Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([S:4]([CH3:6])=[O:5])[S:2][CH3:1])=[CH:17][CH:16]=1
Reactant: CSCS(C)=O
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSC(Cc1ccc(Br)cc1)S(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
1.182 g of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice 229 mg (1.0 equivalent) of sodium hydride was added. The mixture was stirred for one hour. 1.91 g of p-bromobenzyl bromide (0.8 equivalent) was added, and the mixture was further stirred for 13 hours at room temperature. 50 ml. of methylene chloride was added, and the resulting precipitate was filtered. The filtrate was concentrated at reduced pressure, and subjected to column chromatography (silica gel, methylene chloride) to give 698 mg of methyl 2-(p-bromophenyl)-1-methylthioethyl sulfoxide in a yield of 36.5%.
Reaction SMILES: [CH2:1]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:13][O:14]2)=[CH:18][CH:17]=1
Reactant: CCCCCCCCCC(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 10 (40.5 g, 0.2 mol), 4-bromobenzaldehyde (37 g, 0.2 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9].[CH:15]([O-])([O-])OC.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])/[CH:7]=[C:8](\[O:10][CH3:15])/[CH3:9]
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)Nc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 68.5 g of m-bromo-acetylacetanilide, 39.6 g of methyl orthoformate, 160 ml of methanol and 0.5 g of p-toluene sulfonic acid was stirred for 2 hours at 20° C and after the addition of 1 ml of quinoline, the mixture was evaporated to dryness under reduced pressure. The 83 g of colorless oil residue was taken up in 400 ml of toluene and the mixture was heated at 140° C for 4 hours while distilling the toluene-methanol azeotrope formed. After cooling, the toluene was evaporated under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with a 9-1 mixture of methylene chloride and ethyl acetate and the fraction with an Rf = 0.65 was taken up in isopropyl ether to obtain 44 g of m-bromo-3-methoxy-crotonanilide melting at 110° C.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C(OCC)(=O)C>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OO
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 71 %

Procedure:
A mixture of 5 mmol of benzhydrol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of ethyl acetate was stirred at 75° C. in an oxygen atmosphere (1 atm) for 12 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 50% (selectivity: 70%). Separately, as a result of a gas chromatographic analysis of the reaction mixture, the conversion rate from benzhydrol was 72%, and benzophenone was formed in yield of 71%.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N)(OC(C)(C)C)=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:17])[CH3:2]
Reactant: O=CCc1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccccc1C1CCNCC1

Procedure:
A solution of 4-(2-oxoethylphenyl)-piperidine-N-Boc-amine was stirred in a solution of DCM (3 mL) and trifluoroacetic acid (1 mL) for 1 h, concentrated under reduced pressure, residual solvent was coevaporated twice from methanol, and dried under high vacuum to provide the N-deprotected 4-(2-acetylphenyl)piperidine. Using standard reductive amination conditions 4-(2-acetylphenyl)piperidine was reacted with N-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamide and converted to the citrate salt. MS m/z 612 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.Cl.O1CCCCC1[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([C@@H:34]([NH2:36])[CH3:35])=[CH:33][C:28]=2[N:27]=[CH:26]1.CCN(C(C)C)C(C)C>CCCCO>[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([C@@H:34]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([CH:14]5[CH2:16][CH2:15]5)[NH:11][N:10]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)[CH3:35])=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C[C@H](N)c1ccc2c(c1)ncn2C1CCCCO1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]cnc2c1
Temperature: 160 °C

Procedure:
To a solution of 57 (135 mg, 0.5 mmol) in n-BuOH (3 mL) in a microwave vial was added 126 (184 mg, 0.75 mmol), then DIPEA (0.26 mL, 1.5 mmol) was added dropwise. The vial was sealed with a rubber septa and heated in the microwave for 90 min at 160° C. The solvent was evaporated under reduced pressure and the crude residue was taken up in DCM (5 mL) and MeOH (5 mL) and the solvent was again concentrated in vacuo. The residue was diluted in DMF (2 mL) and filtered to remove any undissolved solids. The filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford 13 mg (6%) of I-46.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[S:23])[CH3:20]
Reactant: CCN=C=S
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=S)NC1CCCc2sccc21
Temperature: 50 °C
Reaction time: 0.38 h

Procedure:
A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 100 ml. of dry tetrahydrofuran, and 6.06 grams of triethylamine is added. After stirring for 15 to 30 minutes, 5.23 grams of ethyl isothiocyanate in 20 ml. of dry tetrahydrofuran is added dropwise, and the mixture is heated for 2 hours at 50° C. The mixture is cooled and filtered, and the filter cake is washed with hexane. The filtrate is evaporated to dryness and poured on ice. The oil is extracted with ether, and the extract is washed with 1N sulfuric acid, water, and saturated sodium bicarbonate solution. The ether extract is dried and evaporated to dryness to afford an oil. This oil crystallizes in ether to afford 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea, melting point 106° C. to 112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[C:14](=[O:18])[O:13][C:12]2=[O:19]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:14]([CH:15]2[CH2:16][CH2:17][CH:11]2[C:12]([OH:19])=[O:13])=[O:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C1OC(=O)C2CCC12
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(NC(=O)C2CCC2C(=O)O)cc1Cl
Yield: 35.4 %

