Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][CH2:23][CH2:24]Br>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[N:12]([CH2:22][CH2:23][CH3:24])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: O=c1c2ccc(Cl)cc2nc2[nH]c3cc(Cl)c(Cl)cc3n12
Product: CCCn1c2cc(Cl)c(Cl)cc2n2c(=O)c3ccc(Cl)cc3nc12

Procedure:
3,8,9-Trichloro-6-(n-propyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3,8,9-trichlorobenzimidazo[2,1-b]-quinazolin-12(6H)one and n-propyl bromide.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C=O.P(=O)(O)(O)O.[ClH:19].[C:20](O)(=O)C>O>[Cl:19][CH2:20][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Fc1cccc2ccccc12
Reactant: Cl
Agent: C=O
Agent: O=P(O)(O)O
Solvent: O
Product: Fc1ccc(CCl)c2ccccc12

Procedure:
A solution of 1-fluoronaphthalene (5.5 g, 37.6 mmol), paraformaldehyde (2.5 g, 83 mmol), glacial acetic acid (3.5 mL), phosphoric acid (2 mL) and concentrated hydrochloric acid (5 mL) is heated at 85° C. for 15 h. The reaction mixture is poured into water and extracted three times with dichloromethane. The organic extracts are combined and washed with water and brine, dried (sodium sulfate), filtered, and evaporated to yield the title compound, 6.53 g (98%, as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:29])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([NH:29][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:39])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC(C)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.2 %

Procedure:
To a solution of 1.4 g (3.44 mmol) of 3-nitro-5-(octadecyloxy)benzenamine and 0.75 ml (5.4 mmol) of triethylamine in 85 ml of THF stirred in an ice bath was added 0.25 ml (3.44 mmol) of acetyl chloride. The ice bath was removed after 15 minutes and the reaction mixture was stirred at room temperature for 17 hours. Triethylamine (0.3 ml) and acetyl chloride (0.15 ml) were added and stirring was continued for 5 hours. The solvent was removed at reduced pressure and the residue was crystallized from ethyl acetate-hexane to give 1.3 g (84% yield, mp 103°-107°) of 3-(acetylamino)-5-(octadecyloxy)nitrobenzene. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34]CC)=[O:33])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[NH2:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(O)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Yield: 86 %

Procedure:
A homogeneous solution of 0.175 of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 3 mL of 1N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Addition of 2 mL of acetic acid followed by centrifugation gave 0.125 g (86%) of the title compound, which can be alternatively named as 5,10-dideazafolic acid, as a microcrystalline colorless solid, mp >200° C.; NMR (TFA-d1) delta 2.3-2.7 (m, 2H), 2.7-3.0 (m, 2H), 3.25 (s, 5H), 4.9-5.25 (m, 1H), 7.35, 7.85 (AB q, 4H, J=9 Hz), 8.50 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:1]([P:5]([CH2:20][CH:21]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])(=[O:6])[OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCC[PH](=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2) (6.4 g, 20 mmol) in 20 mL of dichloroemthane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=-butyl, R1=H) (2.9 g, 40%) as a clear and colorless oil. Rf 0.12 (3:1, Hex./EtOAc 5% AcOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[CH2:17](OCC)C>C(O)=O.C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOCC
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Agent: C=O
Solvent: O
Solvent: O=CO
Product: COC1(c2cc(F)cc(F)c2)CCN(C)C1
Temperature: 85 °C

Procedure:
A mixture of (+)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.02 g, 0.094 mmol) in formic acid (1 ml) and formaldehyde (37% solution in water, 1 ml) was heated at 85° C. for 5 h. The mixture was allowed to reach ambient temperature, water (5 ml) and diethyl ether was added, the phases were separated and the aqueous phase was basified by the addition of aqueous sodium hydroxide (5M). The aqueous phase was extracted twice with ethyl acetate, the combined organic phases was dried (Na2SO4) and evaporated to give the crude product which was diluted in methanol and analyzed by GCMS. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (29), 197 (25), 141 (42), 57 (bp).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.[H][H]>CO.[Pd]>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[NH2:17][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Yield: 45.8 %

