Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]=[CH:15][CH2:16][N:17]([CH:24]3[CH2:26][CH2:25]3)C(=O)C(F)(F)F)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]=[CH:15][CH2:16][NH:17][CH:24]3[CH2:26][CH2:25]3)=[CH:10][CH:9]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OCC=CCN(C(=O)C(F)(F)F)C2CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccc(Br)cc1)c1ccc(OCC=CCNC2CC2)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 11.5 g of N-[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-N-cyclopropyl-2,2,2-trifluoroacetamide in 150 ml of methanol and 50 ml of tetrahydrofuran is treated with 5 ml of 20% aqueous potassium hydroxide solution while cooling with ice. The mixture is brought to room temperature and stirred for one hour, concentrated under reduced pressure and the residue is treated with 100 ml of water. The phases are separated and the inorganic phase is extracted with methylene chloride. The organic extracts are washed with saturated sodium chloride solution, dried and evaporated. After purification of the residue over silica gel with ethyl acetate-hexane-triethylamine (50/49/1) there are obtained 7.0 g of (4-bromo-phenyl)-[4-(4-cyclopropylamino-but-2-enyloxy)-phenyl]-methanone, MS: m/e 386 (M+H+, 1Br),
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:46][C:47]1([CH3:59])[O:51][C@H:50]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54]2)[CH2:49][O:48]1>ClCCl>[CH3:46][C:47]1([CH3:59])[O:51][C@H:50]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH:58][C:11](=[O:13])[CH:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:20])[CH2:14][CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:54]2)[CH2:49][O:48]1
Reactant: CC(C)(C)CCC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)CCC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid (32 mg, 0.091 mmol) in dichloromethane (3 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (20 μL, 0.10 mmol) and 1-hydoxybenzotriazole (13 mg, 0.096 mmol) and stirred at 25° C. for 2 h. After this time period, 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 21 mg, 0.109 mmol) was added and stirred for 16 h at 25° C. After this time, the mixture was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 30% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (14 mg, 29%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC.CN(C=O)C.[F-].[K+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([O:17][C:15]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)=[CH2:16])[CH3:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nccc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccnc(SC)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture comprising 16.4 g of 4-chloro-2-methylsulfanylpyrimidine, 38 g of tributyl(1-ethoxyvinyl) tin, 1.43 g of bis(triphenylphosphine)palladium (II) dichloride and 100 ml of DMF was stirred at 80° C. for 3 hours. After cooling the reaction mixture, 300 ml of ethyl acetate and 17.8 g of potassium fluoride were added to the mixture, and the resulting mixture was stirred at room temperature overnight. After filtration with Celite, the filtrate was washed, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethylacetate=20:1) to give 18.9 g of 4-(1-ethoxy-vinyl)-2-methylsulfanylpyrimidine.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].CC(OC(=O)NC1C2C(=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)N(C(=O)C)C(C)C1)C.Br[C:62]1[N:63]=[C:64]([CH:67]=[O:68])[S:65][CH:66]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:62]3[N:63]=[C:64]([CH:67]=[O:68])[S:65][CH:66]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=Cc1nc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(NC(=O)OC(C)C)CC1C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3csc(C=O)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C

Procedure:
1-methylethyl[(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 12) (50 mg, 0.120 mmol) was mixed with 4-bromo-1,3-thiazole-2-carbaldehyde (34.6 mg, 0.180 mmol, available from Frontier), potassium carbonate (33.2 mg, 0.240 mmol), tetrakis(triphenylphosphine)palladium(0) (6.94 mg, 6.01 μmol) and dissolved in ethanol (0.5 mL) and toluene (0.5 mL). The mixture was heated in a nitrogen-flushed microwave vial at 90° C. for 1 hour in a Biotage initiator and the mixture was left to cool to room temperature overnight. The residue was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid. This was purified on a 12+M Biotage silica column eluting with a 0-60% gradient of ethyl acetate in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (23 mg). LCMS (Method C): Rt=0.96, MH+=402
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH3:33])[CH2:28]2)[C:20]=1[C:21]#[N:22]>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([NH:18][C:19]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH:29]([CH3:33])[CH2:28]4)[C:20]=3[C:21]#[N:22])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: CC1CN(c2cccc(N)c2C#N)CCO1
Reactant: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(N3CCOC(C)C3)c2C#N)cc1

