Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:30])C.O>ClCCl>[CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)=[O:30]
Reactant: CC(=O)O
Reactant: Cc1cc2c(cc1C#N)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 18.7 g (82.3 mmol) of 2-cyano-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 280 mL of dichloromethane, cooled at −78°, was added 123 mL (123 mmol) of diisobutyl aluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to gradually warm to room temperature. After 16 hours, the reaction mixture was treated with 30 mL of acetic acid added dropwise, followed by 150 mL of water. The organic layer was separated, diluted with 200 mL of hexane, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution 5-10% ethyl acetate/hexane) on silica gel to afford 11.8 g (63%) of 2-formyl-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1)(=[O:31])[CH3:30]
Reactant: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)[C@]1(C)Oc2ccc(NC(C)=O)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
100 mg (0.25 mmol) of the compound obtained in Example 17 was dissolved in 2 ml of dichloromethane, to which 23 μl (0.25 mmol) of acetic anhydride, 52 μl (0.37 mmol) of triethylamine and 9.1 mg (0.07 mmol) of 4-dimethylaminopyridine were added in that order. The reaction was stirred for 3 hours at room temperature, 10 ml of saturated NaHCO3 solution was added and extraction was performed with 40 ml of dichloromethane. The extract was washed with brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 96 mg (yield: 86%) of the target compound.
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C[C@H](CF)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
3.5 g of ((S)-2-fluoro-1-methyl-ethyl)-benzene (25.32 mmol) were dissolved in 80 ml of dichloromethane. At 0-5° C., 11.81 g of chlorosulfonic acid (101.31 mmol), dissolved in 20 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature and 2 h at 30° C. The solvent was evaporated. 150 ml of diethyl ether were added to the residue, washed once with 150 ml of water, and the organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent to give 1.5 g of the title compound.
Reaction SMILES: [C:1]([CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>CO.C(O)(=O)C>[CH3:22][O:15][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[S:11])[CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=S)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=S)CC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
1-(2-Benzoylthioacetyl)-L-proline obtained in Example 1, is dissolved in methanol and an ethereal solution of diazomethane is added until there is a persistent yellow color. After 15 minutes, a few drops of acetic acid are added and the solvent is removed in vacuo to obtain 1-(2-benzoylthioacetyl)-L-proline methyl ester.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[C:6]([OH:10])(=O)[CH:7]=[CH2:8].[C:11](O)(=[O:14])C=C.C(C(CO)(CO)CC)O.C(C1C=C(CC)C2SC3C(=CC=CC=3)C(=O)C=2C=1)C>C(O)C>[CH3:11][O:14][CH:7]([CH2:6][O:10][CH:2]([CH2:1][OH:5])[CH3:3])[CH3:8]
Reactant: C=CC(=O)O
Agent: CCC(CO)(CO)CO
Agent: CCc1cc(CC)c2sc3ccccc3c(=O)c2c1
Solvent: CCO
Product: COC(C)COC(C)CO
Yield: 39.4 %

Procedure:
A slurry obtained by mixing 6.2 g of a borosilicate glass powder, 56.0 g of nickel-zinc ferrite, 6.2 g of an acrylic organic binder containing hydroxyl groups, 3.1 g of ethanol, 3.0 g of trimethylolpropane triacrylate, 1.2 g of 2-methyl-1-[4-(methylthio)phenyl]-2-morphorinopropane-1-on, 0.3 g of 2,4-diethylthioxanthone and 0.5 g of dipropyleneglycol monomethyl ether was formed into a sheet by the doctor blade method. The sheet was dried at 100° C. to obtain a photosensitive magnetic ceramic green sheet with a thickness of 30 μm.
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[OH-].[Na+].O>CO>[C:17]([O:16][C:14]([NH:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4chlorophenyl)-acrylic acid methyl ester (4.6 g, 14.7 mmol) was dissolved in MeOH (300 ml), 2N NaOH (11 ml, 22 mmol) and water (147 ml) added and stirred at 50° C. for 1 hour. The clear reaction mixture was concentrated to ˜150 ml, acidified to pH 3 and extracted twice with TBME. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the title acid as colorless crystals (3.8 g, 87%).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1>CO.C(Cl)Cl>[NH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: NCCCCCN
Solvent: ClCCl
Solvent: CO
Product: NCCCCCNC(=O)CCC(=O)O
Yield: 80 %

