Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:55][C:35]3=[N:36][C:37]([NH:49][CH2:50][C:51]([F:54])([F:53])[F:52])=[C:38]([C:40]4[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=4)[C:43](O)=[O:44])[CH:39]=[C:34]3[C:33]=2[C:56](=[O:59])[NH:57][CH3:58])=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.Cl.[O:70]1[CH:74]=[N:73][C:72]([C:75]([NH2:78])([CH3:77])[CH3:76])=[N:71]1>CN(C=O)C>[O:70]1[CH:74]=[N:73][C:72]([C:75]([NH:78][C:43]([C:42]2[CH:41]=[C:40]([C:38]3[CH:39]=[C:34]4[C:33]([C:56]([NH:57][CH3:58])=[O:59])=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=5)[O:55][C:35]4=[N:36][C:37]=3[NH:49][CH2:50][C:51]([F:53])([F:52])[F:54])[CH:48]=[CH:47][CH:46]=2)=[O:44])([CH3:77])[CH3:76])=[N:71]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(N)c1ncon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)NC(C)(C)c4ncon4)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (117 mg, 0.308 mmol) was added to stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (100 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.62 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (50 mg, 0.31 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 1 h. The reaction mixture was then purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 5-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide (61 mg, 0.10 mmol, 49% yield)) consistent by LCMS and NMR. LC-MS retention time: 1.73 min; m/z (MH+): 597. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.70 (s, 1H), 8.40-8.32 (m, 1H), 8.01-7.94 (m, 2H), 7.93 (s, 1H), 7.90-7.85 (m, 1H), 7.69 (s, 1H), 7.64-7.57 (m, 2H), 7.38-7.31 (m, 2H), 6.63 (t, J=6.4 Hz, 1H), 4.26-4.12 (m, 2H), 2.80 (d, J=4.8 Hz, 3H), 1.70 (s, 6H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCBr
Temperature: 120 °C
Reaction time: 6 h
Yield: 51.8 %

Procedure:
A suspension of 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane in 100 ml of dimethylformamide was heated under stirring at 120° C. for 6 hours to react them. Insoluble matters were then filtered off from the reaction mixture and the filtrate was then concentrated to dryness under reduced pressure. The residue was washed with hexane and then recrystallized from ethanol-water. Resulting crystals were collected by filtration, washed and then dried to obtain 13.8 g of N-(3-bromopropyl)phthalimide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCCl)c23)ccc1OCc1ccccn1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1ccccn1
Yield: 40 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 14) and pyrrolidine to give the title compound in 40% yield; NMR Spectrum: 1.66 (s, 4H), 2.25 (s, 3H), 2.54 (s, 4H), 2.86 (t, 2H), 4.40 (t, 2H), 5.19 (s, 2H), 6.97 (d, 1H), 7.34 (t, 1H), 7.44 (s+d, 2H), 7.54 (d, 1H), 7.84 (t, 1H), 8.23 (s, 1H), 8.49 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 446 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=O)[CH2:6][C:7]1[N:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[C:23]#[N:24])[CH3:2].[F:27][C:28]([F:37])([F:36])[C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.O>CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8]([CH:9]=[CH:10][C:11]([C:13]3[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12]2)=[C:23]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([C:28]([F:36])([F:37])[F:27])=[CH:30][CH:31]=2)[N:24]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C

Procedure:
Dissolve 3-(5-cyano-3′-trifluoromethyl-[2,2′]bipyridinyl-6-yl)-2-oxo-propionic acid ethyl ester (70 mg, 0.193 mmol) and 4-trifluoromethyl aniline (31 mg, 0.193 mmol) in AcOH (1 mL). Heat the mixture at 100° C. for 1.5 hours. Cool the mixture in ice and add H2O (5 mL). Extract three times with EtOAC (3×10 mL). Combine the organic extracts and wash with 1 N NaOH (30 mL) and brine (30 mL). Dry the organic extract over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with hexane/acetone (3:1) to yield the title compound. MS 507.15 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 467.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[C:14](Cl)[N:15]=2)[CH:12]=[CH:11][C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9]3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:26](OC)[CH2:27][NH2:28]>COCCOCCOC>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:26]=[CH:27][N:28]=[C:14]3[C:13]3[CH:12]=[CH:11][C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2nc(Cl)c3ccc(C(C)(C)C)cc3c2c1
Reactant: COC(CN)OC
Solvent: COCCOCCOC
Product: CC(C)(C)c1ccc2c(c1)c1cc(C(C)(C)C)ccc1n1ccnc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 55 %

