Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([O:12][CH3:13])=[CH:5][CH:4]=1.C[Mg]Br.[C:17](=[O:19])=[O:18].Cl>O1CCCC1.O>[CH3:11][O:10][C:7]1[C:8]([CH3:9])=[C:3]([CH:4]=[CH:5][C:6]=1[O:12][CH3:13])[C:17]([OH:19])=[O:18]
Reactant: COc1ccc(Br)c(C)c1OC
Reactant: O=C=O
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)c(C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of magnesium turnings (0.059 g, 2.40 mmol) in tetrahydrofuran (1 ml) was added a solution of 6-bromo-2,3-dimethoxy toluene (0.660 g, 2.3 mmol) in tetrahydrofuran (1 ml). The reaction was initiated by addition of methylmagnesium bromide and the solution was stirred at room temperature overnight under nitrogen. To the mixture was then added an excess of dry ice. When the addition was complete, water was added (2 ml) followed by 1.5 M hydrochloric acid to pH 2. The water phase was extracted with ethyl acetate (2×5 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give 3,4-dimethoxy-2-methylbenzoic acid (0.315 g, 70% yield). MS (EI) for C10H12O4: 195 (M−H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].N(OC(C)(C)C)=O.[CH3:18][S:19]SC>O1CCOCC1>[OH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[S:19][CH3:18]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: C1COCCO1
Product: CSc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-amino-4-hydroxybenzonitrile (1.00 g, 7.46 mmol) in dioxane (15 ml) was added t-butyl nitrite (1.12 ml, 14.9 mmol) and the resulting mixture was stirred under nitrogen at room temperature for 15 min. Dimethyl disulfide (5 ml) was then added and the resulting mixture was heated to 90° C. for 3 h. The reaction mixture was purified by flash column chromatography to afford the title compound. Mass spectrum (ESI) 164.1 (−1).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:34]([N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 53.9 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (2.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then morpholinocarbonyl chloride (6.8 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and diluted with diethyl ether (2 ml). The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=2/1) to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (9.7 mg) as an oil.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[Br:34][C:35]1[S:39][C:38]([CH:40]=O)=[CH:37][CH:36]=1.O>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:40]\[C:38]2[S:39][C:35]([Br:34])=[CH:36][CH:37]=2)=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(/C=C\c2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a 0° C. suspension of 4-fluorobenzyl triphenylphosphonium chloride (1.82 g, 4.47 mmol) in THF (20 mL) was added a solution of n-BuLi (2.5M in hexane, 1.8 mL, 4.47 mmol) and the reaction mixture was stirred for 1 h. 5-Bromothiophene-2-carbaldehyde was added, the reaction was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was treated with water and extracted with Et2O. The crude product was purified by preparative TLC (30% EtOAc/hex) to give 5-[(1Z)-2-(4-fluorophenyl)vinyl]-2-bromothiophene (170 mg, 13%) as a colorless oil: 1H NMR (CDCl3) δ 6.51 (d, J=11.9 Hz, 1H), 6.59 (d, J=11.9 Hz, 1H), 6.72 (d, J=4.3 Hz, 1H), 6.85 (d, J=3.8 Hz, 1H), 7.04-7.11 (m, 2H), 7.27-7.33 (m, 2H) and 5-[(1E)-2-(4-fluorophenyl)vinyl]-2-bromothiophene (200 mg, 16%) as a white solid: 1H NMR (CDCl3) δ 6.74-6.80 (m, 2H), 6.95-7.07 (m, 4H), 7.39-7.44 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C)([O-])=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc(S(=O)(=O)OCCN=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCN(CCN=[N+]=[N-])CCN=[N+]=[N-]

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)ethylamine (10 mg; 0.6 mmol), 2-azidoethyl p-toluenesulphonate (370 mg; 1.5 mmol; 1.25 equiv) and potassium carbonate (2.4 mmol, 2 equiv) is taken to reflux in nitromethane for 16 hours. The solution is then concentrated and the residual product dissolved in dichloromethane (10 ml), washed with water (5 ml) and purified by column chromatography (EtOAc-hexane 1:3) leading to the title product (130 mg, 70%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]#[N:30])=[CH:26][C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.[Li+].[BH4-]>O1CCCC1.O>[NH2:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:33])[N:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:32])(=[O:31])[C:20]=2[CH:26]=1
Reactant: N#CCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A solution of the product of Example 392A (39 mg, 0.084 mmol) in anhydrous tetrahydrofuran (2 mL) was treated with LiBH4 (1mL, 2M in tetrahydrofuran, 0.2 mmol), stirred at ambient temperature for 30 minutes, then 18 μl water was added and stirred overnight. The solution was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The slurry was filtered and the solvent removed under reduced pressure to give title compound (38 mg, 97%). 1H NMR (500 MHz, BENZENE-d6) δ 0.20 (d, J=3.05 Hz, 2 H) 0.46 (d, J=7.32 Hz, 2 H) 1.01 (m, 1 H) 2.74 (s, br, 2 H) 2.86 (m, 2 H) 4.19 (t, J=4.90 Hz, 2 H) 5.21 (s, br, 2 H) 6.04 (s, br, 1 H) 7.15 (s, br, 1 H) 7.24 (s, br, 2 H) 7.32 (s, br, 1 H) 7.59 (s, br, 1 H) 7.78 (s, br, 1 H) 8.11 (d, J=7.32 Hz, 1 H) 15.65 (s, br, 1 H). MS (ESI−) m/z 468 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].[CH3:17][CH:18]1[C:22](=[O:23])[CH2:21][CH2:20][O:19]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2([OH:23])[CH2:21][CH2:20][O:19][CH:18]2[CH3:17])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: CC1OCCC1=O
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Product: COC(=O)c1sc(C2(O)CCOC2C)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and 2-methyldihydrofuran-3-one were reacted by method M. The product with the molecular weight of 353.32 (C13H14F3NO5S) was obtained in this way; MS (ESI): 354 (M+H+).
