Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[CH:9]=1)#[N:4]>O>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[CH2:10][N:8]1[CH:9]=[C:5]([C:3]([NH2:4])=[O:1])[N:6]=[N:7]1
Reactant: N#Cc1cn(Cc2c(F)cccc2F)nn1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
1 N sodium hydroxide solution (0.11 ml) is added to a mixture of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole (2.20 g) and water (44 ml) at an external temperature of 95-100°C. while stirring. After 90 minutes, the suspension is cooled to 10°C. and the product is isolated by filtration, washed with water and dried at about 60°C. in vacuo. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained in this manner; yield: 99.2% by weight modification A.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9].[CH3:11][O:12][C:13]([CH3:17])([CH3:16])[CH:14]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:11][O:12][C:13]([CH3:17])([CH3:16])[CH2:14][NH:2][C:3]1[N:7]=[CH:6][NH:5][C:4]=1[C:8]([NH2:10])=[O:9]
Reactant: COC(C)(C)C=O
Reactant: NC(=O)c1nc[nH]c1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(C)(C)CNc1nc[nH]c1C(N)=O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
5-Amino-4-imidazolecarboxamide hydrochloride (0.162 g, 1.0 mmol) and 2-methoxy-2-methylpropanal, which was obtained from Example 3(a) (0.204 g, 2.0 mmol) were mixed in methanol (3 mL) at r.t. Acetic acid (141 μL, 2.46 mmol) mL) was then added and the mixture was allowed to stir for 30 min followed by addition of NaCNBH3 (0.063 g, 1.0 mmol). After 3 h, additional 2-methoxy-2-methylpropanal (0.060 g, 0.59 mmol) was added. The reaction mixture was stirred at r.t. for 17 h and was then concentrated and purified by flash silica gel chromatography (CHCl3:MeOH=5:1). The title compound was obtained as an oil in 73% yield (0.155 g). MS (ESI) m/z 213 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][C:16](=O)[CH2:17]2)[C:13]1=[O:22])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][C:16](=[C:24]([C:23]#[N:27])[C:25]#[N:26])[CH2:17]2)[C:13]1=[O:22])[CH3:2]
Reactant: N#CCC#N
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(=O)CC2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(=C(C#N)C#N)CC2C1=O

Procedure:
0.500 g (1.70 mmol) of 2-(2,6-diethyl-4-methylphenyl)tetrahydropentalene-1,3,5-trione (example I-a-4 from WO 2010/040460), 250 mg of malononitrile, 150 mg of ammonium acetate and 0.3 ml of glacial acetic acid in 30 ml of toluene are heated at reflux for 2 h. After cooling, the solvent is distilled off and the mixture is taken up in ethyl acetate, washed twice with water, then dried (magnesium sulphate) and concentrated on a rotary evaporator. What remains is a yellow oil which is chromatographed on silica gel using ethyl acetate/hexane 1:6. This gives 0.32 g (56%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:9]5[CH:10]=[C:11]6[C:6]([CH:5]=[CH:4][CH:3]=[C:2]6[NH:1][S:45]([C:42]6[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=6)(=[O:47])=[O:46])=[CH:7][CH:8]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:36][CH:35]=2)[S:32]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2cccc3ccc(Oc4ccc5nc(COc6ccc(CC7SC(=O)NC7=O)cc6)n(C)c5c4)cc23)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
A mixture of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g), p-toluenesulfonyl chloride (0.30 g), triethylamine (0.16 g) and anhydrous tetrahydrofuran (8 ml) was stirred at 50° C. for 5 hours and then at 70° C. for 2 hours. The reaction mixture was concentrated. To the residue was added water and the precipitate was washed with water and tetrahydrofuran to afford the title compound (0.14 g, mp 137-144° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Na+].[I-].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>CN(C=O)C.O>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][NH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: COCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
Methyl 2-amino-3-nitrobenzoate (3.82 mmol, 0.75 g) in DMF (20 mL) was added NaI (8.40 mmol, 1.26 g). The reaction solution was stirred at 0° C. for 5 min and then added NaH (5.00 mmol, 0.20 g) at 0° C. The reaction solution was stirred at 0° C. for 30 min and then added 1-bromo-3-methoxypropane (5.00 mmol, 0.77 g). The reaction solution was heated to 80° C. and kept stirring at 80° C. for 6 hr. After cooling down the reaction solution was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, EtOAc-hexane: 5:95) to afford methyl 2-(3-methoxypropylamino)-3-nitrobenzoate (44A) (1.49 mmol, 800 mg, yield: 78.1%). ESI-MS: m/z 269.3 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][C:7](=O)[NH:6][C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C=O)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][C:7]1[N:6]=[C:5]2[O:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:2]([I:1])[C:3](=[O:19])[C:4]2=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1ccc2c(=O)c(I)c(-c3ccccc3)oc2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(I)c(-c2ccccc2)oc2nc(Cl)ccc12
Reaction time: 144 h
Yield: 74 %

