Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:28]
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 360 (M+H+, 100), was prepared in accordance with the general method of example 27 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and ethyl chloroformate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[ClH:10]>C(Cl)Cl>[C:2]([Cl:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: C=C(C)c1ccccc1
Reactant: Cl
Solvent: ClCCl
Product: CC(C)(Cl)c1ccccc1

Procedure:
183 g of α-methyl styrene, dissolved in 600 ml of methylene chloride, were reacted with hydrogen chloride at a temperature of from -12 to -10° C. to yield α-cumyl chloride. The resulting solution was added dropwise at a temperature of -10° C. to a mixture of 3 g of anhydrous aluminum trichloride, 12 g of anhydrous iron trichloride, 0.5 g of phosphorus pentoxide and 1800 ml of methylene chloride in the course of 60 minutes, and the mixture was then stirred at -10° C. for a further 4 hours. To terminate the reaction, the reaction mixture was poured into 6 liters of water at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2

Procedure:
63.3 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.23 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.08 mL (0.46 mmol) DIPEA were stirred in 2 mL of DMF for 2 h at RT. The mixture was diluted with methanol. The precipitate was suction filtered, washed with methanol and diethyl ether and dried in the CAD.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2C2C=CC=C(OC)C=2OC)C2CCCCC2)CCCCC1>[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1OC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Nc2ccccc2)cc1
Yield: 62.9 %

Procedure:
A mixture of dicylcohexylphosphino-2′,3′-dimethoxy biphenyl (17 mg, 0.04 mmol), palladium(II) acetate (5 mg, 0.02 mmol) in toluene (20 mL) was degassed with argon gas for 15 min. To the resulting mixture was added aniline (136 mg, 1.4 mmol), K3PO4 (636 mg, 3.0 mmol), and 4-bromobenzoic acid methyl ester (300 mg, 1.4 mmol) and stirring was continued at reflux temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 15% ethyl acetate in hexane as eluent) to afford 200 mg (63.4% Yield) of 4-phenylamino-benzoic acid methyl ester. A stirred solution of 4-phenylamino-benzoic acid methyl ester (98 mg, 0.43 mmol), Palladium acetate (193 mg, 0.86 mmol) in acetic acid (2 mL) was heated at 110° C. for 15 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 10% ethyl acetate in hexane as eluent) to afford 120 mg (60.3% Yield) of 9H-carbazole-3-carboxylic acid methyl ester. LiOH.H2O (680 mg, 16.2 mmol) was added to a stirred solution of 9H-carbazole-3-carboxylic acid methyl ester (120 mg, 0.53 mmol) in the mixture of methanol (1 mL), THF (3 mL) and H2O (1 mL). The reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was concentrated. The residue was diluted with water, acidified with aqueous 10% aqueous HCl solution, filtered the solid to afford 104 mg (92.85% Yields) of 9H-carbazole-3-carboxylic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)=[O:21]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(=C1C=CC(=NOC(=O)C(Cl)(Cl)Cl)C=C1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.83 h

Procedure:
8 g (36 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 7.2 g (39 mmol) of trichloroacetyl chloride to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 50 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator. The residue is diluted with 2-propanol (2-PrOH) and stirred at room temperature overnight. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of an orange solid,mp 147-148° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 6.97 (dd, 1H), 7.30 (dd, 1H), 7.38 (dd, 1H), 7.52 (s, 5H), 7.65 (dd, 1H). 1H-NMR reveals the presence of a single isomer.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.CC(N(C)C)=O.[NH:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N:25]=[CH:24]1>>[CH:11]1([CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH:29]=[CH:30][C:31]4=[N:23][CH:24]=[N:25][C:26]4=[CH:27]3)=[CH:4][CH:5]=2)=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CC1CCCC1)c1ccc(CCl)cc1
Reactant: c1cc2[nH]cnc2cn1
Solvent: CC(=O)N(C)C
Product: O=C(CC1CCCC1)c1ccc(Cn2ccc3ncnc-3c2)cc1
Temperature: 115 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
The product of Example G (270 mg, 0.0011 moles) was dissolved in 5 mls of dimethylacetamide containing 135 mg (0.0011 moles) of 1H-imidazo[4,5-c]pyridine and stirred under nitrogen at 80° C. for 24 hours and at 115° C. for an additional 6 hours. The reaction appeared to be complete by TLC. After cooling, the solvent was removed by vacuum distillation. Chromatography of the crude product (twice) on silica gel using CH3OH/CH2Cl2 /NH4OH (5/95/1) as the eluent gave 200 mg (57%) of the title compound as a monohydrate m.p.=153°-156° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]([F:15])([F:14])[C:8]1[CH:12]=[C:11]([NH2:13])[O:10][N:9]=1.ClCl.C(Cl)(Cl)(Cl)[Cl:19].[OH-].[Na+]>C(O)(=O)C>[F:6][C:7]([F:15])([F:14])[C:8]1[C:12]([Cl:19])=[C:11]([NH2:13])[O:10][N:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Nc1cc(C(F)(F)F)no1
Agent: CC(=O)[O-]
Agent: ClCl
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1onc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Acetic acid (7 ml) and anhydrous sodium acetate (0.57 g, 7.00 mmole) were added to 3-trifluoromethyl-5-aminoisoxazole (1.06 g, 7.00 mmole) with stirring at room temperature and a solution of chlorine in carbon tetrachloride (8.5 ml, 1 mole/1, 8.40 mmole) was then added dropwise to the mixture. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-water (70 ml) and it was adjusted to pH 10 with a solution of sodium hydroxide. It was extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a brown viscous liquid (0.80 g). This product was purified by column chromatography on silica gel to give a dark red liquid (0.54 g). It was further distilled under reduced pressure to give the title compound as a colorless liquid. Yield: 0.41 g (31.5%), b.p. 73.0°-74.5° C./4.0 mmHg. The structure of this product was confirmed with IR and NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1cn[nH]c1
Product: COc1ccc2c(-c3cn[nH]c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 1H-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 221(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C:26](=[O:31])[CH:25]([CH3:24])[NH:29][C:28]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1NC(=O)NC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(C)C4=O)cc3)CC2)c(C)c1
Yield: 20.2 %

