Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][C:37]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:38]=1[NH2:39]>O1CCCC1.ClCCl>[CH3:36][C:37]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:38]=1[NH:39][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (1.56 g, 4.35 mmol) and Hunig's base (1.3 mL, 7.5 mmol) in tetrahydrofuran (50 mL) and dichloromethane (10 mL) was added 2-methyl-5-nitroaniline (726 mg, 4.78 mmol), and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give N-(2-methyl-5-nitrophenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (522 mg, 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 10.03 (s, 1H), 8.49 (d, 1H), 8.27 (d, 2H), 8.10 (d, 3H), 7.80 (m, 5H), 7.73 (m, 3H), 7.66 (d, 1H), 7.50 (dt, 1H), 2.50 (s, 3H). MS (EI) for C28H21N5O3: 476.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9](=[O:11])[CH3:10])=[N:7][CH:8]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:12][CH2:10][C:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)=[O:11]
Reactant: COc1cnc(C(C)=O)cn1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cnc(C(=O)CBr)cn1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
To a chloroform (7.0 mL) solution of 1-(5-methoxypyrazin-2-yl)ethanone (0.35 g), tetrabutylammonium tribromide (1.2 g) was added, and the resultant was heated to reflux for 1 hour. After standing to cool to room temperature, the reaction solution was diluted with chloroform, and a 10% aqueous sodium thiosulfate solution was added to the dilution, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→80/20) to obtain the title compound (26 mg) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:20])(=[O:3])[CH3:2].[CH3:21][CH2:22][O:23][C:24](OCC)(OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=2)[C:6](=[C:24]([O:23][CH2:22][CH3:21])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]1=[O:20])(=[O:3])[CH3:2]
Reactant: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCOC(OCC)(OCC)c1ccccc1
Product: CCCCCC(=O)c1ccc2c(c1)C(=C(OCC)c1ccccc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1-acetyl-5-hexanoyl-2-indolinone and triethyl orthobenzoate
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[C:17]1([C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccccc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
(2R,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (621 mg, 2.05 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 7 mL, 99.92 mmol) and the mixture stirred at room temperature for 24 h. The solvent was evaporated and the residue was purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-phenylpiperidin-4-yl)isoxazol-3(2H)-one (306 mg, 61%) (the isolated sample contained DMSO). 1H NMR (400 MHz, cd3od) δ 1.76-2.02 (m, 2H), 2.11-2.30 (m, 2H), 3.05-3.21 (m, 2H), 3.41-3.49 (m, 1H), 4.14 (dd, 1H), 5.56 (s, 1H), 7.27-7.48 (m, 5H). HRMS Calculated for [C14H16N2O2+H]+: 245.1290. Found: 245.1270
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6](=[O:35])[N:7]([CH3:34])[C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:18])[CH3:17])=[CH:12][C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[N:9]=2)=[O:4].CC([O-])=O.[Na+]>CN(C=O)C.O.CCOC(C)=O>[C:16]([N:15]1[C:14]2[C:13]3[CH:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[C:10]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4[Cl:33])=[N:9][C:8]=3[N:7]([CH3:34])[C:6](=[O:35])[C:5]=2[C:3]([OH:4])=[CH:2]1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1c(C(=O)CBr)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1cc(O)c2c(=O)n(C)c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc3c21
Reaction time: 8 h

Procedure:
To the product of Step A (25 mg) was added NaOAc (60 mg) in DMF (2.5 mL) and water (0.3 mL) at room temperature. The reaction stirred overnight and was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine. The concentrated residue was purified by flash chromatography on silica gel with a gradient elution of 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 512.0 (M+1), 514.0 (M+3); Rt=4.18 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]2[C:14]3[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:15]=3[S:16][C:7]=12.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:21][C:19]1[CH:18]=[CH:17][C:15]2[S:16][C:7]3[C:8](=[N:9][CH:10]=[C:11]([C:12]#[N:13])[C:6]=3[NH:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=3)[C:14]=2[CH:20]=1
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2c(sc3ccc(N)cc32)c1Nc1cccc(Br)c1
Yield: 21.4 %