Procedure:
To a solution of 1,5-pentanediamine (2.5 g, 24 mmol) in dry methanol (20 mL), a solution of succinic acid anhydride (2 g, 20 mmol) in dry methylene chloride (20 mL) was added dropwise in 2 hrs, the product was precipitated as white solid and collected by filtration. Yield 80 %. 1H NMR (500 MHz, D2O, 25° C.) δ 1.280 (quint., J=7.5, 2H, CH2), 1.449 (quint., J=7.5, 2H, CH2), 1.577 (quint., J=7.5, 2H, CH2), 2.337 (s, 4H, CH2), 2.886 (t, J=7.5, 2H, CH2), 3.072 (t, J=7.5, 2H, CH2). 13C NMR (500 MHz, D2O, 25° C.) δ 22.73, 26.22, 27.66, 32.34, 33.13, 38.76, 39.37, 175.72, 180.90.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H]>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N)c1
Yield: 72.5 %

Procedure:
Acetic acid 3-nitro-4-(t-butyl-diphenyl-silanyloxy)-phenyl ester (5.0 g, 11.86 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Excess Raney Ni was added and the mixture placed under an atmospheric of hydrogen overnight. The mixture was filtered through a Celite pad and the solvent removed to give the title compound as a solid (3.5 g, 8.6 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 21 h
Yield: 98.6 %

Procedure:
A typical procedure is given for the reaction of Entry 1 in Table 2. A 4 ml vial was charged with bromobenzene (171 mg, 1.10 mmol), diphenylamine (169 mg, 1.00 mmol), Pd(dba)2 (5.9 mg, 1 mol %), Ph5FcP(t-Bu)2(7.1 mg, 2 mol %), and sodium tert-butoxide (144 mg, 1.50 mmol). Anhydrous toluene (1 ml) was added into the mixture, and the vial was then sealed with a cap containing PTFE septum. The reaction mixture was stirred at room temperature for 1 h. After the starting aryl halide was consumed detected, as determined by GC, the reaction solution was directly absorbed onto silica gel, and the product was isolated by eluting with hexane/ethyl acetate to give 244 mg (99%) of triphenylamine as a white solid. Reaction of chlorobenzene (62 mg, 0.55 mmol) with diphenylamine (85 mg, 0.50 mmol) proceeded at 80° C. over 21 h to give triphenylamine (121 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:33]([O:34][CH3:35])[CH3:32])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a stirred solution of 10.0 g of 3-bromo-4-chlorobenzoic acid in 275 ml of anhydrous dichloromethane at OOC were added 7.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.5 ml of triethylamine followed by 3.9 g of N,O-dimethylhydroxylamine hydrochloride. After stirring overnight at room temperature the mixture was washed with 200 ml of water and then with 200 ml of a 1M solution of hydrochloric acid. The organic solution was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a cream solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C1CC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3CC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=347.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3](=[CH:15][CH3:16])[C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][OH:6])[CH3:2].N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)C>[Si:26]([O:6][CH2:5][C@@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])/[C:3](/[CH2:1][CH3:2])=[CH:15]/[CH3:16])([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC=C(CC)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: C/C=C(\CC)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (S)-tert-butyl 3-ethyl-1-hydroxypent-3-en-2-ylcarbamate (Intermediate 202, 11.855 g, 51.70 mmol) in DCM (120 mL) was added imidazole (5.28 g, 77.55 mmol), DMAP (1.263 g, 10.34 mmol) and TBDMS-Cl (9.35 g, 62.04 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl ether and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (0-50% ethyl acetate/hexanes) afforded the title compound (17.20 g, 97%) as a clear oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:7]3[C:8]=2[C:4]=1[CH:5]=[C:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23]([O-:26])(=[O:25])[CH3:24].[K+].[Cl-].[Na+]>CN(C)C=O>[C:23]([O:26][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:7]3[C:8]=2[C:4]=1[CH:5]=[C:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc2c(CBr)ccc3c2n1CCCCC3=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(COC(C)=O)ccc3c2n1CCCCC3=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-bromomethyl-8-oxo-4H-azocino [3.2.1-hi]indole-2-carboxylate (2.92 g, 8.02 mmol), potassium acetate (1.18 g, 12.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into 10% aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified with silica gel column chromatography (eluated with ethyl acetate/n-hexane= 1/5) to give 2.33 g of ethyl 5,6,7,8-tetrahydro-11-acetoxymethyl-8-oxo-4H-azocino [3.2.1-hi]indole-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])N)[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16]([C@@H:17]1[CH2:19][S:20][C:5]([C:4]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])=[N:6]1)=[O:21])[CH3:14]
Reactant: COc1ccc(C#N)c(OC)c1
Reactant: CCOC(=O)[C@@H](N)CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CSC(c2ccc(OC)cc2OC)=N1