Procedure:
Using (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 5-methylimidazolidine-2,4-dione (55 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (33 mg) was obtained.
Reaction SMILES: O.O.C([O-])(=O)C.[Zn+2:7].C([O-])(=O)C.[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2>CO>[CH:15]1[CH:14]=[C:13]([O-:12])[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:16]=1.[CH:15]1[CH:14]=[C:13]([O-:12])[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:16]=1.[Zn+2:7]
Reactant: Oc1cccc2cccnc12
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: [O-]c1cccc2cccnc12
Yield: 89.4 %

Procedure:
Zinc acetate dihydrate (1.0 g) was dissolved in 75 ml. of hot methanol and 1.4 g of 8-hydroxyquinoline was added to the homogeneous solution. A yellow precipitate formed after a few minutes and the solution was stirred at reflux for 3 hours. The solution was allowed to cool and the precipitate was isolated by filtration and washed with methanol and petroleum ether. After air drying, 1.44 g of bis(8-hydroxyquinolinato)zinc was obtained as a bright yellow solid.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH:16](O)=[O:17]>>[CH2:1]([O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15][CH:16]=[O:17])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: O=CO
Reactant: CCON=C(C(=O)OC)c1nsc(N)n1
Product: CCON=C(C(=O)OC)c1nsc(NC=O)n1
Temperature: 75 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
Methyl 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (5.75 g, 25 mmol) in 99% formic acid (16.3 g) was heated under stirring at 75° C. for 6 hrs. The reaction mixture was treated in the same procedure as in Example 8 to give methyl 2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (3.2 g, yield: 49.6%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To the solution of 2-chloro-3-nitrobenzoic acid (1 g, 4.96 mmol), DMF (0.02 ml, 0.258 mmol) in DCM (20 mL) at 0° C. was added dropwise oxalyl chloride (0.478 ml, 5.46 mmol). The reaction was warmed to rt after the addition. After 3 h, methanol (10 mL) was added dropwise to the reaction mixture and the reaction was stirred at rt for 18 h and then the reaction was concentrated. The residue was dissolved in dichloromethane and passed through a plug of silica gel eluting with a 50% ethyl acetate/n-hexanes mixture. The filtrate was concentrated in vacuo to give the title compound as a white solid (1 g, 93% yield). MS (ESI) m/z: 216.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15])[CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCBr
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCn1c(=O)c2c(ncn2CCC)n(C)c1=O

Procedure:
20.8 g of 3-methyl-7-propyl-xanthine, 13.8 g of anhydrous potassium carbonate and 13.5 g of 4-bromo-but-1-ene are refluxed for 8 hours in 150 ml of dimethylformamide, and the solvent is then removed under reduced pressure. The residue is then dissolved in 150 ml of 1 N sodium hydroxide solution and the alkaline solution is extracted with methylene chloride. The residue obtained after evaporation of the methylene chloride is triturated with 100 ml of diisopropyl ether and unreacted 3-methyl-7-propyl-xanthine is removed. 15.6 g (70% of theory relative to 3-methyl-7-propyl-xanthine consumed) of the title compound of melting point 48° C. (from n-hexane) are obtained from the filtrate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:22]>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH2:21][CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: CCc1ccccc1N
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1CC
Temperature: 65 °C
Reaction time: 4 h
Yield: 29.8 %

