Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:29]([CH3:32])([CH3:31])[CH3:30])=[C:13]([CH2:26][CH2:27][CH3:28])[C:14]2[O:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C.O>O1CCCC1>[OH:10][C:11]1[C:12]([C:29]([CH3:30])([CH3:32])[CH3:31])=[C:13]([CH2:26][CH2:27][CH3:28])[C:14]2[O:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCc1c2c(c(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c2c(c(C(C)(C)C)c(O)c1C(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Yield: 32.1 %

Procedure:
Lithium aluminum hydride (0.08 g) was suspended tn tetrahydrofuran (5 ml) under a nitrogen atmosphere. A solution of 5-acetoxy-4,6-di-tert-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran (0.60 g) in tetrahydrofuran (5 ml) was added dropwise to the suspension and the mixture was refluxed for 4 h. After cooling the reaction mixture to room temperature, water was added dropwise to quench the excess lithium aluminum hydride. Thereafter 1N aqueous sodium hydroxide (5 ml) was added and the mixture was subjected to extraction with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (5% ethyl acetate in n-hexane) to afford 5-hydroxy-4,6-di-tert-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran [0.17 g (yield, 32%)] as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[C:34](Cl)=[C:33](Br)[C:32]=2[O:49][CH2:50][CH2:51][CH2:52]Cl)[O:11][C@@H:10]1[CH2:54][O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[NH4+].[Cl-:69]>C1COCC1>[Cl:69][C:34]1[C:35]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:36][C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:10]([CH2:54][O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:11]2)=[C:32]2[C:33]=1[CH2:52][CH2:51][CH2:50][O:49]2
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCCl)c(Br)c2Cl)cc1
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCCO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of chloride 29-1 (1.03 g, 1.09 mmol) in THF (30 mL) was added n-BuLi (2.5 M in hexane, 0.87 mL, 2.18 mmol) at −78° C. The mixture was allowed to slowly warm to r.t. and stirred at r.t. for 12 hours. To the mixtures was added aqueous saturated NH4Cl solution (50 mL). The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 30 (255 mg, 28%).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:15])([CH3:14])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:16]([N:18]=[C:19]1[NH:23][CH2:22][CH2:21][S:20]1)#[N:17]>N1C=CC=CC=1>[C:16]([N:18]=[C:19]1[N:23]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:15])([CH3:14])[C@H:2]2[OH:1])[CH2:22][CH2:21][S:20]1)#[N:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: N#CN=C1NCCS1
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A mixture of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.51 g), 2-cyanoiminothiazolidine (0.64 g) and pyridine (4.1 ml) was heated at 100° C. for 1.5 hours. Pyridine was removed under reduced pressure. The residue was diluted with ethyl acetate (20 ml). The solution was washed with water (20 ml and 15 ml), 5% aqueous hydrochloric acid (15 ml×2) and saturated aqueous sodium chloride (15 ml) successively, treated with charcoal, and then dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was triturated with ethyl acetate, to give trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.47 g).
Reaction SMILES: C([O:4][CH:5]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C>[OH-].[K+]>[CH3:22][N:20]([CH3:21])[CH2:19][CH:5]([OH:4])[CH:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(CN(C)C)C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 99 %

Procedure:
2-Acetoxy-3-dimethylamino-1,1-diphenyl-propane (200 mg) was dissolved in methanolic potassium hydroxide (5% 10 ml.) and the solution allowed to stand overnight. Solvent was evaporated and the residue dissolved in ether and water. The ether extract was dried and evaporated to give 3-dimethylamino-1,1-diphenyl-propan-2-ol (170 mg., 97%), m.p. 72° - 73°.
Reaction SMILES: [CH3:1][O:2][CH2:3][PH:4]([CH2:6][CH2:7][CH:8]=O)=[O:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([N:17]=[CH:8][CH2:7][CH2:6][PH:4]([CH2:3][O:2][CH3:1])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: COC[PH](=O)CCC=O
Solvent: Cc1ccccc1
Product: COC[PH](=O)CCC=NCc1ccccc1
Yield: 91 %