Procedure:
2,4-Dimethoxybenzonitrile, (R)-cysteine ethyl ester and about 5 equivalents of triethylamine are refluxed in ethanol for about 6-8 hours to obtain ethyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate.
Reaction SMILES: CCCCC.[CH2:6]([C:8]1([CH2:16][O:17][CH2:18][C:19]2([CH2:27][CH3:28])[CH2:24][O:23][CH:22]([CH:25]=[CH2:26])[O:21][CH2:20]2)[CH2:13][O:12][CH:11]([CH:14]=[CH2:15])[O:10][CH2:9]1)[CH3:7]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Fe].C(N(CC)CC)C>[CH2:6]([C:8]1([CH2:16][O:17][CH2:18][C:19]2([CH2:27][CH3:28])[CH2:24][O:23][C:22](=[CH:25][CH3:26])[O:21][CH2:20]2)[CH2:13][O:12][C:11](=[CH:14][CH3:15])[O:10][CH2:9]1)[CH3:7]
Reactant: C=CC1OCC(CC)(COCC2(CC)COC(C=C)OC2)CO1
Agent: [Fe]
Agent: [C-]#[O+]
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC=C1OCC(CC)(COCC2(CC)COC(=CC)OC2)CO1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To 220 mL pentane in a 500 mL photochemical reactor was added 14.32 g (43.9 mmol) di[(5-ethyl-2-vinyl-[1,3]dioxan-5-yl)methyl]ether from the previous step. The solution was refluxed vigorously for 20 minutes to degas it, then 115 μL (171 μg, 0.87 μmol, 0.2 mol %) iron pentacarbonyl was added, and the solution refluxed for an additional 20 minutes. The resulting solution was irradiated for one hour, by when NMR showed no vinyl signals. After cooling to room temperature and the addition of 0.5 mL triethylamine, the solution was sparged with dry air for 4 hours. The pentane was removed by evaporation under reduced pressure, and the residual oil was distilled in a Kugelrohr apparatus (pot temperature 220° C., pressure 1-3 mbar) to give 9.04 g (63% yield) of di[(5-ethyl-2-ethylidene-[1,3]dioxan-5-yl)methyl]ether, 3, as a colorless oil. The identity of the product was confirmed by 1H NMR and mass spectra (observed: 363, 345, calculated for C18H35O7 (M+2H2O+H+): 363; calculated for C18H33O6 (M+H2O+H+): 345).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@H:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH3:27][O:28][C:29](=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Br>>[CH3:27][O:28][C:29](=[O:38])[CH:30]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@@H:9]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: COc1cc2c(cc1OC)[C@H](CCc1ccc(C(F)(F)F)cc1)NCC2
Product: COC(=O)C(c1ccccc1)N1CCc2cc(OC)c(OC)cc2[C@@H]1CCc1ccc(C(F)(F)F)cc1