Procedure:
A mixture of 3-propanoyl-4-chloro-8-(2-methylthioethoxy)quinoline (0.093 g, 0.34 mmol) and 2-ethyl aniline (0.048 g, 0.39 mmol) in acetonitrile (1 ml) was heated to 65° C. and stirred 4.0 h. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed (SiO2 ; ethyl acetate) yielding 40 mg (30%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[CH:30][S:31][CH:32]=1)[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[CH:30][S:31][CH:32]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1cscn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cscn1
Reaction time: 0.42 h
Yield: 76.9 %

Procedure:
To a solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetate (syn isomer) (2.2 g) and anisole (2.2 ml) in methylene chloride (22 ml) was added trifluoroacetic acid (4 ml) at ambient temperature and the mixture was stirred at the same temperature for 25 minutes. To the reaction mixture was added ethyl acetate and the solution was washed with water. To the separated organic layer was added water and the mixture was adjusted to pH 7.5 with 20% aqueous solution of sodium carbonate. The separated aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid. The acidified solution was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with diisopropyl ether and n-hexane to give 2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (1.07 g), mp. 136°-139° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1(NC(NC2CCCCC2)=O)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH:9][C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]=[CH:11][CH:12]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: O=C(Cc1ccc2ncccc2c1)NNc1ccc(Cl)nn1

Procedure:
To a suspension of 3-chloro-6-hydrazinylpyridazine (3 g, 20.75 mmol) and 2-(quinolin-6-yl)acetic acid (4.27 g, 22.83 mmol) in DCM (200 mL) was added DCC (5.14 g, 24.90 mmol). The solution was stirred at it over weekend. The title compound as a white solid containing some dicyclohexyl urea was collected and used in the next step without further purification (8 g, 100%). LCMS (method A): [MH]+=314.1, tR=2.851 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]Cl.C(#N)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19]([I:23])[C:18]([O:21][CH3:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Reactant: ClI
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CO
Product: COc1cc2c(cc1I)C1CCN(C(=O)OC(C)(C)C)CC1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a solution of 7-methoxy-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (500 mg, 2 mmol) in methanol (7 mL, 200 mmol) was added dropwise a solution of iodine monochloride (340 mg, 2.1 mmol) in 5 ml of methanol at RT. The mixture was stirred overnight at RT. After 18 h, the solvent was removed and the crude reaction mixture was treated with 50 mL of acetonitrile, di-tert-butyl dicarbonate (0.5 mL) and 10 mg of DMAP (10 mg). The mixture was stirred overnight at RT. After 18 h, solvent was removed and the crude product was purified by ISCO chromatography (Hexane:EtOAc 70:30) which was obtained as a syrup (321 mg, 45%). MS m/z 454 [M+H]+
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:8]([C:10]1[CH:25]=[CH:24][C:13]([CH:14]=[C:15]([C:21](=O)[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)#[N:9].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:8]([C:10]1[CH:25]=[CH:24][C:13]([CH:14]2[N:4]3[N:5]=[N:6][N:7]=[C:3]3[NH:2][C:21]([CH3:22])=[C:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)#[N:9]
Reactant: Nc1nnn[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 5-amino-1,2,3,4-tetrazole hydrate (1.0 g, 9.7 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (2.6 g, 10.7 mmol, 1.1 eq.) were dissolved in DMF (50 ml), and solid sodium bicarbonate (4.1 g, 48.5 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered and the DMF from the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol and stirred overnight. The product was filtered off and dried under high vacuum. This gave 950 mg (32% of theory) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 1-bromo-4-fluorobenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O)[CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:15]/[CH2:14][C:13]([CH:10]1[CH2:12][CH2:11]1)([CH3:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)C1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1CC1
Yield: 75.2 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with 3-cyclopropyl-3-methyl-butyraldehyde (0.68 g, 5.3 mmol) in CH2Cl2 at room temperature for 5 h to give [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:12][Br:14])[O:13]2)=[CH:6][CH:7]=1
Reactant: C=CCCC(O)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C2CCC(CBr)O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A mixture of 7.4 g of 1-(4-fluorophenyl)-4-penten-1-ol and 8.0 g of N-bromosuccinimide in 100 ml of chloroform is stirred at room temperature for 3 hours. The reaction mixture is then washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant to give 9.8 g of 2-(4-fluorophenyl)-5-(bromomethyl)tetrahydrofuran as colorless oil, nD27 1.5218.