Procedure:
2,9-Di-t-butyl-6-chlorophenanthridine (3.7 grams, 11.0 mmole) was added to a reaction flask containing aminoacetaldehyde dimethylacetal (2.4 grams, 23 mmole) dissolved into 200 mL of diglyme, heated to reflux and stirred under a nitrogen atmosphere. After 96 hours the reaction was complete as determined by TLC. The reaction mixture was cooled to room temperature and the excess solvent removed by distillation. The residue was taken up into methylene chloride. The solvent was dried over magnesium sulfate filtered and concentrated. The crude product was purified by silica gel chromatography using 10% ethyl acetate and 90% methylene chloride as the eluents. The purified product was collected, washed with hexanes, and dried to give 7,10-di-tert-butyl-imidazo[1,2-f]phenanthridine (2.0 grams, 56% yield) as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH:14]=[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])[S:10][C:11]=1[CH3:12]>CCO>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[CH2:14][C:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:3][N:2]=2)[S:10][C:11]=1[CH3:12]
Reactant: NO
Reactant: Cc1sc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reaction time: 12 h
Yield: 54.7 %

Procedure:
Hydroxylamine hydrochloride (13 g) and NaOH (18 g) are added to a solution of 1-(4-bromo-5-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (84 g, 71% purity) in EtOH (1000 ml) at room temperature. After 12 hours at room, the reaction mixture is concentrated in vacuo, diluted with diethylether and water. The aqueous phase is separated and further extracted two times with diethylether. The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on silica gel (1800 g) eluting with a mixture of heptane and dichloromethane (4:1) to yield 3-(4-bromo-5-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (47 g) as a light brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[Cl-].[NH4+]>CO.O.[Fe]>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Br:1])[NH2:8]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cc(N)ccc1Br
Yield: 92.3 %

Procedure:
2-Bromo-5-nitroanisole (31 g, 134 mmoles) in methanol (700 ml) was added to a mixture of iron powder (22.5 g, 400 mmoles), and ammonium chloride (33.5 g, 630 mmoles) in water (600 ml). The mixture was heated under reflux for 3 hrs. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo and the residue partitioned between water and dichloromethane. The organic phase was dried (Na2SO4), filtered and evaporated to dryness to give the title compound (D1) (25 g, 93%).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:29][CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=O)=[C:7]([CH:28]=1)[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O-]CC.[Na+].O>C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:29][CH2:30][C:31]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)=[CH:8][C:7]=2[CH:28]=1
Reactant: Cc1ccc(C(=O)COc2ccc(Br)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C2=Cc3cc(Br)ccc3OC2)cc1
Reaction time: 24 h
Yield: 85.6 %

Procedure:
Into a suspension of [5-bromo-2-[2-(4-methylphenyl)-2-oxoethoxy]benzyl](triphenyl)phosphonium bromide (5.53 g) in ethanol (20 ml) was added at room temperature a 20% solution of sodium ethoxide in ethanol (2.85 g), and the resulting mixture was stirred for 24 hours. After addition of water (15 ml) to the reaction mixture, a solid material was collected by filtration and was washed with water. The solid material were purified by recrystallization (ethanol) to obtain 6-bromo-3-(4-methylphenyl)-2H-1-benzopyran (2.16 g) as colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][CH:31]([NH:34][C:35](=O)[O:36]C7C=CC=CC=7)[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:29][CH2:30][CH:31]([NH:34][C:35]([N:52]7[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]7)=[O:36])[CH2:32][CH2:33]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCC(NC(=O)Oc6ccccc6)CC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)NC2CCN(Cc3ccc(-c4cc5nccc(Oc6ccc(NC(=O)NC7CC7)cc6F)c5s4)nc3)CC2)CC1
Temperature: 92.5 °C
Yield: 79 %