Procedure:
To a suspension of 3-iodo-2-phenyl-8H-pyrano[2,3-b]pyridine-4,7-dione (13 mg, 0.036 mmol) in DCM (3 mL) was added DMF (0.03 mL) and thionyl chloride (0.1 mL). The mixture was heated under reflux for 3 hours, followed by standing at RT for 6 days. Upon evaporation, the residue was subjected to flash chromatography (SiO2, gradient 10 to 25% ethyl acetate in cyclohexane) to afford the title compound (10 mg, 74%) as a colourless gum. LCMS (Method B): RT=4.35 min, [M+H]+=384/386.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]2[CH:19]=[CH:20][N:21]=[C:15]2[CH:14]=1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]2[C:19]([I:8])=[CH:20][N:21]=[C:15]2[CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COC(=O)c1ccn2c(I)cnc2c1
Reaction time: 8 h
Yield: 88 %

Procedure:
NIS (1.5 eq, 1.06 mmol, 238 mg) was added in one portion to a stirred solution of imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (0.705 mmol, 124 mg) in acetonitrile (3 mL). The resulting mixture was stirred overnight. The resulting precipitate was filtered and washed with ethyl acetate. Drying in vacuo at room temperature afforded 3-iodo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester in 88% yield. m/z (M+H)=303.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
To a stirred solution of 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (4.4 gm, 19.05 mmol) in dichloromethane (100 mL) was added pyridine (6.15 mL, 76.19 mmol) under ice cold conditions, followed by addition of benzene sulfonyl chloride (6-01) (6.07 mL, 47.62 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (7-01) (2.3 gm, 32.51%) as an off white solid.
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].Cl>O.C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([C:18]#[N:19])=[N:3][OH:4]
Reactant: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
85% Potassium hydroxide (0.40 g, 6 mmol), toluene (5 ml) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.26 g, 5 mmol). The mixture was stirred at room temperature for 8 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with hydrochloric acid, extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide (1.30 g, Yield: 92.8%, E/Z=15/85).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a suspension of 3-nitrobenzoic acid (6.5 g, 38.9 mmol) in DCM (50 ml) was added oxalyl chloride (5 ml, 58.1 mmol) and DMF (0.5 ml, 6.46 mmol), respectively. The resulting mixture was stirred at room temperature until a clear solution was formed. The solvent was removed under vacuum. 3-Nitrobenzoyl chloride thus obtained was dissolved in DCM (50 ml), Et3N (10.13 ml, 72.7 mmol) and thiomorpholine (5 g, 48.5 mmol) were added at 0° C. Reaction mixture was gradually allowed to reach to room temperature and stirred for 2 hrs. The reaction mixture was concentrated under vacuum and cold water was added to the residue, the solid obtained was filtered and dried under vacuum to give the product (9.2 gm).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.[CH2:16](Br)[CH2:17][CH:18]=[CH2:19]>>[CH2:19]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([OH:15])[CH:10]=1)[CH2:18][CH:17]=[CH2:16]
Reactant: C=CCCBr
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Product: C=CCCOc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine was reacted with but-3-enyl bromide under similar conditions to those described in Example 7a(i) to give 6-(4-but-3-enyloxy-2-hydroxyphenyl)-3-chloropyridazine.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)(C)C>>[C:1]1([N:7]2[C:11]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: c1ccc(-n2cccn2)cc1
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C

Procedure:
The title compound, brown solid (2.0 g, 76%), MS (ISP) m/z=271.6 [(M+H)+], mp 132° C., was prepared in accordance with the general method of intermediate A from commercially available 1-phenyl-1H-pyrazol (1.40 g, 9.71 mmol) and commercially available 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[H][H]>C(O)(C)(C)C.O>[ClH:1].[C:2]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:14])[CH2:9][CH2:10]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)Oc2ccccc2C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: N=C(N)N1CCC(CCC(=O)Oc2ccccc2C(=O)O)CC1
Yield: 79.8 %

Procedure:
5.5 g of o-benzyloxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride was dissolved in a solution of 60 ml of t-butyl alcohol and 60 ml of water. 225 mg of 10% paradium-carbon was added to the solution, and the mixture was stirred at room temperature for 1 hour in the presence of hydrogen (starting pressure: 2.4 kg/cm2). The catalyst was removed by filtration, and the solvent was removed. The residue was washed with t-butyl alcohol to obtain 3.5 g (yield: 79.7%) of o-hydroxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 192° to 194° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:21][O:20][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:31])[C:5]=2[CH:14]=1)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)C(c1ccccn1)=CC(C)(C)O2
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
402 mg of methyl 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxylate were dissolved in 15 ml of dichloromethane at room temperature and 330 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. The product was recrystallized from t-butyl methyl ether to give 65 mg of 2-[6-(methoxycarbonyl)-2,2-dimethyl-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 155°-157° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3].[CH:9]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:17]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C:18]2([F:26])[F:25])[CH:10]=1.Cl>>[F:26][C:18]1([F:25])[C@H:19]([OH:24])[C@@H:20]([CH2:22][OH:23])[O:21][C@H:17]1[N:11]1[CH:10]=[CH:9][C:15]([NH:16][C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3])=[N:14][C:12]1=[O:13]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: COCCOC(=O)Cl
Agent: Cl
Product: COCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 60 %

