Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1.C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:9][CH:8]=1
Reactant: C1CCNCC1
Reactant: OCCc1ccc(Br)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Brc1ccc(CCN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added to a solution of 2-(4-bromophenyl)-ethanol (1.0 g, 4.97 mmol) and triethylamine (0.84 mL, 5.96 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then at ambient temperature for 2 h. The reaction mixture was partitioned between water and DCM and the organic phase was dried over sodium sulfate, filtered and evaporated to give a colourless oil. The resultant residue was dissolved in acetonitrile (10 mL), piperidine (0.491 mL, 4.97 mmol) and potassium carbonate (0.823 g, 5.96 mmol) were added and the reaction mixture was heated at 70° C. for 2.5 h. The reaction mixture was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and evaporated and the resultant residue dissolved in methanol and loaded onto a 10 g SCX-2 cartridge. The column was washed with methanol then eluted with 2N ammonia in methanol and the basic fractions were evaporated to afford the title compound (1.27 g, 95%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): 7.41-7.36 (m, 2H), 7.10-7.04 (m, 2H), 2.79-2.71 (m, 2H), 2.54-2.40 (m, 6H), 1.66-1.56 (m, 4H), 1.50-1.40 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:29])([CH3:28])[C:10]([C:12]2[S:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:15][C:16]=2[CH3:17])=[O:11])=[CH:5][C:4]=1[CH3:30].Cl.N1C=CC=CC=1.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:28])([CH3:29])[C:10]([C:12]2[S:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:15][C:16]=2[CH3:17])=[O:11])=[CH:5][C:4]=1[CH3:30]
Reactant: COc1ccc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)ccc1O
Temperature: 150 °C

Procedure:
To 2-(4-methoxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one (intermediate 104, 0.35 g) in a pressure vessel was added pyridine hydrochloride (10 g), the vessel was sealed and heated to 150° C. for 72 hours. The reaction vessel was then allowed to cool to room temperature and the solid residue partioned between water and CH2Cl2, the aqueous extract was further extracted CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and evaporated to yield a brown oil. Purification by flash column chromatography eluting with 1% EtOAc/cyclohexane yielded the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:5]([O:6][P:7]2[O:12][CH2:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[O:8]2)=[C:4]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[CH3:28]C1C=C(CO)C(O)=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1P(Cl)(Cl)[O-])(C)(C)C.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1P(Cl)(Cl)[O-])(C)(C)C.CC(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1OP1OCC2C=CC=C(C(C)(C)C)C=2O1)(C)C.C(C1C=CC=C(CO)C=1O)(C)(C)C>>[C:24]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:5]=1[O:6][P:7]1[O:12][CH2:11][C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[C:16]([CH3:28])[C:9]=2[O:8]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(O)c(CO)c1
Reactant: Cc1ccc2c(c1)COP(Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C)O2
Agent: CC(C)(C)c1cc(C(C)(C)C)c(OP2OCc3cccc(C(C)(C)C)c3O2)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(C(C)(C)C)c([PH]([O-])(Cl)Cl)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cccc(CO)c1O
Product: Cc1cc(C)c2c(c1)COP(Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C)O2