Procedure:
Sodium sulfate anhydride (120 mg) was added to a solution obtained by dissolving 3-(methoxymethylphosphinyl)-propanal (60 mg) and benzylamine (42.8 mg) in toluene (3 ml), then the resultant solution was stirred for an hour at room temperature. Sodium sulfate was filtered out, and the resultant filtrate was concentrated to obtain N-benzyl-3-(methoxymethylphosphinyl)-propylideneamine (87 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:28](=[O:29])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)[C:9]#[N:10]
Reactant: COc1ccc(N=C=O)cc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)C(C#N)C(=O)c2cccn2C)cc1
Reaction time: 8 h

Procedure:
The suspension of 2.0 g of the 1-methyl-β-oxo-2-pyrrolpropionitrile in 50 ml of toluene and 1.6 g of triethylamine is treated with 2.1 g of p-methoxyphenylisocyanate. The mixture is warmed gently until all is dissolved and allowed to stand overnight at room temperature. It is evaporated, the residue is taken up in methanol and combined with 10 ml of 10% aqueous sodium hydroxide and 250 ml of water. The alkaline solution is filtered, acidified with 5 N hydrochloric acid and the precipitate formed collected. It is washed with water, dried, triturated with warm methanol-ethyl acetate, and recrystallized from ethyl acetate, to yield the 1-methyl-β-oxo-α-(p-methoxyphenylcarbamoyl)-2-pyrrolpropionitrile melting at 192°-193°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][CH2:22][CH2:23][C@H:24]([NH:28][CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH2:25][O:26][CH3:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[N:28]([C@H:24]([CH2:25][O:26][CH3:27])[CH2:23][CH2:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:29][CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC[C@H](CCOCc1ccccc1)NCC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H](CCOCc1ccccc1)N(CC(OC)OC)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.12 g, 5.92 mmol) and ((S)-3-benzyloxy-1-methoxymethyl-propyl)-(2,2-dimethoxy-ethyl)-amine (1.60 g, 5.38 mmol) in N,N-dimethylformamide (16 mL) were added 4-methylmorpholine (1.63 g, 16.1 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.07 g, 8.06 mmol) at room temperature. The reaction mixture was stirred at room temperature was stirred at room temperature for 16 h, then partitioned between water and heptane/ethyl acetate 1:1. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) furnished the title compound (2.20 g, 87%). Colorless oil, MS (ISP)=469.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5][N:4]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH2:3]2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(O)C2)cc1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(OC2CN(S(=O)(=O)c3ccc(C)cc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (15 g, 47 mmole), p-methoxyphenol (7 g, 57 mmole) and triphenylphosphine (15 g, 57 mmole) in 300 ml benzene, cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (10 g, 57 mmole) in 100 ml benzene. After stirring two hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine (8 g, 96%, m.p. 130°-132° C.), then evaporated to an oil which was purified by column chromatography (silica gel, dichloromethane) to give an oil. This oil was crystallized from hexane-ether to give 6 g (30%) of 1-(p-methoxyphenoxy)-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine, m.p. 84°-85° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH2:22][CH:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:21][C:18]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([CH:22]=[CH:23][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:8]=1)([CH3:19])[CH3:20]
Reactant: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1nc(C=Cc2cccnc2)nc(C(C)(C)C)c1O
Temperature: 190 °C
Yield: 49.8 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-α-(3 -pyridinyl)-2-pyrimidineethanol (350 mg), sodium acetate (10 g) and acetic anhydride (7 mL) in toluene (100 mL) is heated at reflux for 8 hours. The reaction mixture is cooled and the solvent is evaporated. Dichlorobenzene (30 mL) is added and the reaction mixture is heated at 190° C. for 30 minutes. The reaction mixture is cooled and partitioned between ethyl acetate and water. The aqueous layer is adjusted to pH 4 with 1N HCl. The organic layer is collected and evaporated. Purification of the residue by flash chromatography (silica, 1:1 ethyl acetate/hexane) followed by recrystallization from hexane gives pure 4,6-bis(1,1-dimethylethyl)-2-[[2-(3-pyridinyl)]ethenyl]-5-pyrimidinol (130 mg, 40%); mp 150°-151° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:17][N:18]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:19](=[O:20])[N:18]([CH3:17])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(C)C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 74.1 %