Procedure:
A mixture of 436 mg (1.03 mmol) of 4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile, 291 mg (5.19 mmol) of iron powder and 416 mg (7.77 mmol) of ammonium chloride in 160 mL of methanol and 110 mL of water is heated at reflux for 5.5 hours. The reaction mixture is filtered hot and the solid residue is extracted with several portions of hot ethyl acetate followed by hot methanol. All the organic layers are combined and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether and hexane are added and the solid is collected by filtration to provide 87 mg of 8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile. The filtrate is concentrated and purified by flash chromatography, eluting with a gradient of 1:1 hexane/ethyl acetate to 100% ethyl acetate to give an additional 56 mg of 8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a bright yellow solid, mp 295–300° C. dec.
Reaction SMILES: CN(C)C(N1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([NH2:26])[C:20]=4[CH3:27])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.ClC1C2C=C(C3CC[O:43]CC=3)NC=2N=CN=1>>[O:43]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1
Reactant: Clc1ncnc2[nH]c(C3=CCOCC3)cc12
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Product: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Intermediate 12 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 11.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[OH:1][CH2:2][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(C#C[Si](C)(C)C)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl [(1S)-2-hydroxy-1-(3-iodobenzyl)ethyl]carbamate (1.0 g, 2.6 mmol), copper(I) iodide (0.020 g, 0.11 mmol), bis(triphenylphosphine)palladium(II) chloride (0.074 g, 0.11 mmol), tetrahydrofuran (7 mL), and triethylamine (0.41 mL, 2.9 mmol) were combined. The reaction mixture was stirred under N2 for 5 min. (Trimethylsilyl)acetylene (1.1 mL, 8.0 mmol) was then added. The reaction mixture was stirred at 65° C. for 1 h, then evaporated under vacuum. The residue was purified by combi-flash chromatography to give 0.84 g (91% yield) of the desired product as light brown solid. LC-MS found: 248.0 (M−Boc+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:23]1[C:27]2=[N:28][C:29]([CH2:32][NH2:33])=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:33][CH2:32][C:29]2[N:28]=[C:27]3[NH:23][CH2:24][CH2:25][C:26]3=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc2c(n1)NCC2
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccc3c(n2)NCC3)cc1

Procedure:
The titled compound was prepared from N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 402 (M+H). Calc'd. for C24H27N5O—401.51.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:43](OC)(OC)(OC)[CH2:44][CH2:45][CH3:46].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:33][C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:16]=4[N:42]=[C:43]3[CH2:44][CH2:45][CH3:46])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC(OC)(OC)OC
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 39.9 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), trimethyl orthobutyrate (2.4 g, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined and treated according to the method described in Part E of Example 18 with the modification that no additional trimethyl orthobutyrate was added. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (2.62 g) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[F:5][CH:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9]CC)=O>>[F:5][CH:6]([C:12](=[O:13])[CH3:14])[C:7]([NH:4][CH2:1][CH2:2][CH3:3])=[O:9]
Reactant: CCCN
Reactant: CCOC(=O)C(F)C(C)=O
Product: CCCNC(=O)C(F)C(C)=O
Reaction time: 2 h

Procedure:
0.8 mol (65.8 ml) of n-propylamine were added dropwise within 0.5 h to 0.2 mol (25 ml) of ethyl 2-fluoroacetoacetat. The reaction mixture was heated and then held for 2 h at 60° C. Then it was evaporated to dryness, dissolved in 50 ml water and 60 ml ethanol and adjusted with 32% HCl to pH 3. It was again evaporated, dissolved in 300 ml ethyl acetate, filtered and again evaporated to dryness. 17 g of crude product was chromatographed over 800 g silica gel with ethyl acetate/hexane 1/1. After drying, 14 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH:26]([C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[F:16])[CH2:24][CH2:25]3)=[O:30])[CH2:32][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(C1CCN(c2ccncc2F)CC1)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
4-Trifluoromethylphenylsulphonyl chloride (0.97 g) was added to a mixture 1-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine hydrochloride (1.22 g) and triethylamine (3.70 ml) in dichloromethane (45 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.99 g) as a solid.
Reaction SMILES: Br[CH:2]([CH2:18]C)[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[O:23]1[CH2:24][CH2:25][N:20]([CH:2]([CH3:18])[C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1

Procedure:
5 g of 5-(α-bromopropionyl)-8-hydroxy-3,4-dihydrocarbostyril (IV) was suspended in 30 ml of benzene, and 4.2 ml of morpholine (III) was added to the suspension followed by allowing the mixture to react for 4 hours while heating under refluxing. The reaction mixture was filtered and the filtrate was washed with water followed by concentration under reduced pressure to remove any remaining water. The resulting residue was dissolved in 50 ml of isopropanol, and the solution was adjusted to a pH of 2 - 3 with concentrated hydrochloric acid. The viscous precipitate formed upon ice-cooling was separated and dissolved in acetone by heating. After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5 - 8 with sodium bicarbonate. The precipitate formed upon ice-cooling was filtered and dissolved in 10 ml of a 47% aqueous hydrobromic acid followed by concentration under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to obtain 2.6 g of white amorphous 5-(α-morpholinopropionyl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide monohydrate having a melting point of 235° - 236° C (with decomposition).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[C:3](=[C:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)/[CH:4]=[CH:5]/[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:26])[C:3](=[C:11]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C/C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)C(/C=C/C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 77.3 %

