Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17]C(C)C)[N:14]([CH3:21])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:21])[C:13](=[S:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(OC(C)C)n2)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)[nH]2)cc1OC
Yield: 12.3 %

Procedure:
A mixture of 6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4(3H)-pyrimidinone (2.5 g) and phosphorus pentasulfide (3.5 g) in pyridine (50 ml) was refluxed for 13 hours with stirring. The reaction mixture was evaporated under reduced pressure. The residue was washed with 1N-hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in ethanol and the resulting precipitate was triturated again in chloroform and collected by filtration to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.27 g).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]([OH:21])=O)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH3:26].C1COCC1>C1(C)C=CC=CC=1.O>[CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]([NH2:26])=[O:21])[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Reactant: N
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution of 1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (300 mg, 1.04 mmol) and thionyl chloride (0.379 mL, 5.20 mmol) in toluene (3 mL) was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (3 mL). 28% Aqueous ammonia (2 mL, 22.87 mmol) was added to the THF solution, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the precipitate was collected by filtration to give 1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (284 mg, 0.988 mmol, 95%) as a white powder.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:27]([Cl:30])([Cl:29])[Cl:28]>>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: ClC(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCCCCCCCC(Cl)(Cl)Cl

Procedure:
It has been disclosed that, when chloroform is reacted with oct-1-ene in the presence of benzoyl peroxide, 1,1,1-trichlorononane is formed in a yield of from 22 to 40%, based on the olefin, and with a selectivity of from 41 to 48%, conversion of the olefin being incomplete (J. Amer. Chem. Soc. 69 (1947), 1100-1104, in particular page 1104; and J. Chem. Soc. 1963, 3921-3927, in particular page 3927). The free-radical addition reactions of chloroform with other olefins also in general give only moderate yields (C. Walling and E. S. Hugser, Org. Reactions 13 (1963), 129).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH3:27].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC1CCCN1CCCCl
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCN1CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 15.6 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-2-methyl-pyrrolidine (344 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (120 mg, 16%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.08-3.96 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.18 (td, 1H), 2.98 (m, 1H), 2.40 (s, 2H), 2.29 (m, 1H), 2.20 (m, 1H), 2.16-1.62 (m, 10H), 1.96 (s, 6H), 1.42 (m, 1H), 1.09 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.096 g, 0.25 mmol) and 4-chlorobenzenesulfonyl chloride (0.070 g, 0.33 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.06 mL, 0.45 mmol), and the mixture was stirred for 15 minutes at room temperature. Once no starting material was seen by analytical LCMS, the solution was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[S:11][CH2:12][C:13]#[N:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Al+3].[Cl-].[Cl-].[Cl-]>CCOCC>[NH2:14][CH2:13][CH2:12][S:11][C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1
Reactant: Cc1cccc2c(SCC#N)c[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: Cc1cccc2c(SCCN)c[nH]c12

Procedure:
The ether solution was separated and dried over MgSO4. The filtered solution was evaporated in vacuo to give 24.4 g (66%) of 7-methylindol-3-ylthioacetonitrile as a tan solid. An ether solution of 14.1 g (70 mmole) of the nitrile was treated with 2.7 g (70 mmole) of lithium aluminum hydride and 9.5 g (70 mmole) of AlCl3. The dried ether solution was evaporated in vacuo to give 3-[(2-aminoethyl)thio]-7-methylindole which was crystalized from isopropanol to give 6.2 g of tan crystals.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][CH3:15])[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O>[C:1]([NH:4][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][CH3:15])[CH:8]=1)[C:16]([O:18][CH2:27][CH:26]=[CH2:25])=[O:17])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(Cc1ccc(N)c(CC)c1)NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A mixture of N-acetyl-4-amino-3-ethylphenylalanine (2.0 g, 8.0 mmol), Cs2CO3 (2.61 g, 8.0 mmol) and allyl bromide (692 μL, 8.0 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 3 hours, concentrated under reduce pressure and partitioned between ethyl acetate and water (100 mL, 1:1). The organic phase was washed with brine (1×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by on silica gel with ethyl acetate/hexane (5:3) to provide titled compound (1.44 g). MS (ESI(+)) m/e 291 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, 1H), 6.77-6.70 (m, 2H), 6.50 (d, 1H), 5.90-5.76 (m, 1H), 5.30-5.15 (m, 2H), 4.67 (s, 2H), 4.54-4.50 (m, 2H), 4.38-4.30 (m, 1H), 2.77(dddd, 2H), 2.39 (q, 2H), 1.80 (s, 3H), 1.10 (t, 3H).
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:9][O:10][N:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.ClCCl>[CH3:9][O:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNOC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Sodium cyanoborohydride (0.22 g, 3.5 mmol) and acetic acid (2 mL) were added to 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime in ethanol (6 mL) and stirred for 2 hours. The pH of the reaction mixture was made basic with potassium carbonate and the reaction mixture was diluted with water (5 mL) and dichloromethane (50 mL). The layers were separated, and the organic layer was dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 0.62 g of crude material with a small amount of ethanol present. Silica gel (1 g) was added to the crude material and the mixture was heated for 2.5 hours at 100° C. The mixture was cooled and the material was filtered with a 1:1 mixture of dichloromethane and methanol. The filtrate was concentrated under reduced pressure to afford 0.35 g of O-methyl-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=2)[C:3]=1[CH:17]=O.FC(F)(F)C(O)=O.C[SiH](C)C>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=2)[C:3]=1[CH3:17]
Reactant: COc1ccc(-c2nn(C)c(Cl)c2C=O)cc1C
Agent: C[SiH](C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nn(C)c(Cl)c2C)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
At 0° C., a mixture of 5-chloro-4-formyl-3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 91) 0.3 g and trifluoroacetic acid 10 ml was added trimethylsilane 0.27 g. The resulting mixture was stirred at room temperature for three hours, and thereto was added water 5 ml. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-chloro-3-(4-methoxy-3-methyl-phenyl)-1,4-dimethyl-1H-pyrazole 0.28 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:14]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@H:12]2[CH3:28])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:29](=[O:31])[CH3:30])[CH2:13][C@@H:12]1[CH3:28])=[O:10]
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](Nc3ccccn3)C[C@@H]2C)c1
Reactant: CC(=O)Cl
Product: COc1cccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccccn3)C[C@@H]2C)c1

