Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47](Br)[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.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>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47]([C:6](=[O:8])[CH3:7])[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.39 mL, 1.15 mmol) was added to a mixture of 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (440 mg, 0.77 mmol), prepared as in Example 2, and tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.077 mmol) in toluene (5 mL). The reaction mixture was heated at 110° C. for 1 hour then cooled to room temperature. The solid so formed was collected by filtration and washed with toluene, then dried to give 4-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. M++1: Calc'd. 534.6. Found 534.2.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[NH2:2].[C:5]1([NH:11][C:12]([N:14]2[CH2:18][CH2:17]N[C:15]2=[O:19])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[Si](C)(C)Cl.C(Cl)(Cl)=O>>[C:5]1([NH:11][C:12]([N:14]2[CH2:18][CH2:17][N:2]([C:1]([Cl:4])=[O:3])[C:15]2=[O:19])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)Cl
Reactant: O=C1NCCN1C(=O)Nc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)Cl
Product: O=C(Cl)N1CCN(C(=O)Nc2ccccc2)C1=O

Procedure:
This carbamic acid chloride was produced as described in Example 1 B from 15.0 parts by weight of N-phenylaminocarbonyl-imidazolid-2-one, 15.8 parts by weight of trimethylchlorosilane and 7.2 parts by weight of phosgene. Recrystallization from acetone/pentane.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:42])([CH3:41])[C:33]1=[O:43].O>CO>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([CH3:42])([CH3:41])[C:33]3=[O:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC1(C)C(=O)N(CCCBr)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN3C(=O)C(C)(C)c4ccccc43)c2CC1
Temperature: 25 °C

Procedure:
Add potassium hydroxide (170 mg, 3.03 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (187 mg, 0.49 mmol) in methanol (10 mL). Heat the reaction at reflux under nitrogen overnight. Then add further portion of KOH (867 mg, 15.45 mmol) and heat at reflux for 3 h. Then cool to room temperature and add 1-(3-bromo-propyl)-1,3-dihydro-3,3-dimethyl-indol-2-one (274 mg, 0.97 mmol, prepared by following the procedure described in Perkin 1 2000, 769-774). Stir the reaction at room temperature overnight. Remove solvents in vacuo, add water and extract with diethyl ether (2×50 mL). Combine the organic extracts, wash with water (2×50 mL) and brine (50 mL). Dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colourless oil (330 mg), 50% contaminated with 1-(3-methoxypropyl)-1,3-dihydro-3,3-dimethyl-indol-2-one. MS (ES+) m/z: 537 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=S
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CCC)c1=S
Yield: 46.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.00 g (16.5 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil and 3.79 g (18.2 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.16 g (yield 46%) of Compound 192 as yellow needles.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].CCN(C(C)C)C(C)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1.[C:50](N1C2C=CC=CC=2N=N1)(=[NH:52])[NH2:51]>CN(C=O)C>[C:39]1([CH3:49])[CH:40]=[CH:41][C:42]([S:45]([OH:48])(=[O:46])=[O:47])=[CH:43][CH:44]=1.[C:50]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)(=[NH:51])[NH2:52]
Reactant: N=C(N)n1nnc2ccccc21
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(C(=N)N)CC1
Reaction time: 24 h

Procedure:
Morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride (0.2 g, 0.47 mmol) was dissolved in 3 mL of DMF and 2 equiv of Hunig's base was added followed by 1-carbamimidoyl-1,2,3-benztriazole p-toluenesulfonate (0.16 g, 0.47 mmol). The reaction was stirred 24 hours at which time the solvent was removed in vacuo. The resulting paste was purified by preparative HPLC to give the title compound; MS, m/z 434, M+1-p-toluene sulfonate).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH:10][S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: Cn1cccc1C(CCN)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cccc1C(CCNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
3-(1-Methyl-2-pyrrolyl)-3-(3-pyridyl)propylamine (0.59 g) and triethylamine (0.31 g) were dissolved in 20 ml of methylene chloride, followed by addition of 0.64 g of p-chlorobenzene sulfonylchloride, and stirred at room temperature for 18 hours. To the reaction mixture was added 2N hydrogen chloride, and the organic phase was separated, which was then extracted with methylene chloride from the aqueous phase. After washing in saturated aqueous sodium hydrogencarbonate and in aqueous saturated sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off to obtain 0.96 g of N-[3-(1-methyl-2-pyrrolyl)-3-(3-pyridyl)propyl ]-4-chlorobenzenesulfonamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:12])=[O:11])[CH:3]=[CH:2]1.C[O:15][C:16](=O)[NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([CH3:26])[N:19]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([CH3:26])[N:19]=[C:18]([NH:17][C:16]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)(=[O:11])=[O:12])=[O:15])[N:23]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2cc[nH]c12
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cc[nH]c23)n1