Procedure:
To a solution of the product from step (a) (4.18 g) in methanol (250 ml) under argon was added p-toluenesulphonic acid monohydrate (2.99 g) followed by 10% Pd on C (1.8 g). The argon was replaced by hydrogen and the reaction mixture was stirred under a blanket of hydrogen for 6 hours. The catalyst was filtered off through a pad of diatomaceous earth and washed with methanol. The blue-coloured filtrate and washings were evaporated to near dryness and excess ether was added. On storage overnight at -10° C. a solid crystallised which was collected, washed with ether and dried to give t-butyl 4-amino-3-methylphenoxyacetate, p-toluenesulphonate salt (2.93 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.42 (9H, s), 2.28 (3H, s), 2.30 (3H, s), 4.63 (2H, s), 6.82 (1H, dd), 6.88 (1H, d), 7.12 (2H, d), 7.24 (1H, d), 7.48 (2H, d), 9.50 (3H, br s); Mass Spectrum m/Z 260 (M+Na)+.
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4].[Na+].[I-:14]>CC(C)=O>[I:14][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4]
Reactant: [I-]
Reactant: O[C@H](CCl)c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@H](CI)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
(S)-2-Chloro-(2′,4′-dichlorophenyl)-1-ethanol (4 g, 17.74 mmol) was dissolved in 100 mL of anhydrous acetone (4 Å molecular sieves). The solution was flushed with nitrogen, and NaI (12.75 g, 85.10 mmol) was added to the solution and the solution refluxed for 3.5 hours under nitrogen. Upon cooling to room temperature, the solution was poured into about 320 mL of hexanes/ethyl acetate (3:1), with stirring. The solution was then filtered to remove excess NaI which had precipitated. The filtrate was evaporated to dryness in vacuo to yield a yellow oil. The oil was decanted, the residue treated with ether, and the ether washings decanted from the solid NaI. The ether solutions were combined and evaporated to dryness. Upon removal of ether, the product was obtained as a yellow crystalline solid. Yield: 4.70 g (84%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[C:21]([F:22])=[C:20]([OH:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[C:8]([F:24])[CH:7]=2)[CH2:3][CH2:2]1.O[CH2:26][C@@H:27]([NH:29][C:30](=[O:36])OC(C)(C)C)[CH3:28].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[C:21]([F:22])=[C:20]([O:23][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[CH3:37])[CH3:28])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[C:8]([F:24])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)cc3F)oc2c1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4CC4)cc3F)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-2,5-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-ol (1.34 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.05 g) and triphenylphosphine (1.57 g) in THF (50 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3.16 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To the obtained solid was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (704 mg).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[F:10][C:11]1[CH:12]=[N:13][C:14](=[O:17])[NH:15][CH:16]=1>CN(C)C=O>[CH2:1]([N:15]1[CH:16]=[C:11]([F:10])[CH:12]=[N:13][C:14]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: O=c1ncc(F)c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: O=c1ncc(F)cn1Cc1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
Benzyl chloride (0.01 mol) was added to a stirred mixture of the potassium salt of 5-fluoropyrimid-2-one (0.007 mol) in dimethylformamide (40 ml) and the mixture stirred at room temperature until chromatography showed the reaction to be complete. The solvent was then evaporated at reduced presure (1 mm Hg) and the residue was extracted with chloroform (100 ml). The chloroform solution was washed with aqueous 2 N NaCH (2×3 ml) and with water (3 ml) before drying (MgSO4) and evaporation; yield 50%, m.p. 163° C. (ethyl actate). (Found: C, 64.69; H, 4.49. Calc. for C11H9FN2O: C, 64.70; H, 4.44).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)C)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Product: COC(=O)C(c1ccc(OCCOc2ccc(F)cc2)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
As described in Example 35, 4.66 g of p-phenoxyphenol is reacted with methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.02 mole) in refluxing methanol-benzene for 24 hrs to give the product as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][C:44]1=[O:49].CCN(CC)CC.O>CN1C(=O)CCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20]2[S:21][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:34])=[O:33])[CH:9]=[C:8]4[C:6]3[N:7]=[C:2]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[C:44](=[O:49])[CH2:45]4)[CH:3]=[N:4][CH:5]=3)=[N:18][N:19]=2)=[CH:29][CH:28]=1
Reactant: CN1CCNCC1=O
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 155 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (100 mg, 0.166 mmol) in NMP (1 mL) was added 1-methylpiperazin-2-one (28.4 mg, 0.249 mmol) and Et3N (69.2 μL, 0.497 mmol). The reaction was stirred at 155° C. for 18 h, then cooled to RT. H2O was added and the resulting suspension was filtered to give the crude material. MS (ESI, pos. ion) m/z: 681 (M+1).
Reaction SMILES: O.NN.[CH3:4][C:5]1[N:6]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=O)[N:9]=1.[OH-].[K+].O>C(O)CO>[CH3:4][C:5]1[N:6]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:7]=[C:8]([CH2:10][C:12]2([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:14]2)[N:9]=1
Reactant: Cc1nc(C(=O)C2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1nc(CC2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Hydrazine hydrate (30 mL) was added to a solution of (2-methyl-1-trityl-1H-imidazol-4-yl)[1-(trifluoromethyl)cyclopropyl]methanone (15.78 g, 34.2 mmol) and powdered potassium hydroxide (9.6 g, 171 mmol) in ethylene glycol (200 mL). After stirring at 120° C. for 20 min, the reaction mixture was heated at 180° C. for 2 h. After cooling to ambient temperature, water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [C:1](OC)([CH3:4])([CH3:3])[CH3:2].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[F:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(F)c1
Reactant: COC(C)(C)C
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Zirconiumtetrachloride (11.7 g, 50 mmol) in DCM (130 ml), tert-butylmethylether (4.44 g, 50 mmol), and 3-fluorophenol (5.6 g, 50 mmol) were mixed at room temperature and the reaction mixture was stirred for 2 hours at 50° C. The reaction was quenched with water and the whole was extracted with ethylacetate and dried over magnesium sulfate. After filtration, evaporation gave a crude residue, which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/ethylacetate (9:1), to afford 4.25 g (51% yield) of the title compound as white solids.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].O.[NH2:21]N>CCO>[CH3:7][C:6]([C:5]1[NH:21][N:2]=[CH:3][CH:4]=1)([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:17]
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccn[nH]1
Temperature: 50 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.36 g, 1.4 mmol.) and hydrazine hydrate (1.0 g, 6.25 mmol.) in EtOH was heated at 50° C. for 3 h. The mixture was concentrated, and the residue was diluted with H2O and EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the titled compound as a yellow solid. MS: 232 (M+1) Calc'd for C12H14N3O2—232.10.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C(CCCC1CCCCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCC1CCCCCCC1)C(=O)OCC

