Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:31]1([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCN)cc1)Cc1ncc[nH]1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC2CCCCC2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
The compound (173.5 mg) obtained in Example 102-4 was dissolved in anhydrous methanol (7.0 ml). Then, the solution was added with cyclohexanone (0.083 ml) and sodium cyanoborohydride (75.4 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. Subsequently, the residue was added with a 1 mol/l sodium hydroxide aqueous solution (7.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (161.6 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8](C)[NH:9][O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=O)=[C:4]([F:24])[CH:3]=1.CI.[C:27](=[O:30])([O-])[O-].[K+].[K+].[CH2:33]1COCC1>O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:33])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:13])[C:27]2=[O:30])=[C:4]([F:24])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1NOc2c1c(Cl)cc(F)c2-n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN1Cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2O1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-[4-chloro-6-fluoro-3-methyl-1,2(2H)-benzisoxazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (3.5 g, 0.010 mole), methyl iodide (2.1 g, 0.014 mole), potassium carbonate (2.0 g, 0.003 mole), and THF (100 mL) was heated to reflux where it stirred for five hours. The reaction mixture was then cooled to ambient temperature where it stirred for about 72 hours. After this time, the reaction mixture was poured into water and thoroughly extracted with ether. The combined extracts were washed with water and an aqueous saturated sodium chloride solution. The organic layer was separated, dried with magnesium sulfate, and concentrated to a residue. The residue was subjected to silica gel column chromatography using 9:1 to 5:1 hexane and ethyl acetate. The product-containing fractions provided 2.0 grams of Compound 27, m.p. 218-219° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=2)=[O:19])[CH2:3][CH2:2]1.[CH2:31]=O.[BH4-].[Na+].Cl>O.CO>[CH3:31][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[N:22]=2)=[O:19])[CH2:5][CH2:6]1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3=CCNCC3)cc12
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC=C(c2ccc3nccc(NC(=O)Nc4cccc(C(F)(F)F)n4)c3c2)CC1
Yield: 96.8 %

Procedure:
To 0.12 g of 1-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-quinolin-4-yl]-3-(6-trifluoromethyl-pyridin-2-yl)-urea (0.290 mmol) were added subsequently 2 ml of methanol, 0.366 ml of formaldehyde (4.64 mmol) and a solution of 0.055 g of sodium borohydride (1.451 mmol) in 0.8 ml of water. The reaction was slightly exotherm. A small amount of 2M HCl was added to the reaction mixture up to a pH of 3 to destroy the excess of sodium bororhydride. After neutralization with sodium bicarbonate, methanol was evaporated under reduced pressure, water added to the residue, the reaction mixture extracted three times with ethylacetate, the organic phases combined and dried over sodium sulfate and the solvent evaporated under reduced pressure. 120 mg of the desired product were obtained as an off white powder (yield: 97%).
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([C:10]1[CH:37]=[CH:36][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]3[CH2:23][CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[O:26][C:21]=3[C:20]=2[CH2:33][CH2:34][CH3:35])=[C:12]([CH2:38][CH2:39][CH3:40])[C:11]=1[O:41][CH3:42])=O)(=O)=O.[CH:45]([NH2:47])=O.CN(C)C=O>C(OCC)(=O)C.O>[CH3:42][O:41][C:11]1[C:12]([CH2:38][CH2:39][CH3:40])=[C:13]([CH:36]=[CH:37][C:10]=1[C:8]1[N:47]=[CH:45][O:6][CH:7]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]2[CH2:23][CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[O:26][C:21]=2[C:20]=1[CH2:33][CH2:34][CH3:35]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)COS(=O)(=O)C(F)(F)F)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCOc2ccc(-c3cocn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2