Procedure:
In a manner similar to Example I, 1-(4-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(2-methyl-4-morpholinyl)benzonitrile to give 1-(4-methoxybenzyl)-N-[2-cyano-3-(2-methyl-4-morpholinyl)phenyl]-1H-tetrazole-5-carboxamide.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[NH:14][C:15]2=[O:18])=[CH:10][CH:9]=1>>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[NH:14][C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: CN
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCBr)cc12
Product: CNCCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Methylamine (40% methanol solution) was added to the 7-(3-bromopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (245 mg, 0.576 mmol) obtained in step A, and the obtained mixture was then stirred at a room temperature for 3 hours. Thereafter, the reaction solvent was distilled away, and the obtained residue was purified by amino silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 142 mg of 7-(3-methylaminopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (66%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COC1CCNCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: COC1CCN(C(=O)c2ccc3c(OC(C)C)nc(Nc4cc(C)[nH]n4)cc3c2)CC1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 4-Methoxy-piperidine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-(4-methoxy-piperidin-1-yl)-methanone. LC-MS: m/e 424 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])C.[CH3:21][NH2:22].CO.O>C(O)(=O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:22][CH3:21])=[O:5])[C:7]1=[O:20])[CH3:19]
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCn1c(=O)c(C(=O)NC)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 4 g. of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) and 30 ml. of 40% aqueous methylamine in 20 ml. of methanol was heated under reflux for 5 hours. The solution was cooled, diluted with 100 ml. of water and was acidified with glacial acetic acid. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 1.9 g. of the title compound, m.p. 150°-4° C.
Reaction SMILES: [Si:1]([N:8]1[C@H:11]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C@H:10]([C@H:18]([OH:20])[CH3:19])[C:9]1=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[C:18]([C@H:10]1[C@H:11]([C:12]#[C:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[N:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:9]1=[O:21])(=[O:20])[CH3:19]
Reactant: C[C@@H](O)[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C#C[Si](C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
Cis-1-(tert-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone (0.15 g) is dissolved in ethyl acetate (20 ml), and 5 g of activated manganese dioxide is added, followed by stirring at 25° C. for 5 hours. The manganese dioxide is filtered off and the filtrate is concentrated to give trans-3-acetyl-1-(tert-butyldimethylsilyl)-4-trimethylsilylethynyl-2-azetidinone (0.14 g).
Reaction SMILES: [I:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[OH-].[K+]>C(O)(C)C>[I:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1I

Procedure:
A mixture of intermediate (27) (0.041 mol) and potassium hydroxide (0.41 mol) in isopropanol (200 ml) was stirred and refluxed for 3 hours and the solvent was evaporated till dryness. Water was added. The mixture was extracted with DCM and the solvent was evaporated, yielding 2-iodo-N-[4-(1-piperazinyl)phenyl]benzamide (intermediate 28).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@H:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:37]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@H:17]([O:19][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][O:37]1)[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (2S,3R)-methyl 2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate (5.0 g, 18.72 mmol) in dichloromethane (100 mL), pyridinium p-toluene sulfonate (0.47 g, 1.87 mmol) and 2,3-dihydropyran (2.6 mL, 28.08 mmol) were added at once and the solution was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (50 mL) and brine solution (50 mL) and dried over sodium sulfate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]([CH2:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)=[O:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:26]2[CH:30]=[CH:31][C:23]([CH2:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])=[CH:24][CH:25]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: COC(=O)CCc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-(2-methoxycarbonyl-ethyl)-benzoic acid
Reaction SMILES: [NH3:1].[C:2]([C:4](=[C:7](SC)[S:8][CH3:9])[C:5]#[N:6])#[N:3]>C(O)C>[NH2:1][C:7]([S:8][CH3:9])=[C:4]([C:5]#[N:6])[C:2]#[N:3]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: N
Solvent: CCO
Product: CSC(N)=C(C#N)C#N
Temperature: 25 °C