Procedure:
To a solution of the phenylcarbamate 356 (0.11 g, 0.169 mmol) in DMF at RT was added the N-methylpiperazine (0.057 mL, 0.51 mmol). The reaction mixture was heated at 90-95° C. for 2 hours, cooled to RT then treated with brine and saturated NaHCO3 solution. A precipitate was formed which was collected by filtration and dried. The crude material was purified by flash column chromatography, eluent 12 to 30% MeOH (containing 2% ammonia) in DCM, to afford the title compound 357 (0.088 g, 79% yield). 1H NMR (400 MHz, CD3OD-d6) δ (ppm): 8.65 (d, J=1.4 Hz, 1H); 8.47 (d, J=5.5 Hz, 1H); 8.15-8.11 (m, 2H); 7.98 (dd, J=8.2, 2.0 Hz, 1H); 7.67 (dd, J=13.1, 2.3 Hz, 1H); 7.30 (t, J=9.0 Hz, 1H); 7.20 (br. d, J=9.0 Hz, 1H); 6.64 (d, J=5.5 Hz 1H); 3.94 (s, 2H); 3.68-3.65 (m, 1H); 3.57 (br. s, 4H); 3.18 (br. d, J=10.4 Hz, 2H); 2.89 (br. s, 4H); 2.65 (s, 3H); 2.63-2.58 (m, 3H); 1.98 (br. d, J=11.7 Hz, 2H); 1.69 (br. d, J=11.0 Hz, 2H); 0.79-0.74 (m, 2H); 0.55-0.52 (m, 2H). [Signals of NH-protons are not seen]. MS (m/z): 659.5 (M+1)+
Reaction SMILES: [CH:1]12[CH2:8][NH:7][CH2:6][CH:5]1[CH2:4][N:3]([C:9]1[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:22])[C:11]=3[CH:10]=1)[CH2:2]2.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>>[CH3:27][N:7]1[CH2:8][CH:1]2[CH:5]([CH2:4][N:3]([C:9]3[CH:21]=[CH:20][C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:22])[C:11]=4[CH:10]=3)[CH2:2]2)[CH2:6]1
Reactant: O=C1c2ccccc2-c2ccc(N3CC4CNCC4C3)cc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: CN1CC2CN(c3ccc4c(c3)C(=O)c3ccccc3-4)CC2C1
Reaction time: 3 h
Yield: 100 %

Procedure:
The product of Example 13B (130 mg, 0.46 mmol) was treated with aqueous formaldehyde (5 mL, 37%; EM Science) and NaBH(OAc)3 (163 mg, 0.77 mmol; Aldrich). After stirring for 3 h, the reaction was quenched with saturated NaHCO3 (5 mL) and diluted with CH2Cl2 (5 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure and purified via column chromatography (silica gel, 1:9:90 NH4OH/CH3OH/CH2Cl2) to give the title compound (>100%, impure). MS (DCl/NH3) m/z 305 (M+H)+.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:41])=[C:34](/[CH:37]=[CH:38]\[CH3:39])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[OH:59])/[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([OH:42])=[O:41])=[C:34](/[CH:37]=[CH:38]/[CH3:39])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=CO
Product: C/C=C/C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
A mixture of the crude product of Example 33 containing 20% of its E isomer (9.2 g, 8.7 mmol) in 85% HCOOH (60 ml) was stirred for 1 hr at room temperature and evaporated in vacuo. The residue was treated with 90%-TFA (60 ml) for 1 hr at room temperature and poured into ice-water (300 ml). The insolubles were filtered off. The filtrate was chromatographed on a reverse phase column (Waters, prepPAK C18, 300 ml) and the column was eluted with 20% MeOH. The polar fractions were combined, concentrated in vacuo and the residue was triturated with isopropyl ether to give 1.15 g (33%) of the Z isomer and the less polar fractions gave 143 mg (4%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:18]([C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)#[C:19][CH3:20]>C(NCC)C.[Cu](I)I>[CH2:18]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:15]2[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)[CH2:19][CH3:20]
Reactant: CCC[C@H]1CC[C@H](C#Cc2ccccc2)CC1
Reactant: CC#Cc1ccc(I)cc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc([C@H]3CC[C@H](CCC)CC3)cc2)cc1