Procedure:
Into 80 ml of dichloromethane, were dissolved 10.8 g of 1-(p-fluorophenyl)piperazine and 6.1 g of triethylamine. To the solution, while being stirred and cooled in ice, was added dropwise 10.0 g of 2,4,4-trimethylallophanoyl chloride. After one hour of reaction at room temperature, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a mixture of ethanol and ether to obtain 13.7 g (74% yield) of 1-(p-fluorophenyl)-4-(2,4,4-trimethylallophanoyl)piperazine having a melting point of 83°-84° C.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:16]=CC(O)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>N1C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Acetic anhydride (50 ml) is added to a solution of 4-nitrophenol (5.56 g, 40 mmol) in dry pyridine (50 ml). The solution is stirred at ambient temperature for 2 hr and then at 70° C. overnight with a reflux condenser under Ar. The mixture is poured onto ice, and a white precipitate is formed after standing for several hours. Water (400 ml) is added, and the white solid is collected by vacuum filtration and dried in vacuo to yield a white solid (5.1 g, 70%). ESI-MS (M+H)+: 182.2. 1H-NMR (CDCl3) δ 8.30 (2H, d, J=9.0 Hz, NO2CCH), 7.31 (2H, d, J=9.0 Hz, OCCH), 2.25 (3H, s, CH3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O>[Pd].C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])[CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)CCc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F

Procedure:
Product from Step F (8.93 g, 18.4 mmol), and 10% palladium on carbon (550 mg) were suspended in THF (200 mL)/water (20 mL) and placed under a hydrogen atmosphere (1 atm) for 7 hours. The reaction solution was filtered through a Celite pad and concentrated in vacuo to provide the title compound as a white foam which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([S:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH2:23][N:24]1C(=O)C2C(=CC=CC=2)C1=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.O.NN>CCO>[C:1]([S:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH2:23][NH2:24])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
2-[2-(Tritylsulfanyl)benzyl]-1H-isoindole-1,3(2H)-dione (4.7 g, 9.19 mmol) was suspended in EtOH (150 mL) and treated with hydrazine monohydrate 65% (4.66 mL, 62 mmol). The mixture was heated under reflux for 1.5 h, cooled to RT and the precipitate was filtered. The filtrate was concentrated, triturated with EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (3.0 g, 86%) as a colourless oil. 1H NMR (300 MHz, CDCl3): δ 7.34-7.28 (6H, m), 7.26-7.18 (9H, m), 7.15 (2H, m), 7.10 (1H, m), 6.93-6.85 (1H, m), 3.40 (2H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2([CH2:17][NH2:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:9][CH:10]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2([CH2:17][NH:18][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:23]4[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=4)[CH:27]=3)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[S:9][CH:10]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3cccs3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3cccs3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 46 %

Procedure:
This compound was synthesized from (4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 46%): 1H NMR (400 MHz, MeOD) δ 8.47 (t, J=1.5 Hz, 1H), 8.26 (m, 1H), 8.00 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.63-7.61 (m, 2H), 7.46 (dd, J=3.8 Hz, 1.0 Hz, 1H), 7.29 (dd, J=5.0 Hz, 1.0 Hz, 1H), 7.01 (dd, J=5.0 Hz, 3.8 Hz, 1H), 3.95-3.92 (dt, J=11.9 Hz, 4.0 Hz, 2H), 3.71 (s, 2H), 3.62-3.56 (m, 2H), 2.42-2.38 (d, J=13.8 Hz, 2H), 2.08-2.02 (ddd, J=14.3 Hz, 10.4 Hz, 4.4 Hz, 2H), MS (ESI) m/z: Calculated for C23H19F3N4O3S2: 520.09. found: 521.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[C:21]([Cl:22])=[C:20]([F:23])[C:19]([Br:24])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[C:19]([Br:24])[C:20]([F:23])=[C:21]([Cl:22])[C:15]=1[F:14])=[O:8])=[O:5]
Reactant: Nc1cc(Br)c(F)c(Cl)c1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Br)c(F)c(Cl)c1F
Reaction time: 5 h