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (1229 mg, 8.06 mmol), 3-oxabicyclo[3.2.0]heptane-2,4-dione (1016 mg, 8.06 mmol) and TEA (1.123 mL, 8.06 mmol) in toluene (10 mL) was stirred at 80° C. for 14 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by COOH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane), and crystallized from ethyl acetate to give 2-((3-chloro-4-cyanophenyl)carbamoyl)cyclobutanecarboxylic acid (795 mg, 2.85 mmol, 35.4%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Si:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]([N:6]2[C:22](=[O:23])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 2-nitro-4-(tert-butyldimethylsilyloxy)aniline (10.3 g, 38.5 mmol) and phthalic anhydride (6.50 g, 41.5 mmol) in toluene (30 mL) was refluxed for 18 h. A Dean-Stark apparatus was fitted to the flask, diisopropylethylamine (0.1 mL) was added and water was removed azeotropically over the next 24 h. About 20 mL of solvent was removed by distillation and the resultant solution allowed to cool to room temperature. The residue was diluted with methylene chloride and passed through a plug of silica gel eluting with methylene chloride. The desired fractions were combined and concentrated in vacuo. Recrystallization from methylene chloride-hexane provided 12.2 g (80%) of the title compound in two crops.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([CH:28]=1)[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1>CO.[Pt]>[NH2:29][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:28][C:13]=1[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[CH3:21])=[O:19]
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1

Procedure:
3-(5-Benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide (0.01 mol) was converted into its corresponding free base. A mixture of the free base (0.01 mol) in methanol (200 mL) was hydrogenated under atmospheric conditions, with 5% Pt/C (2 g) as a catalyst in the presence of 4% thiophene solution (1 mL). After uptake of H2 (3 equiv.), the catalyst was filtered off and the filtrate was evaporated. Toluene was added to the residue, then evaporated again to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13](Cl)=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1COCC1>[NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:14])[C:5]([I:12])=[C:6]([C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:8])[C:10]=1[I:11]
Reactant: C1COCCN1
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: C1CCOC1
Product: Nc1c(I)c(C(=O)N2CCOCC2)c(I)c(C(=O)N2CCOCC2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 5-amino-2,4,6-triiodo-isophthaloyl dichloride (50 g, 84 mmol) was dissolved in anhydrous THF (200 ml), morpholine (29 ml, 333 mmol) was dissolved in 50 ml THF, and added dropwise to the solution over 1 hour. The mixture stirred overnight at ambient temperature. The crude product was loaded onto silica gel (100 g) and separated using a 750 g column eluting with DCM/EtOAc (1:1). This yielded 9 g of the [3-amino-2,4,6-triiodo-5-(morpholine-4-carbonyl)-phenyl]-morpholin-4-yl-methanone.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C32H39N6O2Cl2 [(M+H)+] 609.2506 observed 609.2509.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH:10]=[O:11])(=O)=O.[C:33]1([Sn](CCCC)(CCCC)CCCC)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:28][C:23]1([CH3:27])[CH2:22][CH2:21][C:20]([CH3:29])([CH3:30])[C:19]2[CH:18]=[C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(COc3ccc(C=O)cc3OS(=O)(=O)C(F)(F)F)ccc21
Product: CC1(C)CCC(C)(C)c2cc(COc3ccc(C=O)cc3-c3ccccc3)ccc21
Yield: 64.6 %

Procedure:
3-Trifluoromethylsulphonyloxy-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (42) (0.745 g., 1.58 mmol) is coupled with phenyltributylstannane (0.870 g., 2.38 mmol) via the method of Example 3 to afford 2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy-[1,1'-biphenyl]-5-carboxaldehyde (43) (0.404 g., 1.02 mmol, 65%): chromatographed on silica gel using CH2Cl2 /hexane; 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H, CHO), 7.87 (d, J =2 Hz, 1H, ArH), 7.84 (dd, J=2, 8 Hz, 1H, ArH), 7.57 (m, 2H, ArH), 7.44-7.32 (m, 3H, ArH), 7.25 (m, 2H, ArH), 7.16 (d, J=8 Hz, 1H, ArH), 7.05 (dd, J=2, 8 Hz, 1H, ArH), 5.14 (s, 2H, ArCH2O), 1.65 (s, 4H, CH2CH2), 1.25 (s, 6H, 2×CH3), 1.20 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 190.95 (C=0), 160.72, 145.19, 144.65, 137.22, 132.97, 132.59, 131.86, 131.20, 130.00, 129.54, 128.16, 127.48, 126.71, 124.89, 123.96, 112.57, 70.50, 34.99, 34.27, 34.13, 31.83, 31.80; IR (film) 2960, 2926, 1692, 1596, 1504, 1264, 1182 cm-1 ; MS (DCI) m/e 399 (MH+), 201 (C15H21+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[N+:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([O-:37])=[O:36]>COCCO>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 209 mg (0.6 mmole) of 5-n-butyl-4-[(2'cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (from Example 15, Step C), 209 μl (155 mg, 1.2 mmole) of N,N-diisopropylethylamine, 259 mg (1.2 mmole) of 4-nitrobenzyl bromide, and 2 ml of 2-methoxyethanol was stirred under N2 at room temperature for 2 hours. The solution was then concentrated in vacuo at 30° C. to small volume and then partitioned between a mixture of 25 ml of ether, 5 ml of ethyl acetate, and 25 ml of 0.2 N HCl. The organic phase was washed with an additional portion of 0.2 N HCl and then with saturated NaCl solution. The organic solution was dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (gradient elution with 0-1.6% methanol in CH2Cl2). Concentration of the combined product fractions yielded 252 mg (84%) of the title compound as a sticky foam, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 484 (M+1)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1.C[O-].[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C(O)C>[ClH:1].[CH3:8][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[N:2]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: Cn1ccnc1N
Reactant: COc1ccc(C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C=Nc2nccn2C)cc1
Yield: 30.1 %