Procedure:
At 15°, 650 ml of ethanol was saturated with gaseous ammonia. Seventy-three and three-tenths grams of 2-cyano-3,3-bis(methylthio)propenenitrile were added portionwise during 10 minutes. The reaction mixture was heated to 78° during 15 minutes. The slurry was allowed to cool to ambient temperature, then cooled to 10°. The solid was collected by filtration and washed with cold ethanol to give, when dried, m.p. 228°-229° (Literature m.p. 229°-230°, R. Gompper and W. Topel, Ber. 95, 2871 (1902)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: COc1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3CCN2C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round-bottomed flask containing crude 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (25 mg, 104 μmol) and CH2Cl2 (10 mL) was added 1-fluoro-4-isocyanatobenzene (0.03 mL, 264 μmol). The solution was stirred at RT. After 1 h, the reaction was concentrated in vacuo and taken up in DMF and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini™ column (5 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an linear gradient of 10% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 10 min to give crude product, that was lypholized and resubjected to the same purification conditions to give N-(4-fluorophenyl)-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide, as a white solid that contained 0.66 eq of TFA. MS (ESI pos. ion) m/z: 377 (M+1).
Reaction SMILES: CC([O-])(C)C.[Na+].[C:7]1(I)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[SH:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:7]1([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: CC(C)(C)S
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
In the drybox, 52.0 mg (0.184 mmol) of (Me2CH)PH(O)(2,4-(MeO)2C6H3) from Example 34, 34.0 mg (0.151 mmol) of Pd(OAc)2 and 14.0 ml of toluene were loaded into a reactor (20 ml) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 1 h. Next, 576.0 mg (6.0 mmol) of NaOtBu, 816.0 mg (4.0 mmol) of PhI and 360 mg (4.0 mmol) of HS-t-Bu were added into the mixture above, The resulting mixture was refluxed for 3 days. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 190 mg (29% yield) of t-butyl phenyl sulfide. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.43-7.42 (m, 2H), 7.22-7.19 (m, 3H), 1.17 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): δ137.4, 132.7, 128.5, 128.3, 30.9 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[C:9](\[Cl:16])/[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(Cl)nn1)C(F)(F)F
Solvent: CC(Cl)Cl
Product: FC(F)(F)/C(Cl)=N/c1ccc(Cl)nn1
Temperature: 25 °C

Procedure:
A solution of 3.8 g (17 mmol) of the crude product of Step A and 4.2 g (22 mmol) of phosphorous pentachloride in 200 mL of dichloroethane was heated at reflux temperature under nitrogen. After 6 h the reaction was cooled to ambient temperature then concentrated in vacuo to yield a crude oil which was carried on to Step C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN>O.S([O-])([O-])(=O)=O.[Cu+2].CO>[OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(/C=C/C(=O)O)oc2cccc(O)c12
Agent: [Cu+2]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1c(CCC(=O)O)oc2cccc(O)c12
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of E-3-(4-hydroxy-3-methylbenzofuran-2-yl)propenoic acid (4.5 g, 20 mmoles), methanol (250 ml), 99% hydrazine hydrate (5 ml) and copper sulfate monohydrate (3 crystals) was stirred at room temperature for several days. The mixture was filtered and concentrated to remove methanol. The aqueous residue was acidified with 20% citric acid solution and extracted with diethyl ether. The ether solution was dried with Na2SO4, filtered, concentrated and chromatographed to obtain 950 mg of the title compound, m.p. 114°-117° C.
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:40][CH3:41]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:40][CH3:41]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: COc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4(diethoxyphosphoryl)-3-methyl-but-2E-enoate (233 mg, 0.87 mmol) and (2E)-3-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-146, 116 mg, 0.29 mmol) were reacted to give the title compound as a colorless oil after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane) and HPLC (normal phase, 1% ethyl acetate in hexanes).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.CCCCCC.CN(C)[CH:28]=[O:29].Cl>O1CCCC1>[OH:4][C:5]1[C:6]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:8]=[CH:9][C:10]=1[CH:28]=[O:29]
Reactant: COCOc1ccccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C(F)(F)F)c1O
Reaction time: 1 h

Procedure:
1-methoxymethoxy-2-trifluoromethylbenzene (64.13 g) was dissolved in tetrahydrofuran (500 mL), and a 2.77M n-butyllithium-n-hexane solution (123 mL) was added to the solution over 45 minutes under an argon gas flow at −70° C., and then the mixture was stirred for 1 hour. N,N-dimethylformamide (28.5 mL) was added, followed by stirring at room temperature for 30 minutes. 4N hydrochloric acid (310 mL) was added, followed by stirring at 60° C. for 19 hours. The organic solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (59.16 g) as a yellow crystal.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: N#CCCl
Reactant: O=C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#CC1OC12CCOCC2
Reaction time: 0.17 h

Procedure:
A mixture of tetrahydropyran-4-one (10 mL) and chloroacetonitrile (6.4 mL) in tert-butanol (10 mL) was stirred for 10 minutes. To this solution was added a solution of potassium tert-butoxide (12.11 g) in 200 mL of tert-butanol at room temperature over 40 minutes. The reaction mixture was stirred for 16 hours, diluted with water and quenched slowly with 1 N HCl. The solvent was partially removed by rotary evaporation. It was then extracted with ether (5×200 mL). The combined extracts was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chromatography on silica with 3:7 to 1:1 ethyl acetate:hexanes to provide the title compound.