Procedure:
Pd2(dba)3 (0.05 equ.), and rac-BINAP (0.1 equ.) were added to a flask with degassed toluene and stirred for 1 h. To the above solution was added 2-bromopyridine (1.1 equ.) and NaOtBu (1.1 equ.) and stirred for 30 min. (±)-Cis-(4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone was dissolved in degassed toluene and added to the solution and heated to 100° C. for 17 h. The reaction was diluted with ether and filtered through celite and concentrated down. The compound was purified by Biotage with 20% EtOAc/80% Hexane to 30% EtOAc/70% Hexane to 50% EtOAc/50% Hexane to give 43% of the product. (±)-Cis-(3-methoxy-phenyl)-[2-methyl-4-(pyridin-2-ylamino)-3,4-dihydro-2H-quinolin-1-yl]-methanone was acetylated with acetyl chloride as previously described to give (±)-cis-N-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-pyridin-2-yl-acetamide.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:30][C:19]4([CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:31]([O:34][CH2:35][C:36]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[CH:38][C:37]=1[N:51]1[N:60]=[CH:59][C:58]2[C:53](=[C:54]([F:65])[CH:55]=[C:56]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:57]=2)[C:52]1=[O:66])(=[O:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O>[C:26]([O:25][C:23]([N:21]1[CH2:22][C:19]2([CH2:30][N:17]([C:14]3[CH:15]=[N:16][C:11]([NH:10][C:4]4[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([C:41]5[CH:40]=[CH:39][CH:38]=[C:37]([N:51]6[N:60]=[CH:59][C:58]7[C:53](=[C:54]([F:65])[CH:55]=[C:56]([C:61]([CH3:64])([CH3:62])[CH3:63])[CH:57]=7)[C:52]6=[O:66])[C:36]=5[CH2:35][O:34][C:31](=[O:33])[CH3:32])[CH:3]=4)=[CH:12][CH:13]=3)[CH2:18]2)[CH2:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cn1nc(Cl)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 693 μmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (445 mg, 901 μmol) and Cs2CO3 (677 mg, 2.08 mmol) were combined with dioxane (20 ml) and water (2.00 ml) to give a yellow suspension. The flask was evacuated and filled with argon and PdCl2(DPPF) (17.0 mg, 20.8 μmol) was added. The reaction mixture was heated to 85° C. and stirred for 3 h under argon. Additional PdCl2(DPPF) (17 mg, 20.8 μmol) was added and the reaction mixture was heated to 85° C. and stirred for 60 h. Cooled to 25° C. and diluted with DCM. The reaction mixture was filtered through celite and the filtrate was dried over Na2SO4. The crude reaction mixture was concentrated in vacuo. The brown solid was used crude in the subsequent reaction. (M+H)+=765 m/e.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1Br.C([Li])CCC.[Br:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][N:33]=1)[C:26](N(C)C)=[O:27].C(O)(=O)C>O1CCCC1.O>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:5]([C:26](=[O:27])[C:25]2[CH:31]=[CH:32][N:33]=[C:23]([Br:22])[CH:24]=2)=[CH:6][C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CN(C)C(=O)c1ccnc(Br)c1
Reactant: COc1cc(Br)c(C(OC)OC)cc1OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccnc(Br)c2)c(C(OC)OC)cc1OC
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
To a solution of 2-bromo-4,5-dimethoxybenzaldehyde dimethyl acetal (21.8 g) in tetrahydrofuran (80 ml) is added dropwise a solution of n-butyl lithium (1.6 M hexane solution, 46.8 ml) at a temperature below -50° C. under nitrogen atmosphere, and the mixture is stirred for 20 minutes. The resulting solution is added dropwise into a solution of 2-bromo-N,N-dimethylisonicotinamide (18.1 g) in tetrahydrofuran (80 ml) at a temperature below -60° C., and the mixture is stirred for 30 minutes. To the reaction mixture is added acetic acid (4.5 ml), and the mixture is poured into water, and extracted with ethyl acetate. The extract is washed, dried, and concentrated, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde dimethyl acetal (13.9 g) as an oily product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([Cl:14])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CCCCC1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to a constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH2:1]([C:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OC1C=C(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A solution of compound 3-benzyl-2-cyclopenten-1-one (3.1 g, 18 mmol) in ether (100 mL) was slowly added to a suspension of lithium aluminum hydride (LAH) (684 mg, 0.87 mol) and ether (100 mL) at 0° C. under N2. The resulting mixture was stirred overnight at ambient temperature and cooled to 0° C. Saturated K2CO3 solution was added to quench the excess LAH, the mixture was filtered through Celite and washed with several portions of ether. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give compound the title compound (3 g, 94%) as a colorless oil. NMR(CDCl3):3.41 (ABq, J=6 Hz, 2H, benzylic protons), 4.80 (bs, 1H, CHOH), 5.22 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic protons).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1)[CH:5]=C.CSC>C(OCC)(=O)C>[O:1]=[CH:5][CH2:4][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: C=CCc1ccc2c(-c3ccccc3)cc(C#N)nc2c1
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CSC
Product: N#Cc1cc(-c2ccccc2)c2ccc(CC=O)cc2n1
Reaction time: 1 h