Procedure:
The compound of Example 3 (0.10 g, 0.155 mmol) was stirred with 0.5 ml of formamide and 0.2 ml of dimethyl formamide (DMF) for 1.5 hours at 170° C. The reaction mixture was cooled and poured into ethyl acetate/water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was flash chromatographed on silica gel using 10:1 to 4:1 hexane/ethyl acetate eluant to give the product, 0.057 g (0.109 mmol), 35%.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.ClC(N(C)C)=C(C)C.[NH2:41][C:42]1[S:43][C:44]2[CH2:71][CH2:70][CH2:69][CH2:68][C:45]=2[C:46]=1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][C:58]2[CH:67]=[CH:66][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=2)=[CH:52][CH:51]=1)=[O:48]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:41][C:42]1[S:43][C:44]2[CH2:71][CH2:70][CH2:69][CH2:68][C:45]=2[C:46]=1[C:47]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH2:57][C:58]2[CH:59]=[CH:60][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:66][CH:67]=2)=[CH:54][CH:55]=1)=[O:48])=[O:25])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CC(C)(C)[Si](OCCc1cccc(C(=O)O)c1)(c1ccccc1)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 480 mg of 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoic acid and 10 ml of methylene chloride was added 160 mg of 1-chloro-N,N,2-trimethylpropenylamine under ice cooling, followed by stirring for 1 hour at room temperature. 10 ml of a methylene chloride solution containing 450 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 0.20 mL of pyridine was added to the reaction mixture under ice cooling, followed by stirring for 1 hour under ice cooling and then for 4 days at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), thereby obtaining 830 mg of methyl 4-[2-(4-{[(2-{[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: [C:1]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:6]=[CH:5][C:4]([N:7]([C:43]2[CH:55]=[CH:54][C:53]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]([CH3:57])([CH3:56])[C:45]=3[CH:44]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:24](=[CH:25][CH:26]=3)[N:23](C(OC(C)(C)C)=O)[C:22]3[CH:21]=[C:20]5[C:34]([CH3:42])([CH3:41])[C:35]6[C:40]([C:19]5=[CH:18][C:17]4=3)=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[C:1]1([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:2]=[CH:3][C:4]([N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]3[CH:21]=[C:20]5[C:34]([CH3:41])([CH3:42])[C:35]6[C:40]([C:19]5=[CH:18][C:17]4=3)=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:12][CH:13]=2)[C:43]2[CH:55]=[CH:54][C:53]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]([CH3:56])([CH3:57])[C:45]=3[CH:44]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(-c3ccc(N(c4ccc(-c5ccccc5)cc4)c4ccc5c(c4)C(C)(C)c4ccccc4-5)cc3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5[nH]c6cc7c(cc6c5c4)-c4ccccc4C7(C)C)cc3)cc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
20.0 g (24.4 mmol) of tert-butyl 7-{4-[biphenyl-4-yl-(9,9-dimethyl-9H-fluoren-2-yl)amino]phenyl}-12,12-dimethyl-12H-10-azaindeno[2,1-b]fluorene-10-carboxylate are dissolved in 250 ml of dichloromethane and 2.65 ml (24.4 mmol) of anisole, and 5.4 ml of trifluoroacetic acid are subsequently added. The mixture is stirred at 40° C. for 3 h and, when the reaction is complete, neutralised by means of ice-water and 20% NaOH solution. The mixture is extracted with dichloromethane, dried and purified by recrystallisation from toluene/heptane, giving 15.7 g (89%) of the product as a white solid.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[N:13][N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1.[Br:31]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:31][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:8]=1[Br:7])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[N:13]=[C:12]2[NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: BrBr
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Reaction time: 18 h

Procedure:
3.3 cm3 of pyridine are added to 4 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 51, in 80 cm3 of chloroform, followed by dropwise addition of 2 cm3 of bromine, and the mixture is then left stirring for 18 hours. The reaction medium is diluted with 100 cm3 of methylene chloride and the organic phase is washed with 2×100 cm3 of 10% sodium thiosulphate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.), then dried (90 Pa; 45° C.) to give 4.24 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow solid melting at 134° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[C:31]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:31][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[N:13]=2)[CH:10]=[N:9]1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1ncc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A suspension of 3-(3-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (325 mg, 0.85 mmol), iodomethane (0.081 mL, 1.3 mmol), and K2CO3 (235 mg, 1.7 mmol) in DMF (3 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give 3-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 30% yield) as a white solid: mp 193-195° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.74 (3H, s), 6.61 (1H, d, J=7.9 Hz), 6.91 (1H, dd, J=2.3, 8.3 Hz), 7.25 (1H, s), 7.33-7.40 (3H, m), 7.45-7.52 (4H, m), 8.12 (1H, d, J=7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m/z 397 [M+H]+. Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.56; H, 3.88; N, 14.09.
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][N:9]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[C:16]3[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]3=[O:25])=[CH:10]2)[CH2:5][O:4]1.O>C(#N)C>[OH:7][CH:6]([CH2:5][OH:4])[CH2:8][N:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:16]2[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]2=[O:25])=[CH:10]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(C)(C)O3)cc2n(C)c1=O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (2 M in diethyl ether) (92 ml, 185 mmol) was added dropwise to a solution of 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (7.15 g, 18.46 mmol) and water (6.65 g, 369 mmol) in acetonitrile (35.1 mL). The mixture was stirred at room temperature for 30 minutes. Evaporation of the reaction mixture under vacuum afforded the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[N+:11]([C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)[C:3]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2scc(Br)c2c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc2scc(-c3ccncc3)c2c1
Yield: 56.1 %

