Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:17][N:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]1=[O:26]>FC(F)(F)C(O)=O>[C:1]1([C:7]2[C:15]([CH2:17][N:18]3[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]3=[O:26])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3ncccn3n2)cc1
Reactant: CCCC1CC(=O)N(CO)C1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cccnc23)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
To a solution of 2-phenylpyrazolo[1,5-a]pyrimidine x124 (25.6 mmol, 1 eq, 5 g) in trifluoroacetic acid (150 ml) is added 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (38.4 mmol, 1.5 eq, 6 g). The resulting solution is stirred at room temperature for three days. The solvent is removed under reduce pressure, ice is added and the mixture is alkalinized by solid NaHCO3. The mixture is extracted by AcOEt, the organic layers are washed with brine and dried over Na2SO4. The solvent is removed under reduce pressure and the crude reaction mixture purified by chromatography on silicagel (AcOEt/hexane 40/60). After crystallisation in AcOEt/hexane, to afford 2.06 g of 1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 191 are obtained.
Reaction SMILES: [CH3:1][Li].[OH:3][CH:4]1[CH:9]2[C:10]([CH3:16])([CH3:15])[CH:11]3[CH2:14][C:8]2([CH2:13][CH2:12]3)[C:7]([CH3:18])([CH3:17])[CH2:6][C:5]1=[O:19].[Cl-].[NH4+]>C(OCC)C>[CH3:17][C:7]1([CH3:18])[CH2:6][C:5]([CH3:1])([OH:19])[CH:4]([OH:3])[CH:9]2[C:10]([CH3:15])([CH3:16])[CH:11]3[CH2:14][C:8]12[CH2:13][CH2:12]3
Reactant: CC1(C)C2CCC3(C2)C1C(O)C(=O)CC3(C)C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CC(C)(C)C23CCC(C2)C(C)(C)C3C1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
Methyllithium (63 ml of a 1.6M solution in diethyl ether, 0.10 mol) was added over 1 h to a solution of crude 5-hydroxy-2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undecan-4-one (4, 20 g, obtained as in Example 1c) in diethyl ether (200 ml), cooled below 10° C. After 1.5 h stirring, an additional portion of methyllithium (50 ml of a 1.6M solution in diethyl ether, 0.080 mol) was added and stirring continued overnight at room temperature. The reaction mixture was poured onto a stirred mixture of saturated aqueous solution of ammonium chloride (200 ml) and ice (100 g), the phases separated and the aqueous phase extracted with MTBE (200 ml). The combined organic phases were washed with water (3×200 ml), dried (Na2SO4), concentrated in vacuo and the residue (21 g) purified by flash chromatography (MTBE/hexane 1:3 to 1:2) to afford 2,2,4,7,7-pentamethyltricyclo[6.2.1.01.6]undecane-4,5-diol (5b, 5.7 g, ˜46% yield starting from 3, white solid).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)=[O:13])[CH:10]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.[N+](C1C=CC([C:53]2[CH:61]=[CH:60][CH:59]=[CH:58][C:54]=2[C:55]([O-])=[O:56])=CC=1)([O-])=O>C(Cl)Cl>[C:55]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)=[O:13])[CH:10]=1)=[NH:3])(=[O:56])[C:54]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:53]=1
Reactant: O=C([O-])c1ccccc1-c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(NC(=O)Cc2cc(C(=N)N)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1

Procedure:
350 mg (0.69 mmol) of 2-(5-carbamimidoyl-2-benzyloxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetamide-hydrochloride are suspended in 40 ml of methylene chloride and combined with 1.0 ml of triethylamine and 300 mg (1.3 mmol) of 4-nitrophenylbenzoate. The reaction mixture is refluxed for 4 hours. After the addition of 100 ml of saline solution the aqueous phase is extracted 3× with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[NH4+].[OH-]>Cl>[F:8][C:5]1[CH:6]=[C:7]2[C:2](=[C:3]([OH:9])[CH:4]=1)[N:1]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: C/C=C/C=O
Reactant: Nc1ccc(F)cc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2cc(F)cc(O)c2n1
Yield: 82.5 %

Procedure:
To 2-amino-5-fluorophenol (5.0 g, 39 mmol) in refluxing 6N HCl (50 mL) was added dropwise over 10 minutes (E)-but-2-enal (5.5 g, 79 mmol). The reaction was heated to reflux for 3 hours then cooled down and neutralized (pH=7-8) by addition of NH4OH. The aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated to yield 6-fluoro-2-methylquinolin-8-ol (5.7 g, 82% yield) as a dark oil which solidified upon standing.