Procedure:
Trans-4-propylcyclohexylphenylacetylene (2.3 g, 0.01 mol) and 4-(1-propynyl)iodobenzene (2.4 g, 0.01 mol) were dissolved in diethylamine (20 ml), and then copper iodide (0.11 g, 0.15 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g, 0.3 mmol) were added. The resulting mixture was subjected to reaction and purification operation in the same manner as in Example 1 to obtain the objective 4-(trans-4-propylcyclohexyl)-4'-(1-propyl)tolan (compound No. 57) (1.8 g). (CS point: 118.9° C., SN point: 127.4° C., NI point: 245.1° C.)
Reaction SMILES: [CH:1]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[N:5]=1)(C)[CH3:2].[Br:18]Br.O>C(O)(=O)C>[Br:18][CH:1]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CC(C)c1nc2ccc(C#N)cc2c(=O)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)c1nc2ccc(C#N)cc2c(=O)n1C
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution 2-isopropyl-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (0.35 g, 1.64 mmol) in glacial acetic acid (10 ml) cooled in an ice bath was added dropwise a solution of bromine (0.52 g, 3.28 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. At which time it was allowed to cool to room temperature. Water was then added to the solution and the mixture was extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×10 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give 2-(1-Bromo-ethyl)-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (Yield 0.35 g, 73.1%). 1H NMR (400 MHz, CDCl3): δ 2.20 (d, 3H, J=6.54 Hz), 3.78 (s, 3H), 5.17 (q, 1H, J=12.88, 6.54 Hz), 7.81 (d, 1H, J=8.84 Hz), 7.94 (dd, 1H, J=8.34, 2.02 Hz), 8.61 (d, 1H, J=2.02 Hz). MS m/z calc. 291.0, found (ESI); 292.0 (M+1)+. Retention time 2.95 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=[NH:32])[NH:34][OH:35])[CH:26]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cccc2c1cc(C(=O)NCCc1ccc(O)cc1)n2Cc1cccc(C#N)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc2c1cc(C(=O)NCCc1ccc(O)cc1)n2Cc1cccc(C(=N)NO)c1
Yield: 63 %

Procedure:
The starting material 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 2-(4-hydroxyphenyl)ethyl amide (example 25/1) was dissolved in ethanol and hydroxylamine hydrochloride and triethylamine were added. After reflux for 5 h the reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane/methanol 19:1 to give 63% of the desired product, which solidified under water. M.p. 173-175° C. (dec.). MS: 459.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>C(O)CCC>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:26][C:25]4[CH:27]=[CH:28][C:29]([F:30])=[C:23]([Cl:22])[CH:24]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCCCO
Product: CCOC(=O)c1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Temperature: 145 °C
Reaction time: 2 h

Procedure:
3.6 g (12 mmol) 4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) are suspended in 80 ml n-butanol and treated with 3.5 g (24 mmol) 3-chloro-4-fluoro-aniline. The mixture is heated to 145° C. under stirring. After 30 min a clear brown solution is obtained which turns into a thick suspension after 2 h. After a total of 3 h the reaction mixture is cooled in an ice bath and the product collected by filtration; m.p.>300° C.; Rf(dichloromethane/ethanol 95:5 plus 1% conc. ammonia)=0.29; HPLC tR=11.66 min.
Reaction SMILES: [N:1]([N:3]([C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:10])[CH3:9])[NH:4][C:5](N)=[O:6])=[O:2].C(O)(=O)C>C(Cl)(Cl)Cl>[C:14]([NH:13][C:11]([C:8]([N:3]1[N:4]=[C:5]([O-:6])[O:2][NH2+:1]1)([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)C(C)(C)N(N=O)NC(N)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)C(C)(C)N1N=C([O-])O[NH2+]1
Temperature: 25 °C

Procedure:
A mixture of 12.0 g of the compound 4c), 30 ml of glacial acetic acid and 70 ml of chloroform is heated under reflux for 3 h. After cooling to room temperature, it is washed with sodium bicarbonate solution and with water, and the chloroform solution is dried using sodium sulphate and concentrated. The residue is recrystallized from tert-butyl methyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.3 %

Procedure:
To a solution of 3-Hydroxybenzaldehyde (3.05 g, 24.97 mmol) in acetonitrile (15 ml) was added K2CO3 (7.6 g), followed by N-(2-chloroethyl)morpholine hydrochloride (4.65 g). The reaction mixture was stirred at room temperature for 30 minutes, then at reflux overnight. Additional N-(2-chloroethyl)morpholine hydrochloride (0.93 g) and K2CO3 (0.7 g) were added and the mixture was refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and chloroform, the layers were separated and the aqueous layer was extracted with chloroform (2×75 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford 7.3 g of 3-[2-(4-morpholinyl)ethoxy]benzaldehyde, as an amber liquid.