Procedure:
A stirred mixture of 3-bromo-5-nitrobenzo[b]thiophene (J.Amer. Chem. Soc, 1948, 1955) (4.2 g, 0.016 mole,) pyridin-4-ylboronic acid (2.0 g, 0.016 mole) and sodium carbonate (4.3 g, 0.048 mole) in DME (150 ml) and water (150 ml) was de-gassed by bubbling argon through for 15 minutes, then tetrakis(triphenylphosphine)palladium (0) (400 mg) was added and the mixture heated at reflux under argon for 18 hours. The reaction mixture was cooled and concentrated in vacuo to approx 150 ml volume, then acidified with 2M HCl acid (200 ml) and shaken well with ethyl acetate (400 ml). The solid present was filtered off, shaken with 10% Na2CO3 solution and dichloromethane, and the organic layer separated, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an orange/yellow solid (2.3 g, 56%).
Reaction SMILES: [Cl-].C1([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2C=CC=CC=2)N2C=C(CCC)N=C2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:36]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][OH:44])[N:38]=[CH:37]2)C=CC=CC=1.S(Cl)(Cl)=O.C1(CC[O-])C=CC=CC=1.[Na+]>>[C:23]1([CH2:8][CH2:17][O:44][CH2:43][CH2:42][CH2:41][C:39]2[N:38]=[CH:37][NH:36][CH:40]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]CCc1ccccc1
Solvent: O=S(Cl)Cl
Product: c1ccc(CCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propane chloride, prepared from 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol with thionyl chloride, and 15 mmol of sodium 2-phenylethanolate are treated as described in Example 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2.O>C(O)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:21])([CH3:22])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:17])[F:18])[CH:14]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture that consists of 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (320 mg, 1 mmol) and 5-amino-2-methylquinoline (190 mg, 1.2 mmol) in acetic acid (2 ml) is stirred for 16 hours at room temperature, diluted with 10 ml of toluene and heated for 4 hours in a water separator. The batch is concentrated by evaporation, whereby the acetic acid is removed azeotropically with toluene. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 274 mg of the product accumulates as colorless crystals.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:7][CH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:20][S:21]([O:5][CH2:4][C:3]([CH2:2][Br:1])([CH2:7][CH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[CH3:6])(=[O:23])=[O:22]
Reactant: CC(CO)(CBr)CC1C=CC=C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CBr)(COS(C)(=O)=O)CC1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
In a 200 ml Schlenk tube fitted with a septum, 6.97 g of crude product 3 and 4.35 ml (45 mmol) of triethylamine were dissolved in 100 ml of methylene chloride. At 0° C., 2.37 ml (31 mmol) of methanesulfonyl chloride were injected over a period of 2 minutes. After half the methanesulfonyl chloride had been added, a colorless precipitate formed. The suspension was held at this temperature for another half hour and was then stirred for 2 hours at room temperature. The reaction solution was subsequently hydrolyzed with 20 ml of water. The phases were separated and the aqueous phase was extracted three times with 20 ml of methylene chloride. The combined organic phases were washed with sodium chloride solution until neutral and dried over sodium sulfate. Removal of the solvent in an oil pump vacuum gave a slightly brownish oil which was dissolved in methylene chloride and absorbed on kieselguhr. This was followed by flash chromatography on a silical gel column (4*25 cm; PE/THF in a ratio of 8:2; RF =0.42). Evaporation of the product fractions in an oil pump vacuum gave 5.9 g (66%) of 4 as a colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](/[CH:10]=N/O)=[O:9])=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:14]>>[NH:7]1[C:4]2[C:3](=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:10](=[O:14])[C:8]1=[O:9]
Reactant: O=S(=O)(O)O
Reactant: O=C(/C=N/O)Nc1ccccc1
Product: O=C1Nc2ccccc2C1=O

Procedure:
treating the isonitrosoacetanilide compound of step (1) with sulfuric acid, followed by ice and purification with ethanol to obtain an isatin compound of the formula ##STR42##
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]#[N:13])[C:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:10]([NH:11][C:34]([CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[C:9]([C:12]#[N:13])[C:8]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)Cc1ccccc1
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile (2.3 g, 8.6 mmol), CHCl3 (50 ml) and pyridine (20 ml) in an ice bath was added a solution of phenylacetyl chloride (2.3 ml, 17.2 mmol) in CHCl3 (10 ml) over a period of 20 minutes. The reaction mixture was stirred in an ice bath for 3 hours, then at room temperature for 2 hours. The solvent was removed in vacuo, the residue was partitioned between CHCl3 (100 ml) and water (50 ml) , and the organic layer was separated. Concentration of the organic layer afforded a gummy solid which was recrystallized from isopropanol to afford 1.1 g (88%) of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole, as white needles, m.p. 166-168° C.