Procedure:
Ozone was bubbled into a solution of 7-allyl-4-phenylquinoline-2-carbonitrile (1.5 g, 5.6 mmol) in ethyl acetate (100 mL) at −78° C. for 1.5 h. Nitrogen was then bubbled into the solution and methylsulfide (2.1 mL, 28 mmol) was added. The reaction was brought back to room temperature, stirred for 1 h and concentrated to give the title compound. MS (+ESI): 273 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9]([CH:10]([OH:21])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[C:12]=2[Cl:20])=[CH:8][CH:7]=[N:6]1)[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:20][C:12]1[C:13]([Cl:19])=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]([C:9]1[N:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]=[CH:7][CH:8]=1)=[O:21]
Reactant: CCOCn1nccc1C(O)c1ccc(OC)c(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOCn1nccc1C(=O)c1ccc(OC)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 27 h
Yield: 90 %

Procedure:
2.72 g of manganese dioxide are added to a solution of 1.04 g of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-methoxybenzylalcohol in methylene chloride and the mixture is stirred at room temperature for 27 hours. The reaction mixture is filtered and the filtrate is condensed to an oily residue, which is then crystallized from isopropyl ether to give 0.93 g of (2,3-dichloro-4-methoxyphenyl)(1-ethoxymethyl-5-pyrazolyl)methanone.
Reaction SMILES: Br.C[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1.C(O)(=O)C>O>[CH3:10][C:9]1[C:4]([OH:3])=[N:5][CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:8]=1
Reactant: COc1ncc(C(F)(F)F)cc1C
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(F)(F)F)cnc1O

Procedure:
Two ml of 48 percent hydrobromic acid were added with stirring to mixture of 1.38 g (5.5 mol) of 2-methoxy-3-methyl-5-(trifluoromethyl)pyridine and 6 ml of glacial acetic acid at 100° C. and the mixture was allowed to react at about 95° C. for 20 min. The mixture was then cooled and poured onto ice and the solid that formed was collected by filtration. A second crop of solid was obtained by adding more water to the filtrate. The combined solids were dried to obtain 0.40 g (40 percent of theory) of the title compound as a white powder melting at 141°-143° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17](Br)[CH:16]=[CH:15][C:14]=3[CH3:20])[CH3:2].[C:25]([Cu])#[N:26]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:25]#[N:26])[CH:16]=[CH:15][C:14]=3[CH3:20])[CH3:2]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(Br)c21
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Temperature: 220 °C
Yield: 87.5 %

Procedure:
5-Bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.27 g, 3.22 mmol) and CuCN (0.433 g, 4.83 mmol) was dissolved in N-methyl-2-pyrrolidinone (15 mL) and the solution was divided into the 4 microwave reaction vessels (3.75 mL each). The reaction vessels were heated in microwave at 220 ° C. for 15 minutes. The reaction mixtures in 4 vessels were combined and then diluted with water (30 mL). The crude mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 0.959 g (88%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 9.75 (bs, 1H), 7.33 (d, J=7.52 Hz, 1H), 6.93 (d, J=7.52 Hz, 1H), 4.21 (m, 2H), 4.11 (m, 1H), 4.03 (m, 1H), 3.08 (t, J=5.52, 2H), 2.99 (d, J=4.17 Hz, 2H), 2.57 (s, 3H), 2.06 (m, 2H), 1.42 (m, 1H), 1.26 (t, J=7.16 Hz, 3H), 1.18 (m, 1H), 0.88 (t, J=7.32 Hz, 3H).