Reaction SMILES: C[Mg]I.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)C(OC)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:22]1C[CH2:25][CH2:24][CH2:23]1>CCOCC>[CH2:4]([O:11][C:12]1[C:21]([CH2:25][CH2:24][CH2:23][OH:22])=[CH:20][CH:19]=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Agent: C[Mg]I
Solvent: CCOCC
Product: OCCCc1ccccc1OCc1ccccc1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a 0° solution of 2.2 mole of methyl magnesium iodide in 1.5 l. ether is added a solution of 200 g. (1.06 mole) of methyl 3-benzyloxybenzoate in 500 ml. ether and 500 ml. tetrahydrofuran. The reaction mixture is stirred for 3 hours and then added to 1.5 l. ice cold saturated ammonium chloride and 2 l. ether. The organic extract is dried over magnesium sulfate and evaporated to an oil. Crystallization of the crude oil in petroleum ether gives 186 g. (93%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 4 from 1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4-amino-3,5-dichloro-phenyl}-ethyl)-amino]-propane and hydrogen in the presence of palladium-on-charcoal in glacial acetic acid.
Reaction SMILES: Cl.[N:2]1([C:7]2[N:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[C:9]([CH3:15])[N:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:23](=[N:14][CH2:13][C:11]1[CH:10]=[C:9]([CH3:15])[N:8]=[C:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[N:12]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(CN)nc(-n2ccnc2)n1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CN=C(c2ccccc2)c2ccccc2)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A mixture of (2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)methanamine hydrochloride (20.4 g, 90.3 mmol) and triethylamine (60.0 mL, 452 mmol) in dichloromethane (300 mL) was stirred at room temperature for 30 min then the mixture was concentrated under vacuum. The residue was dissolved in toluene (500 mL) then benzophenone (57.5 g, 316 mmol) and p-toluenesulfonic acid monohydrate (4.50 g, 23.7 mmol) were added to the solution. The mixture was heated to 110° C. for 12 h then concentrated under vacuum. The residue was extracted with ethyl acetate (2×500mL), washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated. The product was purified using column chromatography (1:10 EtOAc/hexanes to EtOAc) to afford benzhydrylidene-(2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amine as a yellow solid (14.0 g, 42.6%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[C:37]([NH:56][CH2:57][CH2:58][CH2:59][NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:60]([CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:67])([CH3:69])[CH3:68])[CH2:59][CH2:58][CH2:57][NH:56][C:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCNCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1ncc(NC(=O)N(CCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 87.7 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)pyrazol-4-yl]carbamate (423 mg) and tert-butyl 2-{[3-(tritylamino)propyl]amino}ethylcarbamate (410 mg) in dehydrated chloroform (2.5 ml) was added N-ethyldiisopropylamine (0.152 ml), and the mixture was stirred under reflux for 16 hours. To the reaction mixture was added ethyl acetate, and the solution was washed successively with water, 5% aqueous citric acid solution, 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/methylene chloride to give tert-butyl (2-{N-({[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}carbonyl)-N-[3-(tritylamino)propyl]amino}-ethyl)carbamate (657 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][NH:5][C:4](=[O:8])[N:3]=1.[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]=[O:11]>CO>[O:8]=[C:4]1[N:3]=[C:2]([NH:1][C:10]([NH:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])[CH2:7][O:6][NH:5]1
Reactant: CCOC(=O)CN=C=O
Reactant: NC1=NC(=O)NOC1
Solvent: CO
Product: CCOC(=O)CNC(=O)NC1=NC(=O)NOC1

Procedure:
A solution of 1.0 g (0.0086 mole) of 5-amino-6H-1,2,4-oxadiazin-3(2H)-one and 1.0 g (0.0086 mole) of ethyl isocyanatoacetate in methanol is combined with cooling and stirring to give the desired product of N-(3,6-dihydro-3-oxo-2H-1,2,4-oxadiazin-5-yl)aminocarbonyl-glycine, ethyl ester which was isolated by filtration, followed by washing with ether and drying. A yield of 0.5 g (72 percent) is obtained.