Procedure:
Other cyclic phosphites prepared as described above were 2-[4-methyl-2,6-bis(1,1-dimethylethyl)phenoxy]-6-methyl-4H-1,3,2-benzodioxaphosphorin, melting point 117°-123° C., molecular weight 486, by the reaction of 4-methyl-6-hydroxymethylphenol with 2,6-di-t-butyl-4-methylphenylphosphorodichloridite; 2-[2,4,6-tris(1,1-dimethylethyl)phenoxy]-6,8-bis(1,1-dimethylethyl)-4H-1,3,2-benzophosphorin, melting point 166°-255° C., molecular weight 526, by the reaction of 2,4,6-di-t-butyl-6-hydroxymethylphenol with 2,4,6-tri-t-butyl-phenylphosphorodichloridite; and 2-[2,4,6-tris(1,1-dimethylethyl)phenoxy]-8-(1,1-dimethylethyl)-4H-1,3,2-benzodioxaphosphorin, melting point 120°-127° C., molecular weight 470, by the reaction of 2-t-butyl-6-hydroxymethylphenol and 2,4,6-tri-t-butyl-phenylphosophorodichloridite. The structures were confirmed by Nuclear Magnetic Resonance and Infra-Red Analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCc1ccccc1
Temperature: 95 °C
Yield: 88.1 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (3 g, 10 mmol), (prepared as described for the starting material in Example 1), 5-hydroxyindole (1.46 g, 11 mmol) in DMF (30 ml) containing potassium carbonate (2.75 g, 20 mmol) was heated at 95° C. for 2 hours. After cooling the mixture was poured onto water (100 ml). The precipitate was filtered, washed with water and dried under vacuum at 50° C. over phosphorus pentoxide. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.5 g, 88%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:27][C:28]([CH2:30]Br)=[CH2:29].[NH4+].[Cl-]>C1COCC1>[Br:27][C:28](=[CH2:29])[CH2:30][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Lithium diisopropylamide (29.1 mL, 58.3 mmol) was added dropwise at −78° C. To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (9.56 mL, 38.9 mmol) in THF (200 mL), and stirred at this temperature for 50 min. 2,3-Dibromoprop-1-ene (5.47 mL, 56.0 mmol) in THF (10 mL) was added to the reaction mixture slowly and the resulting mixture was stirred for 1.5 hr at −78° C. The reaction mixture was queched with NH4Cl solution (15 mL) and was allowed to warm to room temperature and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organics were washed with brine (30 mL), dried over MgSO4 and concentrated to get the crude product which was purified by silica gel column chromatography (RediSep 220 g Gold column) using (0-30) % EtOAc/Hexanes as mobile phase to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]([CH2:37]/[CH:38]=[N:39]/[S:40]([C:42]([CH3:45])([CH3:44])[CH3:43])=[O:41])[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([N:20]([CH2:37][CH:38]([NH:39][S:40]([C:42]([CH3:45])([CH3:44])[CH3:43])=[O:41])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)N(C/C=N/S(=O)C(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(CC(NS(=O)C(C)(C)C)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
4-Bromopyridine (360 mg, 2.28 mmol) in ether (5 mL) was added dropwise to a solution of n-butyllithium (2.5 M, 1.0 μL, 2.5 mmol) in ether (15 mL) at −78° C. After 30 min, benzyl 4-((tert-butoxycarbonyl) {(2E)-2-[(tert-butylsulfinyl)imino]ethyl}amino)piperidine-1-carboxylate (364 mg, 0.759 mmol) in ether (6 mL) was added to the mixture. After 1 h, the reaction was warmed to ambient temperature, quenched with saturated ammonium chloride solution (2 mL), and partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography chromatography (75%-100% ethyl acetate/hexanes) to give the title compound (230 mg). MS 559.2 (M+1)
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15][N:14]=[C:13]([C:16](OCC)=[O:17])[CH2:12]2)=[CH:7][CH:6]=1>C(O)C>[F:22][C:4]([F:3])([F:21])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[O:15][N:14]=[C:13]([CH2:16][OH:17])[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred mixture of sodium borohydride (378 mg, 10.0 mmol) in ethanol (20 ml) was added slowly a solution of ethyl 5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate (1.6 g, 5.75 mmol) in ethanol (10 mL). The resulting reaction mixture was stirred under an atmosphere of nitrogen for 8 hours. Ethanol was removed under reduced pressure and water (20 ml) added. The aqueous mixture was acidified to about pH 3 with concentrated HCl, and the acidic solution extracted with ethyl acetate (3×20 ml). The resulting organic phase was washed with saturated aqueous sodium bicarbonate (20 ml), 30% aqueous ammonium chloride(20 ml), brine, dried over sodium-sulfate, concentrated, and purified using chromatography (3% MeOH in CH2Cl2) to afford (5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol (1.1 g, M+1=246.1).
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:5]OCC)=O.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].[OH-].[Na+]>CO>[CH3:1][C:2]1[NH:20][C:18](=[O:19])[C:17](=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:15]#[N:16]
Reactant: CCOC=C(C(C)=O)c1ccncc1
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccncc1

Procedure:
The process according to claim 4 where 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone is reacted with cyanoacetamide in the presence of at least a molar equivalent quantity of sodium hydroxide per mole of cyanoacetamide in methanol and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](OB(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(Br)cc2c1OCc1ccccc1
Reactant: OB(O)Oc1cccnc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(-c3cccnc3)cc2c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of 4-(benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (300 mg) in dioxane (10 mL) were added pyridin-3-yl boric acid (135 mg), tetrakis(triphenylphosphine)palladium(0) (65 mg), and a 1M aqueous sodium carbonate solution (1.60 mL), followed by stirring at 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added thereto, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/85) to obtain 4-(benzyloxy)-3-methyl-6-(pyridin-3-yl)-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (265 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1.[OH-].[K+]>O.C(O)C.CCCCCC.C(OCC)(=O)C>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH2:6][O:5][C:4]1[CH:3]=[C:2]([CH:19]=[CH:18][CH:17]=1)[O:1][CH2:21][CH2:22][CH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1
Reactant: ClCCCc1nnn[nH]1
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc(OCCCc2nnn[nH]2)cc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 3.51 g (0.014 mol) 2-[(3-hydroxyphenoxy)methyl]quinoline, 2.04 g (0.14 mol) 5-(3-chloropropyl)tetrazole and 2 g (0.036 mol) KOH in 5 ml water and 50 ml ethanol is heated over a steam bath for a period of 3 hours. Reaction mixture is concentrated to dryness and slurried into water and extracted with methylene chloride. The methylene chloride extract is washed with water, dried over MgSO4 and concentrated under reduced pressure to obtain solid which is passed through a silica gel column using hexane/ethyl acetate (55:45) as eluent. Evaporation of eluent gives 5-[3-(3-(2-quinolylmethyloxy)phenoxy)propyl]tetrazole (M.P. 147°-149° C.).
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2.S(Cl)([Cl:16])=O>>[C:1]12([C:11]([Cl:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)O1)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C12CC3CC(CC(C3)O1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 56B (0.1 g, 0.55 mmol) in 5 mL of thionyl chloride was warmed to reflux and stirred for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 5 mL of toluene and concentrated under reduced pressure three times to afford title compound, which was used without additional purification or characterization.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([F:19])[CH:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(F)cc2c1=O
Temperature: 25 °C