Procedure:
This compound is prepared by reaction of (1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydroisoquinoline with α-bromo-phenyl-acetic acid methyl ester.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[CH2:5]Cl.CC1C=C(C)C=C(C)C=1C[Mg]Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[N:40][CH:41]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CCOCC.C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([C:36]2[CH:41]([CH2:5][C:4]3[C:3]([CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[NH:40][C:39]([CH3:42])=[N:38][CH:37]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2)cc1
Agent: Cc1cc(C)c(C[Mg]Cl)c(C)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)C2=CN=C(C)NC2Cc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of magnesium (240 mg, 10 mmol) and ether (20 mL) was added 2,4,6-trimethylbenzyl chloride (1.69 g, 10 mmol) in ether (20 mL) dropwise at reflux under N2. The freshly prepared solution of 2,4,6-trimethylbenzylmagnesium chloride in ether was added to a solution of 5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (264 mg, 1.0 mmol) in THF (10 mL) dropwise at 0° C. The mixture was stirred under N2 at 0° C. for 1 h and then quenched by addition of saturated aqueous NH4Cl. The organic layer was separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc) to provide 5-(4-methoxy-benzenesulfonyl)-2-methyl-6-(2,4,6-trimethylbenzyl)-1,6-dihydro-pyrimidine (203 mg, 51%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 6.99 (d, J=9.0 Hz, 2H), 6.83 (s, 2H), 4.40 (dd, J=10.8, 3.2 Hz, 1H), 3.86 (s, 3H), 2.96 (dd, J=14.2, 10.8 Hz, 1H), 2.87 (dd, J=14.2, 3.2 Hz, 1H), 2.25 (s, 6H), 2.24 (s, 3H), 1.91 (s, 3H); ESI MS m/z 399 [(M+H)+, calcd for C22H27N2O3S, 399.2].
Reaction SMILES: CS([C:5]1[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1)(=O)=O.[C-:17]#[N:18].[K+]>CN(C=O)C>[NH2:14][C:11]1[N:9]2[N:10]=[C:5]([C:17]#[N:18])[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2=[N:13][N:12]=1
Reactant: Cc1c(S(C)(=O)=O)nn2c(N)nnc2c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C#N)nn2c(N)nnc2c1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
6-Methane sulfonyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.130; 1.0 g) was dissolved in DMF (30 ml) and admixed with potassium cyanide (405 mg). After stirring at 100° C. for 1 h, the mixture was dried. The residue was stirred in EA and chromatographed using a short silica gel column with EA. Fractions concentrated by rotary evaporation. 560 mg of the title compound were obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:12][C:13](=O)[CH3:14])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:14][C:13]1[NH:3][N:2]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccccc2)n[nH]1
Reaction time: 14 h
Yield: 155.2 %

Procedure:
Hydrazine hydrate (9.0 mL, 99 mmol, 35 wt. % in H2O; 0.64 equiv) was added to a solution of benzoylacetone (25.00 g, 154.1 mmol, 1 equiv) in ethanol (250 mL). After stirring 14 h, more hydrazine hydrate (8.0 mL, 88 mmol, 0.57 equiv) was added. After 2 h, the reaction solution was concentrated (95° C.) to give the title compound as a white solid (24.31 g, 99.7%). HRMS Calculated for C10H11N2: m/z 159.0922. Found: 159.0917.
Reaction SMILES: [N+](C1C=C([O:11][C:12]([F:15])([F:14])[F:13])C=CC=1N)([O-])=O.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]2[CH:27]=[CH:28][C:29](C(F)(F)F)=[CH:30][C:25]=2[N:24]=[C:23]1/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:30][C:25]=2[N:24]=[C:23]1/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Product: FC(F)(F)Oc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-nitro4-trifluoromethoxyaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). MW: 381.36; mp: 92.0-93.0° C.; 1H-NMR (CDCl3) δ: 8.81-8.77 (1H, m), 8.02 (1H, d, J=16.5 Hz), 8.05-7.98 (1H, m), 7.71-7.68 (1H, m), 7.54-7.45 (4H, m), 7.45 (1H, d, J=8.8 Hz), 7.42-7.30 (3H, m), 7.17-7.10 (1H, m), 7.10 (1H, d, J=16.1 Hz)