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH:29]=O.[Cl:39][C:40]1[CH:41]=[C:42]([CH2:47][CH2:48][NH2:49])[CH:43]=[CH:44][C:45]=1[Cl:46].[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH2:29][NH:49][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:40]([Cl:39])[CH:41]=1
Reactant: COC(C)(C)c1ccc(C=O)cc1Cl
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: COC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 77 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (0.36 mmol) (described in example S117), 69 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.36 mmol) and 21 mg of sodium borohydride (0.54 mmol). The isolated colorless liquid (126 mg, 90%) was used in the following step without further purification. MS (ISP) 386.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:29]3[S:30][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
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: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C=O)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridine-6-ylamine (100.0 mg, 0.238 mmol), 5-formyl-2-thiopheneboronic acid (55.7 mg, 0.357 mmol), Pd(PPh3)4 (10.0 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (10 mL) was heated to 90° C. overnight. The material was concentrated in vacuo, redissolved in DCM and transferred to a separatory funnel, extracting with sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 2% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 6.53 (q, J=6.7 Hz, 1H), 7.20-7.25 (m, 1H), 7.41 (dd, J=8.8, 4.8 Hz, 1H), 7.59 (d, J=3.8 Hz, 1H), 7.94 (d, J=4.0 Hz, 1H), 8.13 (s, 1H), 8.28 (s, 1H), 9.89 (s, 1H). MS (ES+): m/z 450.92 (100) [MH+]. HPLC: tR=3.75 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9](S(C)=O)[N:8]=1.[N:32]1[CH:33]=[CH:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][C:36]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([N:38]2[CH2:39][CH2:40][N:35]3[CH:34]=[CH:33][N:32]=[C:36]3[CH2:37]2)[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Reactant: c1cn2c(n1)CNCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of whole amount) of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine (prepared in the above (5)), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 73 mg, triethylamine 0.083 ml and N,N-dimethylacetamide 4 ml is stirred at 110° C. for 4 hours. After cooling the reaction mixture is diluted with a 10% aqueous citric acid solution and washed with ethyl acetate. The organic layer is extracted with a 10% aqueous citric acid solution. The water layer is made basic with sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:methanol=100:1→50:1), and then crystallized from a mixture of ethyl acetate, methanol and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 20 mg.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:8]1)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: COc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CC(=NNC(=N)N)c3c(C)coc3C2)cc1
Yield: 58.8 %

Procedure:
A mixture of 3-methyl-6-(4-methoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.10 g), aminoguanidine hydrochloride (0.045 g), concentrated hydrochloric acid (0.02 ml), water (0.02 ml) and ethanol (30 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-6-(4-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 36) (0.08 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[C:5]([C:4]1[CH:3]=[C:2]([N:1]([S:14]([CH3:13])(=[O:16])=[O:15])[S:14]([CH3:13])(=[O:16])=[O:15])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc(C#N)cc([N+](=O)[O-])c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a suspension of 3-amino-5-nitrobenzonitrile (161 mg, 0.987 mmol) in DCM (8 mL) was added TEA (0.55 mL, 3.95 mmol), followed by methanesulfonyl chloride (0.165 mL, 2.12 mmol). The reaction mixture was stirred at room temperature for 60 min., then diluted with DCM, washed with H2O, dried over Na2SO4, and concentrated. The crude solid was triturated with DCM and isolated by filtration to give Intermediate 76A (242 mg, 76%) as a white solid. HPLC: Rt=1.198 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, CDCl3) δ ppm 8.65 (1H, s), 8.45 (1H, s), 7.98 (1H, s), 3.48 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)[CH:4]=1.[I:32]I>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:32][C:6]1[C:5]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:4][C:3]([O:2][CH3:1])=[C:8]([CH3:9])[CH:7]=1
Reactant: COc1cc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)ccc1C