Procedure:
2-[(4-Fluoro-phenylamino)-methylene]-malonic acid diethyl ester (11.5 g, 40.9 mmol)) was added in portions to hot diphenylether (80 mL), while heating at reflux. The resultant mixture was heated an additional 2 hours, then allowed to cool to room temperature. A solid white precipitate developed. The mixture was diluted with heptanes, and the product was collected by filtration, washed with heptane, to give the product as a colorless crystalline solid, 3.0 g (31%). MS: m/z 235.9 (MH+).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[CH:11]=[C:12]2[C:25]3[CH:15]([CH2:16][C@@H:17]4[C@@H:22]([C:23]=3[CH:24]=1)[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]4[CH3:34])[CH2:14][N:13]2[Si](C(C)(C)C)(C)C>>[Cl:1][C:10]1[CH:11]=[C:12]2[C:25]3[C:15]([CH2:16][C@@H:17]4[C@@H:22]([C:23]=3[CH:24]=1)[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]4[CH3:34])=[CH:14][NH:13]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(13-bromo-1-tert-butyldimethylsilyl-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1([CH3:71])[CH2:64][C:63]2[CH:65]=[CH:66][CH:67]=[C:68]([CH2:69]O)[C:62]=2[O:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:69][C:68]2[C:62]3[O:61][C:60]([CH3:71])([CH3:59])[CH2:64][C:63]=3[CH:65]=[CH:66][CH:67]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)Cc2cccc(CO)c2O1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cccc3c2OC(C)(C)C3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: COc1cc(C=O)cc(OCCO)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OCCO)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 117.5 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (7.50 g, 38.2 mmol) and 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde (7.50 g, 38.2 mmol) in N,N-dimethylacetamide (30 mL) were added NaHSO3 (58.5 wt %, 4.37 g, 42.0 mmol) and p-TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to 115-120° C. for 16 hours, and then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with water (50 mL), and the solid was filtered, collected and mixed with ether (50 mL), filtered, and dried under vacuum, to give 2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 10 g (70%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Cc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2c1
Yield: 101.8 %

Procedure:
A mixture of 250 g (1.75 m) of 2-methylnaphthalene and 312.5 g (1.75 m) of N-bromosuccinimide in 1125 ml of carbon tetrachloride in a 3 liter round bottom flask fitted with a stirrer and reflux condenser with a drying tube was refluxed for twenty hours. The insoluble succinimide (171 g, 1.73 moles) was filtered and washed with 250 ml of carbon tetrachloride. Concentrated in vacuo gave 395 g of an oil to which was added 800 ml of petroleum ether. Solid crystallized immediately and was filtered and washed with 500 ml of petroleum ether. The first crop was air-dried to give 298 g, m.p. 48°-65° C. (Lit. m.p. 56° ). Concentration of the filtrate led to the isolation of another 33 g, m.p. 45°-50° C. of product to give a total of 331 g (86%) of good quality crude product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si](CC)(CC)CC)[C:4]([F:7])([F:6])[F:5].[Li]CCCC.[F:39][C:40]([F:51])([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O>C1COCC1.CCCCCC>[F:39][C:40]([F:51])([F:50])[CH2:41][N:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:3]([OH:8])([C:2]([F:1])([F:33])[F:32])[C:4]([F:7])([F:5])[F:6])[CH2:21][CH2:20]1)[S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)N(CC(F)(F)F)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.45 g (0.87 mmol) of trans N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide in 5 mL of dry THF was cooled to −78° C. and treated dropwise with 0.7 mL (1.13 mmol) of a 1.6M solution of nBuLi in hexane. The solution was warmed to −40° C., treated with 1.0 g (4.33 mmol) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester and then allowed to reach RT. The mixture was stirred for 30 min at RT and then refluxed for 2 hrs. The solvent was evaporated, the residue redissolved in 2 mL of THF and treated with an excess of TBAF. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases and chromatography on silica gel with heptane/EtOAc 2:1 gave 0.17 g (40%) of trans N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a light yellow oil, MS: 486 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-])=O.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:22])[CH:18]=[N:19][C:20]=1[CH3:21].Cl[Sn]Cl>N1C=CC=CC=1.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:22][C:17]1[CH:18]=[N:19][C:20]([CH3:21])=[C:15]([CH3:14])[CH:16]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(N)cnc1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1cc(NS(=O)(=O)c2ccccc2N)cnc1C
Yield: 105.7 %

Procedure:
The title compound (2.7 g, 13.0 mmol) was prepared in two steps from 2-nitrobenzenesulfonyl chloride (3.20 g, 14.4 mmol) and 5,6-dimethylpyridin-3-amine (1.5 g, 12.3 mmol) in pyridine (20 mL) at rt; followed by SnCl2 (8.88 g, 46.8 mmol) in ethanol at reflux for 2 h using the methods of (IntA1), steps 1 and 2.