Procedure:
To a solution of 1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene chloride (100 ml) was added trimethylaluminum (3.2 ml of a 2.0M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to an oil. The oil was dissolved in ether from which it quickly crystallized to give pure product (TLC) (0.56 g, m.p. 207°-209° C.).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]=[O:13].O>O1CCCC1>[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylmagnesium bromide (1.6 mL, 1.0 M tetrahydrofuran solution, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 2-Fluoro-5-methoxybenzaldehyde (500 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) in tetrahydrofuran (16 mL, manufactured by Wako Pure Chemical Industries, Ltd.) at 0° C., and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×20 mL), washed with brine (20 mL) and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 480 mg of the title compound. LC-MS: HPLC retention time 3.90 minutes, m/z 233 (M+H), condition B-1.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(OC(C)C)(C)C>C(O)(C)C>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: Nc1ncc(Cl)cc1/C=C/C(=O)N1CCOCC1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and morpholine as a yellow solid following crystallisation from isopropyl alcohol and trituration with diisopropyl ether:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:6]2[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(Cl)c2Cl)CC1

Procedure:
A solution of 2,4,5,6-tetrachloro-pyrimidine (1.67 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.85 g (29%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.49-1.60 (m, 2H), 1.73-1.77 (m, 2H), 2.81 (br s, 2H), 3.95-3.98 (m, 2H), 4.09-4.16 (m, 1H), 7.88 (d, J=8.0 Hz, 1H). 13C NMR (100 MHz, DMSO): δ 28.07, 30.45, 43.33, 48.90, 78.65, 109.37, 153.80, 154.62, 155.66, 158.74. MS (ISP): 383.0 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[CH2:6]1)=[N+]=[N-].[H][H]>C1COCC1.CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[CH2:6]1
Reactant: CN1CCc2cc(N3C[C@@H](CN=[N+]=[N-])OC3=O)ccc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCc2cc(N3C[C@H](CN)OC3=O)ccc2C1

Procedure:
184 mg (0.6 mmol) (S)-5-azidomethyl-3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-oxazolidin-2-one are dissolved in a mixture of 2 ml THF and 10 ml of methanol, combined with 50 mg palladium/charcoal (5%) and hydrogenated for two hours at 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated to dryness i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](=[O:11])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccccn1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 261, step 1, from (R)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 142, step 1) and 2-methyl-pyridine was prepared the title compound as a yellow oil, MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CCOCC>[Si:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 4-hydroxybenzyl cyanide 77 (2.0 g, 15.0 mmol) in DMF (10 ml) was added t-butyldimethylsilyl chloride (2.5 g, 16.5 mmol). The reaction mixture was cooled to 0° C. and imidazole (2.3 g, 33.0 mmol) was added and then the mixture was allowed to warm to ambient temperature. After stirring for 3 hours, the reaction mixture was diluted with ether and washed with 0.5 M HCl, sat. aq. NaHCO3, water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (8:1)) to give 78 as a clear oil (3.6 g, 98% yield). 1H-NMR (400 MHz, chloroform-d) δ7.87 (d, J=8.5 Hz, 2 H), 6.86 (d, J=8.5 Hz, 2 H), 3.54 (s, 2 H), 0.98 (s, 9 H), 0.23 (s, 6 H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[C:4]([C:17]([F:20])([F:19])[F:18])[NH:3]1.[CH3:21]NN>>[CH3:21][O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:19])([F:20])[F:18])[C:5]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CSc1ccc(Cc2c(C(F)(F)F)[nH]n(C)c2=O)cc1
Reactant: CNN
Product: COc1c(Cc2ccc(SC)cc2)c(C(F)(F)F)nn1C