Procedure:
2-Amino-1-methylimidazole hydrochloride (0.3 g) was dissolved in ethanol (4 ml), and sodium methoxide (28% methanol solution: 0.5 ml) and p-anisaldehyde (0.34 g) were added. The mixture was heated at reflux overnight. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: methanol-chloroform=5:95), and the solvent in the desired fraction was evaporated. The precipitated pale yellow prisms were separated by filtration using hexane. The resulting crystals were dissolved in chloroform, and 4N hydrochloric acid--ethyl acetate (0.22 ml) was added. The solvent was evaporated, and the precipitated pale yellow was separated by filtration using diethyl ether to give the title compound (0.17 g, 26.9%).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C)C=O>[CH:23]1([CH2:22][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:25][CH2:24]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a mixture of 4-difluoromethoxy-3-hydroxy-benzaldehyde (5.0 g, 27 mmol) and potassium carbonate (5.5 g, 40 mmol) in dimethylformamide (30 ml) under inert atmosphere at 60° C. was added bromoethylcyclopropane (5 g, 37 mmol). The mixture was stirred and heated at 65° C. After 1.5 hour, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (2×25 ml) and water (25 ml). The organic layer was washed with water (25 ml), brine (25 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde as an oil (6.4 g, 100%). 1HNMR (CDCl3): 0.38-0.44 (m, 2H), 0.62-0.75 (m, 2H), 1.15-1.36 (m, 1H), 3.98 (d, J=4.5 Hz, 2H), 6.78 (t, JH-F=75 Hz, 1H), 7.30-7.50 (m. 3H), 9.96 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:34]1(=[O:44])[N:38]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC#CCCCCc1cccc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A solution of 6-(3-chlorophenyl)hexyn-1-ol (11.5 g, 55 mmol), triphenylphosphine (14.5 g, 55 mol) and phthalimide (8.1 g, 55 mol) in dry THF (110 ml) was treated with a solution of diethylazodicarboxylate (9.6 g, 55 mmol) in THF (20 mol) over several minutes. After 16 h, violates were removed in vacuo and the residue treated with ether. The precipitated solid was removed, the filtrate evaporated and the residue purified by flash chromatography on silica using dichloromethane as eluant. Evaporation of the appropriate fractions gave the product as a solid (16.5 g, 89%)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[N:29]([CH2:35][CH:36]1[CH2:38][CH2:37]1)[CH:28]=[C:27]2[C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:37][CH2:38]3)[CH:28]=[C:27]4[C:39]([O:41][CH3:42])=[O:40])[CH:7]=2)=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.24 g) [prepared as described in US2005020590], the product of step iii) (4.3 g), tetrakis(triphenylphosphine)palladium(0) (1.5 g) and potassium carbonate (3.54 g) in DMF (50 mL) was heated to 80° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate and evaporated. The crude product was purified (SiO2, 50 to 70% ethyl acetate in isohexane as eluent) to yield the sub-title compound (2.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=O.F[P-](F)(F)(F)(F)F.[N:21]1([O:30][C:31](N(C)C)=[N+](C)C)[C:25]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:31][O:30][N:21]([CH3:25])[C:11]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)[nH]c2ccccc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1[nH]c2ccccc2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
A mixture of 3-methyl-1H-indole-2-carboxylic acid (from Matrix Scientific, 1.0 g, 5.7 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.3 g, 11 mmol) and triethylamine (4.0 mL, 28 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.84 g, 8.6 mmol) was added and the resulting suspension was stirred at room temperature over the weekend. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-30% EtOAc/hexane) to give the desired product (1.1 g, 88%). LCMS calculated for C12H15N2O2(M+H)+: m/z=219.1. Found: 219.1.