an off- white foam (0.11 g, 94%), mp 75°-76° C. Anal. (C25H26O5S.0.25 H2O) calcd: C, 67.78; H, 6.03; found: C, 67.73; H, 5.80.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH2:35][OH:36])[CH2:24][CH2:25][N:26]3[CH2:33][CH2:32][C:29]4([CH2:31][CH2:30]4)[C@H:28]([OH:34])[CH2:27]3)[C:19](=[O:37])[C@@H:18]2[CH3:38])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(NCC)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[O:36][CH2:35][C@@H:23]([N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[NH:14][C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[C@@H:18]([CH3:38])[C:19]1=[O:37])[CH2:24][CH2:25][N:26]1[CH2:33][CH2:32][C:29]2([CH2:31][CH2:30]2)[C@H:28]([OH:34])[CH2:27]1
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cl
Solvent: CCNCC
Solvent: ClCCl
Product: COC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)[C@@H](C)C1=O
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Methyl chloroformate (9 mg, 0.1 mmol) was added at 0° C. to a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (example 106; 50 mg, 0.10 mmol) in dichloromethane (1 mL). The ice bath was removed, then after 30 min the reaction mixture was cooled to 0° C., treated with diethylamine (4 mg, 50 μmol), and evaporated. Chromatography (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) provided the title compound (52 mg, 93%). White solid, MS (ISP)=557.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:28]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]#[N:27])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:28][C:17]1[C:18]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]#[N:27])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#C[C@H]1CCC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#C[C@H]1CCC[C@@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 85 °C
Yield: 80.9 %

Procedure:
A mixture of cis 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)cyclohexanecarbonitrile (730 mg, 1.72 mmol), ammonium chloride (552 mg, 10.3 mmol) and iron powder (384 mg, 6.88 mmol) in methanol/H2O (3:1, v/v) was heated at 85° C. for 3.5 hr. The cooled reaction mixture was filtered through celite and the filtrate concentrated under vacuum. The residue was dissolved in DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to a foam. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 4% MeOH in DCM) to afford 0.55 g (81%) of cis 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-cyclohexanecarbonitrile. LCMS (Method H, ESI): RT=2.45 min, m+H=396.1; 1H NMR (400 MHz, DMSO) δ: 8.01 (d, 2H), 7.66 (m, 1H), 7.57 (m, 3H), 7.49 (d, 1H), 6.75 (d, 1H), 5.14 (d, 1H), 4.36 (s, 2H), 3.72 (m, 1H), 2.98 (m, 1H), 2.22 (m, 1H), 2.01-1.84 (m, 2H), 1.75 (m, 1H), 1.53-1.36 (m, 3H), 1.22 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:11]3[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)cc(-c2ccc3[nH]ccc3c2)c1
Temperature: 85 °C
Reaction time: 13 h

Procedure:
A mixture of methyl 3-methoxy-5-trifluoromethanesulfonyloxybenzoate (314 mg, 1.00 mmol), 5-indoleboronic acid (193 mg, 1.20 mmol), tetrakis(triphenylphosphine)palladium(0) (57.8 mg, 0.050 mmol), potassium phosphate (318 mg, 1.50 mmol) and 1,2-dimethoxyethane (5.0 ml) was stirred in a nitrogen atmosphere at 85° C. for 13 hours. After left cooled, the reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.