Reaction SMILES: C(O[C:9]([CH2:11][N:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1.C[O-].[Na+].C(Cl)(=O)C(C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:49]=[CH:50][CH:51]=1)[C:37]([C:39]1[C:40]([NH:46][CH2:47][CH3:48])=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=1)=O>C(O)C.C1COCC1.[C].[Pd]>[Cl:33][C:34]1[CH:35]=[C:36]([C:37]2[C:39]3[C:40](=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=3)[N:46]([CH2:47][CH3:48])[C:9](=[O:10])[C:11]=2[N:12]2[CH2:13][CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:21][CH2:22]2)[CH:49]=[CH:50][CH:51]=1
Reactant: CCOC(=O)C1CCN(CC(=O)OCc2ccccc2)CC1
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)C(=O)Cl
Agent: C[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2c(-c3cccc(Cl)c3)c3ccc(C)nc3n(CC)c2=O)CC1

Procedure:
Ethyl 1-(benzyloxycarbonylmethyl)isonipecotate was subjected to catalytic reduction under a hydrogen atmosphere of 1 atm in ethanol in the presence of 10% palladium-carbon. The resulting compound was treated with sodium methoxide in ethanol and then reacted with pivaloyl chloride in THF. The resulting compound was reacted with 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine under heating, and further treated with sodium methoxide in ethanol. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain ethyl 1-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]piperidin-4-carboxylate as a yellow oily substance. MS: 454.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([Li])(CC)C.[CH3:16][S:17]SC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:17][CH3:16])[C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CSSC
Reactant: COc1cc(Cl)ccc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(SC)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-chloro-1-fluoro-2-methoxybenzene (2.0 g) and THF (dry) (100 mL) was added sec-butyllithium (1.04 mol/L cyclohexane solution, 23.95 mL) dropwise over a period of 45 min at −78° C. After stirring at −78° C. for 30 min, to the mixture was added dimethyl disulfide (2.468 mL) at the same temperature. The mixture was stirred at −78° C. for 1.5 h under argon atmosphere. The mixture was quenched with saturated aqueous NH4Cl at −78° C. and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give a solid. The solid was washed with hexane to give the title compound (1.77 g).
Reaction SMILES: Cl[CH2:2][C:3](=[O:18])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)[CH2:6][CH3:7].[N-:19]=[N+:20]=[N-:21].[Na+]>CO>[N:19]([CH2:2][C:3](=[O:18])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)[CH2:6][CH3:7])=[N+:20]=[N-:21]
Reactant: CCC(CC(=O)CCl)c1ccc(C(=O)OC)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC(=O)CN=[N+]=[N-])c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
A mixture of the chloromethyl ketone (7, 5.9 g, 0.022 mol), 10.8 g (0.16 mol) of NaN3 and 180 ml of 80% MeOH was stirred at room temperature for 20 hours. After evaporation of MeOH the aqueous residue was diluted to 100 ml with H2O and extracted with three 50 ml portions of CHCl3. The CHCl3 was dried (MgSO4) and evaporated to leave 5.5 g (91%) of a yellow oil (8); TLC (silica gel, CHCl3 0C6H6, 1:1) Rf 0.30 single spot; IR cm-1 2105 (--N3); NMR (CDCl3) δ 0.80 (3H, t, CH3), 1.70 (2H, m, CH2CH3), 2.80 (2H, m, CH2C=O), 3.15 (1H, m, Ar--CH), 3.77 (2H, s, CH2N3), 3.90 (3H, s, OCH3), 7.30 (2H, d, 3', 5'--ArH), 8.05 (2H, d, 2', 6'--ArH).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:25][OH:26])[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]([CH3:23])=[CH2:22])[C:13]1=[O:24].COCCOC>O>[O:26]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21]([CH3:23])=[CH2:22])[C:13]2=[O:24])=[N:25]1
Reactant: C=C(C)n1c(=O)n(CC(=NO)c2ccccc2F)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Temperature: 85 °C
Yield: 56.8 %

Procedure:
A 25 ml pear-shaped flask was charged with sodium hydride (60% oil dispersion, 68 mg, 1.7 mmol) which was washed with hexanes and then diluted with DME (3 ml). The 1-{2-(2-fluoro-phenyl)-2-[hydroxyimino]-ethyl}-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (0.5 g, 1.5 mmol) was introduced as a DME (3 ml) solution in a dropwise manner. The resulting mixture was warmed to 85° C. for 20 h and cooled to ambient temperature. The reaction was diluted with water and the product was extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 40% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 0.26 g (55%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:14][CH2:13][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([O:11][CH3:12])=[O:10])(=[O:26])[CH3:25]
Reactant: COC(=O)C(CO)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(COC(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.5 %

Procedure:
methyl 2-(tertbutoxycarbonyl)-3-hydroxypropanoate (29) (2.2 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by CH2Cl2 (40 mL). Next, DIEA (2.1 mL, 12.0 mmol, 1.2 equiv.) and acetic anhydride (1.2 mL, 13.0 mmol, 1.3 equiv.) were added to the reaction mixture and the solution was stirred at rt. The reaction solution was stirred for a total of 21 h. The solution was transferred to a separatory funnel with CH2Cl2 (75 mL), washed with 1% HCl (2×50 mL), and sat. NaCl (2×50 mL). The organic layers were dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give 2.4 g (91%) of 30 as a clear oil which crystallized to a white solid upon standing. Rf=0.37 (25% EtOAc/hexanes); mp=61-62° C.; IR (KBr) 3327, 2985, 1742, 1683, 1533, 1348, 1241, 1166, 1071, 1038 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.33 (br d, J=8.0 Hz, 1H, carbamate-NH), 4.58 (m, 1H, Boc-NH—CH), 4.44 (dd, J=11.0, 3.5 Hz, 1H, CH—CH2), 4.33 (dd, J=11.0, 3.5 Hz, 1H, CH—CH2), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, O═C—CH3), 1.46 (s, 9H, t-butyl-CH3).; 13C NMR (125 MHz, CDCl3) δ 170.6, 170.5, 155.3, 80.5, 64.5, 53.0, 52.9, 28.4, 20.8; LRMS (ESI-MS m/z): Mass calcd for C11H19NNaO6 [M+Na]+, 284.26. Found 284.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=[S:24])[CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared by heating under reflux overnight a stirred mixture of 3-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluorobenzonitrile and an equal weight of phosphorus pentasulfide in pyridine and workup as in the previous example gave a yellow solid: mp. 240-242° C. dec.; 1H-NMR (DMSO-d6) δ 12.37 (s, 1H), 8.13 (s, 1H), 7.98 (dt,1H, J=10.4 and 5.4 Hz), 7.81 (d, 1H, J=8.4 Hz), 7.7 (d, 1H, J=1.8 Hz), 7.68 (dd, 1H, J=8.3 and 1.9 Hz), 7.22 (d, 1H, J=8.3 Hz), 2.85 (s, 2H), 1.27 (s, 6H); MS m/z 309 [M−H]− Anal. Calc. For C18H15FN2S 0.10 H2O: C, 69.25, H, 4.91, N, 8.97. Found: C, 69.15, H, 4.74, N 8.75.
Reaction SMILES: COC(=O)CCC(C)=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].N1C=CC=CC=1.NC(N)=S.C[OH:42]>C(Cl)Cl>[CH3:19][O:18][C:17]1[C:16]([CH3:20])=[C:15]2[C:11]([C:12](=[O:21])[O:13][CH2:14]2)=[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:9]=1[CH2:8][CH:7]=[O:42]
Reactant: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: CO
Agent: NC(N)=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH2Cl2 (10 mL) and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dry ice/acetone bath according to the procedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through the reaction via a gas dispersion tube until the reaction became blue in color (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for another 15 minutes when the blue color disappeared. To this solution at −70° C. was added thiourea (75.7 mg, 0.994 mmol) in one portion, and the cooling bath was removed. The reaction was allowed to warm to room temperature and stirred for 15 hours. The reaction was worked up by filtration to remove solid thiourea S-dioxide, and then partitioned between CH2Cl2 and water. The organic layer was removed. The aqueous layer was washed with CH2Cl2 one more time and the organic extracts were combined. The organic layer was washed with aqueous 1N HCl, saturated NaHCO3 and brine. The organic extracts were dried in vacuo and the residue was purified to by silica gel chromatography to afford 357 mg (75%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J=1 Hz).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:42]([NH2:60])=[N:43][C:44]3[C:49]([CH:50]=2)=[CH:48][C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=3)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:70]1[C:75]([CH3:76])=[CH:74][CH:73]=[CH:72][C:71]=1[C:77]#[C:78][C:79]([CH3:82])([CH3:81])[CH3:80]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:80][C:79]([CH3:82])([CH3:81])[C:78]#[C:77][C:71]1[CH:72]=[CH:73][CH:74]=[C:75]([CH3:76])[C:70]=1[C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]=[C:42]([NH2:60])[C:41]([N:38]1[CH2:37][CH2:36][O:35][CH2:40][CH2:39]1)=[CH:50]2
Reactant: Cc1cccc(C#CC(C)(C)C)c1Br
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cccc(C#CC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A microwave vial was charged with a mixture of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.040 g, 0.084 mmol), Pd2(dba)3 (0.019 g, 0.021 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.15 g, 0.422 mmol, prepared as in Example 2, Step 1-2) and potassium phosphate (0.175 mL, 2.11 mmol). The vial was evacuated and backfilled with N2. This procedure was repeated twice. Degassed dioxane (2.8 mL) and water (1.4 mL) was added. Then 2-bromo-1-(3,3-dimethylbut-1-ynyl)-3-methylbenzene (0.138 g, 0.549 mmol) was added and the reaction mixture was heated to 140° C. for 12 min in the microwave. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic phase was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (50-100% EtOAc/hexanes). The obtained solid was dissolved in MeOH (4 mL) and treated with 1N HCl (1 mL). The solution was eluted on an SCX cartridge with MeOH followed by 2M NH3/MeOH. The basic fraction was concentrated to afford the titled compound as a beige foam. MS (ESI, pos. ion) m/z: 400 (M+1).