Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH:25]1([N:28]2[C:36]3[C:31](=[C:32]([O:40][CH2:41][CH3:42])[CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:37]([C:34]3[CH:35]=[C:36]4[C:31]([CH:30]=[CH:29][N:28]4[CH:25]4[CH2:27][CH2:26]4)=[C:32]([O:40][CH2:41][CH3:42])[CH:33]=3)=[O:38])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3]
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: CCOc1cc(C(=O)O)cc2c1ccn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NCC(N)=O)ccc2O3)cc2c1ccn2C1CC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
N-Carbamoylmethyl-4-oxospiro[chroman-2,4′-piperidine]-6-carboxamide hydrochloride (389 mg), 1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylic acid (245 mg), WSC hydrochloride (230 mg), HOBT (183 mg) and triethylamine (0.209 mL) were suspended in DMF (8 mL), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed successively with water, 1 N hydrochloric acid, aqueous saturated sodium bicarbonate and saturated saline water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (chloroform/methanol) to afford the title compound as a colorless amorphous substance. 1H-NMR (400 MHz, DMSO-d6) δ: 8.78-8.71 (1H, m), 8.32-8.30 (1H, m), 8.08 (1H, dd, J=8.7, 2.3 Hz), 7.34 (1H, s), 7.28 (1H, d, J=3.4 Hz), 7.22-7.16 (2H, m), 6.99 (1H, s), 6.56 (1H, s), 6.38 (1H, d, J=3.4 Hz), 4.27-4.15 (1H, br m), 4.15 (2H, q, J=7.0 Hz), 3.77 (2H, d, J=5.9 Hz), 3.46-3.25 (3H, br m), 3.45-3.39 (1H, m), 2.95 (2H, s), 2.09-1.75 (4H, br m), 1.38 (3H, t, J=7.0 Hz), 1.08-1.01 (2H, m), 0.95-0.90 (2H, m); MS [M+H]+=545.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])OC1C=CC=CC=1)#[N:2].[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:3]=[C:4]([N:12]([CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:33]1)#[N:2]
Reactant: CCOC(=O)CN(CC=C(C)C)C(=NC#N)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC=C(C)C)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1

Procedure:
Prepared by reacting cyanimino-[N-(3-methyl-2-buten-1-yl) -N-(ethoxycarbonylmethyl)-amino]-phenyloxy-methane with 3-(tert.-butyloxycarbonylamino)-piperidine in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]#[N:9])=[C:5]([Cl:7])[N:6]=1.C(N(CC)C(C)C)(C)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)C.O>[Cl:7][C:5]1[N:6]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:3][C:4]=1[C:8]#[N:9]
Reactant: C1COCCN1
Reactant: N#Cc1sc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: N#Cc1sc(N2CCOCC2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
2,4-dichloro-5-cyanothiazole (1.26 g, 0.00704 mol) and N,N-diisopropylethylamine (3.68 mL, 0.0211 mol) were dissolved in ethanol at 70° C. Morpholine (0.614 mL, 0.0704 mol) was added to the hot solution and the mixture was stirred for 30 minutes, cooled down to rt, diluted with water (50 mL) and the formed precipitate was collected to give the title compound (1.55 g, 91%). LCMS: (FA) ES+, 230. 1H NMR (300 MHz, d6-DMSO) δ: 3.71-3.67 (m, 4H), 3.52-3.48 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](=O)(O)[O-].[Na+]>Cl>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc(C)c(O)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
The solution of 3-hydroxy-4-methylbenzoic acid (commercially available) in 32 mL hydrochloric acid (1.25M in methanol) was refluxed for 5 h. After cooling to room temperature the solution was poured on saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate and filtered to give the product as a white solid (99%) which was pure enough for the next step. MS (Turbo Spray): m/z=165.1 [M−H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>CN(C=O)C>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH:3]=3)=[CH:9][C:10]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(-c4nccs4)c3)cc21
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.25 g, 0.75 mmol), tri-n-butyl-thiazol-2-yl tin (0.5 g, 1.3 mmol) in DMF (5 mL) was degassed to remove oxygen and then heated under nitrogen at 90° C. for 3 hours. The reaction mixture was cooled to rt and treated with ice-water (70 mL). Ethyl acetate (100 mL) was added and organic layer was separated, washed with brine, and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel column (hexane:ethyl acetate/1:1) to give the title compound as a white solid (60 mg, 23%): mp 223-224° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (bs, 1H), 7.67-7.61 (m, 4H), 7.53 (t, 1H, J=7.68 Hz), 7.00 (d, 1H, J=8.81 Hz), 1.7 (s, 6H); MS (APCI) m/z 337([M+H]+, 100%); Anal. Calc. For C19H16N2O2.S0.25 H2O: C, 66.94, H, 4.88, N, 8.22. Found: C, 66.57, H, 4.65, N, 7.92.