Procedure:
5.5 g of 5-cyclooctyl-2-methylenevaleric acid ethyl ester, in the form of an oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 10.1 g of (3-cyclooctylpropyl)-malonic acid ethyl ester, 1.28 g of paraformaldehyde, 10 ml of pyridine and 0.5 ml of piperidine.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH2:19][CH3:20])=[CH:18][C:5]=2[NH:4][C:3]1=[O:21].[CH3:22][C:23]1([NH:29][C:30](=[O:33])[CH2:31]I)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:22][C:23]1([NH:29][C:30](=[O:33])[CH2:31][N:4]2[C:5]3[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:6]=3[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][CH:2]([Br:1])[C:3]2=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCc1ccc2c(c1)NC(=O)C(Br)CC2c1ccccc1
Reactant: CC1(NC(=O)CI)CCCCC1
Product: CCc1ccc2c(c1)N(CC(=O)NC1(C)CCCCC1)C(=O)C(Br)CC2c1ccccc1
Yield: 80 %

Procedure:
Prepared as in Example 20I from 3-bromo-5-phenyl-8-ethyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one using N-(1-methylcyclohexyl)-iodoacetamide, M.P. 156°-158° C., 80% yield for the trans isomer.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C1O[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15]C1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[OH:22][C:19]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:20][CH2:21][C:16](=[O:15])[CH2:17][CH2:18]1
Reactant: Brc1ccncc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccncc2)CC1
Yield: 82.6 %

Procedure:
35 ml of ether was cooled to -78° C. and 20 ml of a 1.6 M solution of n-butyllithium in hexane was added thereto. To the obtained mixture, 5 g of 4-bromopyridine dissolved in 30 ml of ether was added. Then 5 g of 1,4-cyclohexanedione monoethylene acetal dissolved in 30 ml of tetrahydrofuran was further added thereto. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and purified by extracting with chloroform to give 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O=[C:24]([CH2:28][CH3:29])[C:25]([OH:27])=[O:26]>C(O)C>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[N:6]=[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([C:12]([F:22])([F:21])[F:11])[CH:14]=1)[C:28]([CH3:29])=[C:24]2[C:25]([OH:27])=[O:26]
Reactant: CCC(=O)C(=O)O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COc1cc(N)ccc1Br
Solvent: CCO
Product: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of the 4-bromo-3-(methyloxy)aniline (25 g, 124 mmol) and 3-(trifluoromethyl)benzaldehyde (21.54 g, 124 mmol) in ethanol (300 mL) was stirred at reflux for 1 h. 2-Oxobutanoic acid (12.63 g, 124 mmol) was added portionwise. The reaction mixture was stirred at reflux for additional 3 h, warmed to room temperature, and stirred overnight. The solid precipitate was collected by filtration, washed with ethanol, and air dried to give 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (42.6 g, 78% yield). MS (m/z) 441.0 (M+H+).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>CN(C1C=CN=CC=1)C.C(#N)C.N1C=CC=CC=1>[SH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([OH:14])(=[O:15])[CH2:10][CH2:11][C:12]([OH:5])=[O:13]
Reactant: O=C1CCC(=O)O1
Agent: CCOC(=O)CCS
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in FIG. 2, Ethyl 3-mercaptopropionate (2.95 g, 22 mmol) was added under argon to a stirring solution of succinic anhydride (2.0 g, 20 mmol) and DMAP (122 mg, 1 mmol) in 25 ml of acetonitrile-pyridine (9:1). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in 50 ml of EtOAc. The EtOAc solution was washed with 0.1 N HCl aqueous solution 30 ml×3, H2O×3, dried over anhydrous MgSO4. After filtration, the solution was concentrated to dry under reduced pressure and in vacuo. 1H NMR (CDCl3, 500 MHz) δ 10.23 (s, br), 4.14 (2H, q, J=7.0 Hz, —CH2—CH3), 3.13 (2H, t, J=7.0 Hz, —S—CH2—), 2.88 (2H, t, J=7.0 Hz, —S—CO—CH2—), 2.69 (2H, t, J=7.0 Hz, —S—CH2—CH2—), 2.62 (2H, t, J=7.0 Hz, —CH2—COOH), 1.25 (3H, t, J=7.0 Hz, —CH2—CH3).