Procedure:
3.75 g of 2,6-difluorobenzoyl isocyanate are added dropwise at room temperature, with stirring, to 5 g of 2,4-difluoro-3-chloro-5-bromoaniline dissolved in 50 ml of dry toluene, and the mixture is stirred for a further 5 hours. Approximately 75% of the solvent is then removed in a rotary evaporator. The residue is diluted with hexane and the resulting precipitate is filtered off with suction, washed with hexane and dried in vacuo. The title compound of formula ##STR14## is obtained in the form of colourless crystals; m.p. 225°-227° C.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH:17]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[C:16]([C:27]([O:29][CH3:30])=[O:28])=[C:15]([CH3:31])[N:14]=[C:13]1[CH3:32])=[O:10])C1C=CC=CC=1>CO.O.[Pd]>[CH3:30][O:29][C:27]([C:16]1[CH:17]([C:18]2[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=2)[N:12]([CH2:11][C:9]([OH:10])=[O:8])[C:13]([CH3:32])=[N:14][C:15]=1[CH3:31])=[O:28]
Reactant: COC(=O)C1=C(C)N=C(C)N(CC(=O)OCc2ccccc2)C1c1cc(F)c(F)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)N=C(C)N(CC(=O)O)C1c1cc(F)c(F)c(F)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a suspension of 10% Pd-C (30 mg) in MeOH (10 mL) and H2O (2 mL) was added a solution of 1,6-dihydro-1-{bezyloxycarbonylmethyl)-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine (300 mg) in methanol (1 mL) and the mixture was hydrogenated at 80 psi for 4 h. The black suspension was filtered through a pad of Celite and washed thoroughly with MeOH (100 mL). Solvent was evaporated from the combined filtrate to leave the product 1,6-dihydro-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine-1-acetic acid as a white solid (0.225 g). It was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[O:20][C:19]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[CH2:21][C:19]1[O:20][C:16]([CH2:15][O:14][CH2:13][CH2:12][CH2:11][NH:10][C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:17][CH:18]=1
Reactant: CN(C)Cc1ccc(COCCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCCOCc1ccc(CN(C)C)o1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a stirred solution of 1,1-bis(methylthio)-2-nitroethene (3.96 g) in dry dioxan (25 ml) at 70° was added dropwise 5-[(3-aminopropoxy)methyl]-N,N-dimethyl-2-furanmethanamine (1.27 g). After 1 hr the reaction was allowed to cool and the solid which separated was filtered. The filtrate and washings were combined and evaporated to dryness, a solution of succinic acid (1 g) in water (25 ml) added to the residue and the suspension filtered. The filtrate was washed with ethyl acetate (2×40 ml) then evaporated to 10 ml. The solution was basified with sodium carbonate and the oily precipitate which separated was extracted into ethyl acetate (3×25 ml). The combined extracts were dried (anhyd. sodium carbonate), the suspension filtered and evaporated to dryness to yield the title compound (1.34 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:19])=[O:18]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 28.7 %

Procedure:
2-amino-benzimidazole (1.0 g, 7.5 mmol) was dissolved in 15 mL of anhydrous CH2Cl2 and 3 mL anhydrous DMF and cooled to ˜0° C. Trethylamine(1.6 mL, 1.5 eq.) was added followed by an addition of methanesulfonylchloride (580 μL, 7.5 mmol) over 1 minute. After 1 minute at ˜0° C., the reaction was warmed to RT. After 1 hour the reaction was quenched with water, and partitioned between a saturated sodium bicarbonate solution and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with water (2 times), brine then dried over NaSO4, filtered and the solvent was removed in vacuo to give 455 mg of N-methanesulfonyl-2-aminobenzimidazole. HPLC shows the material to be 91% pure, (ret. time=3.70). LCMS: obs. M+H@212.1 amu. The material was carried on without purification.