Procedure:
A toluene (8 ml) solution of the above ester (2.38 g, 6.7 mmol) was added to powdery sodium hydroxide (0.34 g, 8.5 mmol) under argon atmosphere, and the whole was stirred at 60° C. for 5 hours. The reaction mixture was neutralized with 1M hydrochloric acid (10 ml) and extracted with ethyl acetate (25 ml×3 times). The organic layer was washed with water, saturated sodium chloride aq solution and then dried over anhydrous magnesium sulfate. Concentration of the organic layer in vacuo followed by recrystallization from a mixed solvent (hexane:ethyl acetate=4:1) gave 1.70 g (78% yield) of (E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenoic acid. mp=225°-230° C. Rf =0.52 (hexane:ethyl acetate=1:1) IR (KBr): 3350, 2400, 3025, 1690, 1615, 1515, 1430, 1320, 1225, 1165, 1100, 1080, 1005, 965, 860, 850, 595, 580 cm-1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:34])[C:21]([NH2:33])=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[F:17][C:18]1[C:23]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][C:21]2[NH:33][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:34][C:20]=2[CH:19]=1
Reactant: Nc1cc(F)c(OCCN2CCCCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCN3CCCCC3)cc2[nH]1

Procedure:
A solution of 248 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde and 278.9 mg of 4-fluoro-5-(2-piperidin-1-ylethoxy)benzene-1,2-diamine in 12 mL of methanol is stirred at ambient temperature overnight. In order for the reaction to be complete, heating is carried out for a further half an hour at reflux and then overnight at ambient temperature. After concentration under vacuum in a rotary evaporator, 515 mg of 5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-(2-piperidin-1-ylethoxy)-1H-benzimidazoleare isolated in the form of a dark solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): for this batch, we observe a 60%-40% resolution of tautomers with: from 1.31 to 1.78 (m, 9H); from 1.87 to 2.30 (m, 3H); 2.46 (m partially masked, 4H); 2.72 (t, J=6.0 Hz, 2H); 3.69 (m, 1H); 4.00 (m, 1H); 4.19 (t, J=6.0 Hz, 2H); 5.60 (dd, J=2.0 and 9.0 Hz, 1H); 7.26 (d, J=7.5 Hz, 0.6H); 7.41 (d, J=11.5 Hz, 0.4H); 7.45 (d, J=7.5 Hz, 0.4H); 7.53 (d, J=11.5 Hz, 0.6H); 9.18 (s, 1H); 12.85 (broad m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[Cl:1][C:2]1[C:7]([NH:8][C:13]2[C:14](=[O:19])[C:15](=[O:16])[C:12]=2[O:11][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccnc2Cl)c(=O)c1=O

Procedure:
A solution of 2-chloro-3-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[O:11][CH2:12][CH2:13][N:14]=1)[CH3:9]>>[CH2:1]([S:7][CH2:12][CH2:13][NH:14][C:10](=[O:11])[CH2:8][CH3:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccco1
Reactant: CCC1=NCCO1
Product: CCC(=O)NCCSCc1ccco1

Procedure:
In this example furfurylmercaptan and 2-ethyl-2-oxazoline are reacted to form N-furfurylthioethylpropionamide. Furfurylmercaptan (13.04 grams, 0.11 mols) is heated under nitrogen to 155° C. in a flask. 2-Ethyl-2-oxazoline (11.4 grams, 0.115 mols) is slowly added from a dropping funnel over a period of two hours. The mixture is post-reacted at 155° C. for an additional 11/2 hours. The product is isolated by distillation at reduced pressure: BP 136°-137° C. at 0.2 millimeters Hg. The spectral and elemental analyses correspond to those of the N-furfurylthioethylpropionamide mentioned above. Analysis for the crude reaction mixture by internal standard gas/liquid chromatography shows 1.7 weight percent 2-ethyl-2-oxazoline, 0.8 weight percent furfurylmercaptan and 95.8 weight percent N-(2-furfurylthioethyl)propionamide. This is a reaction yield based on starting materials of 96 percent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[Cl-].[NH4+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:10]#[N:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1ccc(C(C#N)c2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(C#N)(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 69.5 %

Procedure:
To a solution of bis(4-methoxyphenyl)acetonitrile (1.0 g, 4 mmol) in N,N-dimethylformamide (5 ml) was added 60% oil sodium hydride (0.24 g, 6 mmol) while stirring under ice-cooling. The mixture was stirred for 30 minutes under the same conditions, to which was added, while stirring under ice-cooling, ethyl 6-bromohexanoate (0.89 g, 4 mmol). The mixture was stirred for 2 hours at room temperature, to which was added a saturated aqueous solution of ammonium chloride. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, which was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with hexane--ethyl acetate (4:1) to give 1.1 g of the title compound.