Procedure:
Using Method A and 2-methoxyethyl chloroformate, gemcitabine hydrochloride was converted to 50 (white solid, 60% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.25-8.27 (d, 1H), 7.11-7.13 (d, 1H), 6.30-6.32 (t, 1H), 6.18-6.22 (t, 1H), 5.32-5.35 (t, 1H), 4.23-4.26 (m, 2H), 4.13-4.22 (m, 1H), 3.86-3.90 (m, 1H), 3.78-3.81 (m, 1H), 3.62-3.66 (m, 1H), 3.54-3.57 (m, 2H), 3.32 (s, 3H).
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[S:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)sc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)sc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzothiazole-7-yl)-acetonitrile (40 mg 0.23 mmol) (Starting Material 8) was suspended in concentrated H2SO4 /H2O (1/1, 2 mL) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. Subsequently, to a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (88.4 mg, 1.36 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[5,4-e]indol-7-one. (Yield 12 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[N:19]=[C:18](Cl)[N:17]=3)[C@H:12]([CH3:30])[CH2:11]2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br.[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[N:19]=[C:18]([N:34]4[CH2:35][CH2:36][CH2:37][C@H:33]4[CH3:32])[N:17]=3)[C@H:12]([CH3:30])[CH2:11]2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: C[C@@H]1CCCN1
Reactant: COc1ncc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)[C@H](C)C2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCC[C@H]4C)n3)[C@H](C)C2)n1

Procedure:
Dissolve 5-chloro-4-((R)-4-(2-chloro-6-(4-fluorophenyl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-methoxypyrimidine (45 mg, 0.1 mmol) and (R)-2-methylpyrrolidine hydrobromide (0.2 mmol, prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54:209-216) in CH3CN (2.0 mL) under nitrogen atmosphere. Add K2CO3 (55 mg, 0.4 mmol) and heat at 80° C. for 20 hours. Concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 20% EtOAc/hexane to afford the title product as viscous oil. NMR (CDCl3) δ 1.3 (6H, m), 1.69 (1H, m), 1.91 (1H, m), 2.06 (2H, m), 3.21 (1H, m), 3.35 (2H, m), 3.63 (2H, m), 3.94 (3H, s), 4.28 (2H, m), 4.45 (2H, m), 4.64 (1H, bs), 6.19 (1H, s), 7.07 (2H, t), 7.97 (2H, m), 8.08 (1H, s). Mass spec m/z=498.17.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:23][CH3:24])[CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][C:16]=2[O:23][CH3:24])[CH2:7]1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(Cl)ccc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-chloro-2-methoxybenzoic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:23]=[C:22]3[S:32][C:33]([CH3:42])([CH3:41])[C:34]([O:36]C(C)(C)C)=[O:35])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>ClCCl>[CH:8]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:24][N:23]=[C:22]3[S:32][C:33]([CH3:42])([CH3:41])[C:34]([OH:36])=[O:35])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (25 mg, 0.051 mmol) in dichloromethane (2 mL) and the mixture stirred at room temperature for 20 hours. The mixture was then concentrated, dissolved in ethyl acetate (5 mL) and washed with water (2×5 mL). The combined aqueous layers were washed with ethyl acetate (5 mL) and the combined organic extracts were dried over sodium sulfate, filtered concentrated and purified by column chromatography (1% AcOH/40% EtOAc/hexanes) to give 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as a brown paste (14 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].[H-].[Na+].[CH3:34]I>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH3:34])[N:11]=[CH:10]2)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cnn(C)c2cc1C
Yield: 73 %

Procedure:
The compound (871 mg, 2.07 mmol) of step B was dissolved in N,N-dimethylformamide (19 ml), 60% sodium hydride (109 mg, 2.73 mmol) was added under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hr. Then, methyl iodide (0.44 ml) was added, and the mixture was stirred under ice-cooling for 90 min. The reaction mixture was diluted with 10% citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane→ethyl acetate-methanol) to give the title compound (653 mg, yield 73%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: Clc1ccc(-c2ccccn2)cn1
Product: CCN1CCN(c2ccc(-c3ccccn3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethylpiperazine and 6′-chloro-[2,3′]bipyridinyl.