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([C:9]1[CH:10]=[N:11][C:12]([N:16]2[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]2[CH2:22][OH:23])=[CH:13][C:14]=1[I:15])[CH3:8])(C)(C)C.Cl.C(N(C(C)C)C(C)C)C.[F:35][C:36]([F:54])([F:53])[C:37]1[CH:38]=[C:39]([C:47](C)([CH3:51])[C:48](Cl)=O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>ClCCl.C(OCC)C>[F:35][C:36]([F:53])([F:54])[C:37]1[CH:38]=[C:39]([C:47]([CH3:51])([CH3:48])[C:6]([N:7]([C:9]2[CH:10]=[N:11][C:12]([N:16]3[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]3[CH2:22][OH:23])=[CH:13][C:14]=2[I:15])[CH3:8])=[O:24])[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.6 %

Procedure:
To a solution of 8.94 g (19.9 mmol) (2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester in 85 ml dichloromethane were added 50 ml of a 2 M solution of hydrogen chloride in diethylether at 0° C. The reaction mixture was stirred at room temperature for 22 h and concentrated in vacuo. The residue was re-dissolved in 85 ml dichloromethane and treated with 17 ml (99.4 mmol) N-ethyldiisopropylamine. At 0° C. 19.0 g (59.7 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo. After addition of 250 ml methanol and 70 ml 3 N potassium hydroxide solution the mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove methanol and extracted with four 750 ml-portions of dichloromethane. The combined organic layers were washed with 500 ml 1 N sodium hydroxide solution and 500 ml brine, dried over sodium sulfate and evaporated. Flash-chromatography gave 11 g (87%) of the title compound as a light yellow foam.
Reaction SMILES: C[Si](I)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:23]=[C:24]([C:30]([F:33])([F:32])[F:31])[C:25]([C:28]#[N:29])=[N:26][CH:27]=3)[C:18](=[O:34])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:9][C:8]=1[O:35]C.O>C(#N)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:23]=[C:24]([C:30]([F:32])([F:33])[F:31])[C:25]([C:28]#[N:29])=[N:26][CH:27]=3)[C:18](=[O:34])[C:14]32[CH2:15][CH2:16][CH2:17]3)=[CH:9][C:8]=1[OH:35]
Reactant: COc1cc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)ccc1F
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(F)c(O)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Trimethylsilyl iodide (7.0 ml, 51.1 mmol) was added to a solution of 5-(5-(4-fluoro-3-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 32, 3 g, 5.1 mmol) in acetonitrile (50 mL) and the mixture was refluxed for 24 h. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc (3×). The organics were combined, washed with sat'd solution of NaHSO3, dried over MgSO4, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexane=1/5 to afford 1.1 g of 5-(5-(4-fluoro-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile. 1H NMR (400 MHz, CDCl3) δ 9.10 (d, 1H), 8.38 (d, 1H), 7.27-7.22 (m, 1H), 6.93 (dd, 1H), 6.78 (m, 1H), 2.74-2.55 (m, 1H), 2.23 (m, 1H), 1.80-1.59 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Br.O>CN(C)C=O>[CH3:27][O:26][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:34][CH:36]1[CH2:37][O:38]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (200 mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution. Potassium carbonate (230 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (152 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17]>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH:17][CH2:3][C:2]([CH3:1])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)[CH3:5]
Reactant: CC(C)(C)CN
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with 2,2-dimethyl-propyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3) 0.74 (s, 9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s, 1H), 7.9 (s, 1H); MS m/z 255.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[N:9][C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O-:24][CH2:25][CH3:26].[Na+]>C(O)C>[CH2:25]([O:24][C:2]1[C:11]2[CH:10]=[N:9][C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:26]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Yield: 90.7 %

Procedure:
A mixture containing 3.0 g of ethyl 5-chloro-2-(4-methyl-1-piperazinyl)pyrido[2,3-d]pyrimidine-6-carboxylate, 0.7 g of sodium ethoxide, and 50 ml of absolute ethanol was heated to reflux for 2 hours. The ethanol was removed by distillation in vacuo, the residue was extracted with chloroform and the extract washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off the residue was crystallized from n-hexane to give 2.8 g of the product as pale yellow needles, m.p. 105° - 108°C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[NH2:30])[CH3:7]>C(Cl)Cl.O>[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[CH:17]=[CH:16][C:15]=1[NH:30][C:3](=[O:4])[CH2:2][Br:1])[CH3:7]
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NC(=O)CBr
Reaction time: 0.5 h

Procedure:
A solution of 1.44 g (7.15 mmol, 1.1 eq.) bromoacetyl bromide in 10 mL of methylene chloride was added over 10 mins. to a stirred biphasic solution of 2.38 g (6.5 mmol, 1.0 eq.) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-β-alanine ethyl ester in 100 ml of methylene chloride and 30 mL of water cooled to 0° C. The reaction was complete in 1/2 hr. (TLC, 96 CH2Cl2 :4 MeOH, product Rf =0.71) and was partitioned between dilute aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated to give 3.11 g (98%) of off white crystals of N-(5-(4-cyanobenzyloxy)-2-(bromoacetyl)aminobenzoyl)-β-alanine ethyl ester which was used unpurified but may be recrystallized from ethyl acetate/hexane. 1H NMR (CDCl3, δTMS) 8.41(1H,d,ArH), 7.60 (4H,abq,ArH), 7.02(2H,d,ArH), 6.98(1H,t,NH), 5.12 (2H,s,ArCH2O),4.16 (2H,q,COOCH2),3.97 (2H,s,CH2Br), 3.68 (2H, q, NCH2), 2.61 (2H,t,CH2COO), 1.25 (3H,t, CH3). IR (KBr): 3389(NH), 3355(NH), 2226(CN), 1735(ester), 1675,1642(amides),1609,1523,1423,1244,1184,819. MS (FAB,M+H+) cald for C22H22N3O5Br 488.3, found (M+H+) 489.
Reaction SMILES: CN(C)C=O.[CH3:6][S-:7].[Na+].Cl[C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:31])[CH:16]=2)[N:11]=1.Cl>O>[CH3:6][S:7][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:31])[CH:16]=2)[N:11]=1
Reactant: C[S-]
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
20 ml of N,N-dimethylformamide and 221 mg of sodium thiomethoxide were added to 1 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline. The obtained mixture was stirred at 110° C. for one hour, neutralized with 1N hydrochloric acid and stirred at room temperature for one hour, followed by the addition of water. The crystals thus precipitated were recovered by filtration to give 780 mg of the title compound.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]2[C:7]3[C:12]([CH2:13][CH2:14][C:3]=12)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN1CCCC1=O.C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[O:6][N:5]=[C:4]3[C:7]4[C:12]([CH2:13][CH2:14][C:3]=23)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1onc2c1CCc1ccccc1-2
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: c1ccc(CN2CCN(c3onc4c3CCc3ccccc3-4)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 3-chloro-4,5-dihydronaphth[1,2-c]isoxazole (2.0 g, 9.75 mmol), 1-benzylpiperazine (17 ml, 97.5 mmol) and K2CO3 (2.7 g, 19.5 mmol) in 18 ml of N-methylpyrrolidinone under N2 was lowered into an oil bath preheated to 150° C. The mixture was heated while stirring under N2 for 2 hours. At that time, TLC (CH2Cl2) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature and extracted with heptane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain a crude solid. The solid was collected, titrated with Et2O, recrystallized from Et2O and dried in vacuo (0.1 mm) at 85° C. to provide pure product, mp of 164°-166° C., homogeneous by TLC [silica, 1:1 EtOAc, Rf=0.80]. The IR (CHCl3), NMR (CDCl3) and Mass Spectrum (M+ =345, EI, 70 eV) were consistent with the structure. The yield was 1.219 g (3.53 mmol, 36.24%).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.COC1C=CC(C[O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[O:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=2)=CC=1.C(Cl)Cl.O>CC(=O)OCC>[OH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COc1ccc(COC2CCCCC2Oc2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC2CCCCC2O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 32 %

Procedure:
2,3,-Dichloro-5,6-dicyano-1,4-benzoquinone (hereinafter “DDQ) (18.2 g, 80.2 mmol) was added to a solution of 4-[2-(4-methoxy-benzyloxy)cyclohexyloxy]-2-trifluoromethyl-benzonitrile (17.77 g, 43.83 mmol), methylene chloride (500 mL) and water (50 mL). The reaction was allowed to stir at room temperature for 3 days. A solid formed and was filtered off. The resulting filtrate was passed through a silica plug and condensed under reduced pressure. A column was run using a gradient of 17-80% EA in Hexanes. A second column was run using 4:1 Hex:EA. This yielded the desired product, 4-(2-hydroxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile (4.0 g, 32% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:25]>C(O)C.Cl>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:21][C:4]=2[CH:3]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Heat a solution of 2-(4-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (9.995 g, 30.73 mmol) in ethanol (170 ml) to 60° C. Add to this a solution of tin (II) chloride (29.1 g, 153.67 mmol) in 5.0 N hydrochloric acid (170 ml). Heat the resulting mixture to reflux for 18 hours. Cool the reaction to room temperature and place in a freezer for 24 hours. Precipitate the product from the solution and collect by filtration to btain 2.253 g of the title compound (6.79 mmol, 22% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 296(M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.ClC1C=C(C=CC=1)C(OO)=[O:16].O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:1][C:2]1[NH:3][C:4]2=[N+:5]([O-:16])[CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1
Reactant: Cc1cc2cccnc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2ccc[n+]([O-])c2[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2-methyl-7-azaindole (5 g, 37.8 mmol) in 1,2-dimethoxyethane (40 ml) is added m-chloroperoxybenzoic acid (10.4 g, of a 77% w/w solid, 46.6 mmol). The reaction mixture is stirred at 0° C. for 30 minutes, at room temperature for 3 hours and then poured into water (400 ml). The solution is basified to pH 9-10 using saturated potassium carbonate solution. The aqueous is extracted with DCM (2×100 ml) and the organic portions are combined, dried (MgSO4) and concentrated in vacuo. Purification of the resulting crude by chromatography on silica eluting firstly with neat ethyl acetate followed by DCM/MeOH (10:1) yields the titled compound as a yellow powder. (MH+ 297 appears as a dimer)
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:24]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH2:24][NH:6][CH3:5]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: O=Cc1c[nH]c2c(Cl)cccc12
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2c(Cl)cccc12
Yield: 92 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-chloro-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (440 mg, 92%) was obtained as an off white solid: MS (ES) m/e 195.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]=[C:6]([CH3:8])[CH2:5][C:4]([CH3:10])([CH3:9])[CH:3]1[C:11](=[CH2:16])[CH2:12][C:13](=[O:15])[CH3:14].C[O-].[Na+]>CO>[CH3:1][C:2]1([CH3:17])[CH:7]=[C:6]([CH3:8])[CH2:5][C:4]([CH3:9])([CH3:10])[CH:3]1[C:11]([CH3:16])=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: C=C(CC(C)=O)C1C(C)(C)C=C(C)CC1(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)C=C(C)C1C(C)(C)C=C(C)CC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A mixture of 4-(2,2,4,6,6,-pentamethyl-3-cyclohexen-1-yl)-4-penten-2-one (1.50g, 0.0063 mol) methanol (30 mL) and sodium methoxide (0.02g) was stirred at 25° C. for 18 hr. The mixture was then heated at reflux for 3 hr. The mixture was cooled to 25° C. and most of the methanol was evaporated under reduced pressure. The residue was partitioned between ether (75 mL) and water (15 mL). The aqueous layer was extracted with ether (50 mL). The ether extracts were washed with saturated sodium bicarbonate solution, brine and dried. Evaporation of solvents and kugelrohr distillation of the residue provided 1.28g (85% yield) of 4-(2,2,4,6,6 -pentamethyl-3-cyclohexen-1-yl)-3-penten-2-one (GLC purity: 93.5%). 1H-NMR (60 MHz) δ0.93 (12h, broad s), 1.57 (3H, broad s), 1.5-1.9 (2H, m), 1.88 (1 H, broad s), 3.42 (3H, s), 5.01 (1 H, broad s), 6.02 (1 H, broad s); IR (film) vmax 2950, 1685, 1600, 1440, 1380, 1365 cm-1 ; MS m/e 234, 216, 191, 149, 135, 121.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ccc(C)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5-dimethyl-benzaldehyde. MS (ESI) m/z 497.