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c(I)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 3-[3-(6-methoxy-p-tolyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.34 g, 0.00300 mol), silver trifluoroacetate and methylene chloride is treated with iodine (1.14 g, 0.00450 mol) in portions, stirred overnight at room temperature, diluted with methylene chloride, washed with 1M sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to a brown oil which solidifies on standing. Recrystallization from ether affords the title compound as a light yellow crystalline solid (1.50 g, 87.2%, mp 210-212° C.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14]>C(O)=O.CO>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH2:13][CH3:14])[CH3:11])[N:5]=1)[CH3:2])[CH3:14]
Reactant: CCc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CO
Solvent: O=CO
Product: CCc1ccccc1N=C(C)c1cccc(C(C)=Nc2ccccc2CC)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
One g of 2,6-diacetylpyridine and 3.0 ml of 2-ethylaniline were added to a round-bottom flask with 30 ml of methanol. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 24 hours at 50° C. The flask was then cooled to room temperature and placed in a freezer at -30° C. After 1 day, yellow crystals had formed. The crystals were isolated by filtration and identified by 1H NMR as the desired product (1.25g, 55.2%). 1H NMR (CDCl3): δ 8.38(d, 2, Hpyr), 7.86(t, 1, Hpyr), 7.20(m, 4, Haryl), 7.07(t, 2, Haryl), 6.65(d, 2, Haryl), 2.49(q, 4, Hbenzyl), 2.35(s, 6, N--C--CH3), 1.14(t, 6, CH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][C:24](Cl)=[CH:25][C:26]=1[CH3:27].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][C:24]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][C:26]=1[CH3:27]
Reactant: c1cn[nH]c1
Reactant: COc1cccc(C)c1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc(C)c1N(C)C(=O)c1ccc(Cl)c(-c2cnc(-n3cccn3)cc2C)c1
Temperature: 130 °C
Yield: 6.3 %

Procedure:
A mixture of 4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide 2-31 (66.0 mg, 0.16 mmol) and pyrazole (12.9 mg, 0.19 mmol) was added to CuI (6.0 mg, 0.032 mmol), K2CO3 (43.9 mg, 0.32 mmol) and N,N′-dimethylethylenediamine (1.4 mg, 0.016 mmol) in dioxane (1 mL). The reaction vessel was sealed and heated at 130° C. for 24 hrs. The mixture was then filtered and purified by HPLC giving 4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-pyrazol-1-yl-pyridin 3-yl)-benzamide 25-1 (4.5 mg). MS (M+H)+: 446.8, tR=8.60 min (method 2).
Reaction SMILES: C(OP([CH:9]([Cl:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=O)OCC)C.C[O-].[Na+].[CH3:21][C:22]1([CH3:30])[C@@H:24]([CH:25]=O)[C@@H:23]1[C:27](=[O:29])[CH3:28].O>O1CCCC1.CO>[CH3:21][C:22]1([CH3:30])[C@@H:23]([C:27](=[O:29])[CH3:28])[C@@H:24]1[CH:25]=[C:9]([Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)[C@H]1[C@H](C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 23.7 g (0.08 mol) of α-chloro-(4-chlorobenzyl)-phosphonic acid diethyl ester in 40 ml of tetrahydrofuran was added dropwise to a solution of 17.8 g (0.084 mol) of sodium methylate in methanol and 160 ml of tetrahydrofuran at 0°-10° C. and the mixture was subsequently stirred at 0°-10° C. for 1 hour. 11.2 g (0.08 mol) of trans-3,3-dimethyl-2-acetyl-cyclopropanecarbaldehyde were then added at 10° C. and the reaction mixture was subsequently stirred for 2 hours, without further cooling, and then poured onto 800 ml of water. The aqueous solution was extracted three times with 200 ml of methylene chloride each time and the combined organic phases were dried over sodium sulphate and evaporated in vacuo. 19.7 g (87% of theory) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chlorophenyl)-vinyl)-1-acetyl-cyclopropane were thus obtained as a yellow oil with a boiling point of 120°-128° C./0.1 mm/Hg. ##STR53##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:24][CH2:25][CH3:26].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-145, 34 mg, 0.09 mmol) tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (21 mg, 0.18 mmol) were reacted in dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[OH:13])=[CH:8][CH:7]=1>C(O)C>[OH:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH:14]1[CH2:15][CH2:16][N:17]([CH2:3][CH2:2][C:1]#[N:4])[CH2:18][CH2:19]1
Reactant: C=CC#N
Reactant: OC(c1ccc(F)cc1)(c1ccccn1)C1CCNCC1
Solvent: CCO
Product: N#CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccccn2)CC1

Procedure:
2.3 ml (0.035 mol) of acrylonitrile are added dropwise to a solution of 10 g (0.035 mol) of α-(4-fluorophenyl)-α-(2-pyridyl)-4-piperidinemethanol in 60 ml of ethanol and 1 ml of Triton B.