Procedure:
The title compound was prepared as in Example 1 from 1-methyl-4-[(4-methylthiophenyl)methyl]-3-(trifluoromethyl)-2H-pyrazol-5-one, which was also prepared as in Example 1 except that methylhydrazine was used instead of hydrazine and recrystallization from toluene-hexane mixture provided the intermediate compound as off-white crystals, mp 138°-139° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:18].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>CN(C=O)C.CCOCC>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:9][S:8][C:6]2[CH:5]=[CH:4][C:3]([O:18][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[C:2]([CH3:1])[CH:7]=2)=[CH:11][C:12]=1[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(SSc2ccc(O)c(C)c2)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(SSc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To an ice cooled solution of 4.75 g (17.06 mmol) 4,4′-dithio-bis-(2-methyl-phenol) and 5.55 ml (37.6 mmol) bromo-acetic acid tert-butyl ester in 50 ml DMF was added 204 mg (85.3 mmol) sodium hydride (55% in oil). The reaction mixture was stirred over night at RT and then it was taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 providing 3.4 g pure [4-(4-tert-butoxycarbonylmethoxy-3-methyl-phenyldisulfanyl)-2-methyl-phenoxy]-acetic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=O.Cl.Cl.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CN=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>CO>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:22]/[C:18]1[NH:17][CH:21]=[CH:20][N:19]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ncc[nH]1

Procedure:
Free base of the titled compound was prepared from 2-methyl-1-(2-pyridyl)-1H-benzimidazole and 2-imidazolcarboxaldehyde according to the preparation of (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole dihydrochloride (Example 44). The free base and oxalic acid were dissolved into MeOH. Concentration and recrystallization from ethyl EtOH/n-hexane yielded the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19].O>CN(C=O)C>[CH2:18]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
To 5-fluoro-2-nitrophenol (8.3 g, 52.83 mmol) in 50 mL of DMF was added K2CO3 (14.6 g, 105.7 mmol), and ethyl iodide (8.53 mL, 105.7 mmol). The mixture was stirred at 60° C. for 24 h in a sealed tube. The mixture was poured into 500 mL of H2O and extracted with diethyl ether, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (9.69 g, 52.33 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.94 (m, 1H), 6.71-6.77 (m, 1H), 6.66-6.71 (m, 1H), 4.11-4.19 (m, 2H), 1.45-1.51 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][S:25]([CH:22]5[CH2:24][CH2:23]5)(=[O:27])=[O:26])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: O=S(=O)(Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2)C1CC1
Yield: 9.1 %

Procedure:
Prepared from N2-(3-Cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 119) (200 mg, 0.72 mmol) and cyclopropanesulfonyl chloride (161 mg, 1.1 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (25 mg, 9%), MS (ISP) m/e=382.4 [(M−H)−].
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(CC#Cc1cccnc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 49 (43 mg, 0.17 mmol) in CH2Cl2 (0.8 mL) at 0° C. was added TFA (1.5 mL, excess), the ice bath was removed and the resultant solution was stirred at ambient temperature for 1 h. The solvent and excess TFA were removed under a stream of argon and the residue was dissolved in HCl(aq) (1.0 M, 1 mL) and washed with CH2Cl2 (3×10 mL). To the aqueous fraction was added CH2Cl2 (8 mL) and water (8 mL) and the pH was adjusted to 10 with NaOH(aq) (10 N) while stirring. The organic fraction was collected and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 10/90, Rf=0.16) to afford the title compound 50 (13 mg, 53% yield) as an orange oil: 1H NMR (CDCl3) δ 8.65 (m, 1H), 8.51 (m, 1H), 7.07 (m, 1H), 7.23 (m, 1H), 3.64 (br s, 2H), 2.50 (br s, 3H); LRMS (ESI) m/z calcd for C9H11N2 [M+H]+ 147. found 147; LRMS (ESI) m/z calcd for C8H6N [M−NH(CH3)]+ 116. found 116; HRMS (ESI) m/z calcd for C9H11N2 [M+H]+ 147.0922. found 147.0921; HPLC>98% (tR=7.25 min, 60 (A):40 (B): 0.02 (C); tR=2.91 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([I:45])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: II
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCC(I)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) stirred solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (1.0 g, 5.80 mmol) in 1:2 CH2Cl2/CCl4 (52 ml) is added triphenylphosphine (1.82 g, 6.96 mmol), imidazole (473 mg, 6.96 mmol), and iodine (1.79 g, 7.08 mmol). The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of saturated sodium thiosulphate (c.a. 50 ml) and stirred until the solution becomes clear. The layers are separated and the aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic phases are washed with sodium thiosulphate (30 ml), brine (30 ml), dried with anhydrous MgSO4, filtered and evaporated at reduced pressure to an oily solid. Purification by dry flash chromatography, Keiselgel 15-40 grade silica, eluting with 3% ethyl acetate/iso hexane yields the title compound as a clear colourless oil.