Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Mg].Cl[P:14]([C:31]1[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:34]([O:41][CH3:42])=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=1)[C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([O:25][CH3:26])=[C:17]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:16]=1.[OH:47]O>C1COCC1.II.O>[C:37]([C:35]1[CH:36]=[C:31]([P:14](=[O:47])([C:15]2[CH:20]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:18]([O:25][CH3:26])=[C:17]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:16]=2)[C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=2)[CH:32]=[C:33]([C:43]([CH3:44])([CH3:46])[CH3:45])[C:34]=1[O:41][CH3:42])([CH3:38])([CH3:40])[CH3:39]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1c(C(C)(C)C)cc(P(Cl)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1C(C)(C)C
Reactant: OO
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
1-Bromo-3,5-dimethoxybenzene (25.5 g, 117.5 mmol) in THF (150 mL) was added to a mixture of magnesium (3.14 g, 129.2 mmol) and iodine (120 mg) in THF (100 mL). The mixture was refluxed for 1 hour after the addition was completed. It was cooled to RT. The resulting light brown solution was transferred to another flask. It was cooled to −78° C. and chlorobis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine (59.3 g, 117.4 mmol) in THF (100 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 0.5 h, then slowly warmed up to RT and stirred at RT for 1 hour. To the resulting mixture water (300 mL) was added, then H2O2 (17 mL, 30%) was added dropwise at 0° C. The mixture was stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL×2) and CH2Cl2 (200 mL×1). The combined organic layer was washed with brine (200 mL×2), NaHSO3 (200 mL×3) and dried over MgSO4. It was filtered and the solvent was removed. The viscous residue was dissolved in CH2Cl2 (30 mL) and ether (100 mL), then hexane (400 mL) added. The mixture was concentrated to 400 mL under reduced pressure and then seeded. The suspension was stirred for 1.5 hour and the resulting solid was collected by filtration and dried to give the product as a colorless solid (57 g). a second crop (13 g) was collected from the mother liquor. Yield=95.7%. 1H NMR (300 MHz, CDCl3) δ: 7.47 (d, J=12.6 Hz, 4H), 6.83 (dd, J1=12.6 Hz, J2=2.1 Hz, 2H), 6.60 (t, J=2.1 Hz, 2H), 3.78 (s, 6H), 3.68 (s, 6H), 1.35 (s, 36H). 31P NMR (121.5 MHz, CDCl3) δ: 32.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=4)[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: COc1cccc(NC(=N)N)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: COc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(3-methoxyphenyl)guanidine were converted to I-15 (25%): HRMS Calcd. for C19H15ClN4O2: 367.0961, Found 367.0961.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:32])[N:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].C1COCC1.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1>CCOC(C)=O.CCCCCC>[CH3:39][N:40]1[CH2:41][CH2:42][N:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:32])[N:25]=[C:26]([C:28]([CH3:30])([CH3:29])[CH3:31])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:48][CH:47]=2)[CH2:44][CH2:45]1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cc(C(C)(C)C)nn6C)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
A small screw cap test tube was charged with 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 128 mg, 0.288 mmol) and THF (3.0 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (54.8 mg, 0.286 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜10 mL) to afford the title compound in 29% yield (0.051 g, 0.083 mmol).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:34])([F:33])[CH:30]1[O:32][CH2:31]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:31][CH:30]([OH:32])[C:29]([F:34])([F:33])[F:28])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: FC(F)(F)COc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Product: OC(CN(Cc1cccc(OCC(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 20.4 %

Procedure:
The N-(3-phenoxyphenyl )[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine (0.50 g, 1.35 mmol) product from EX-659B and 1,1,1-trifluoro-2,3-epoxy-propane (1.0 ml, 11 mmol) were heated to 90° C. in a sealed container under argon for 2 d. The resulting mixture was eluted from silica gel with 4% ethyl acetate in hexane, and fractions were pooled based on TLC analysis to give 134 mg (21%) of the desired 3-[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear, colorless oil. 1H NMR (C6D6) δ6.80-7.08 (m, 7H), 6.64 (d, 1H), 6.53 (bt, 1H), 6.49 (t, 1H), 6.44 (dd, 1H), 6.34 (dt, 2H), 4.23 (s, 2H), 3.84 (m, 1H). 3.61 (m. 2H), 3.53 (dd, 1H), 3.20 (m, 1H), 2.03 (d, 1H). 19F NMR (C6D6) δ−74.20 (t, 3F), −78.95 (d, 3F). HRMS calcd. for C24H21F6NO3: 486.1504 [M+H]+, found: 486.1498.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[OH:49]>C(#N)C.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCOCOc1ccc(C=CC(=O)O)cc1OCOCCOC
Reactant: Nc1ccccc1O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COCCOCOc1ccc(C=CC(=O)Nc2ccccc2O)cc1OCOCCOC
Yield: 12.4 %

Procedure:
To a solution of 1.21 g (3.40 mmol) of 3-{3,4-di-(β-methoxyethoxymethoxy)phenyl}-2-propenic acid in dry acetonitrile (30 ml) were added in an argon atmosphere 1.73 g (6.76 mmol) of 2-chloro-1-methylpyridinium iodide and 2.40 ml (17.2 mmol) of triethylamine and 799 mg (7.32 mmol) of o-aminophenol, successively. The mixture was reacted at room temperature for 60 hours, followed by addition of water. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with 1N-aqueous hydrochloric acid, water, aqueous solution of sodium carbonate and water. The organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography. There was obtained 188 mg (0.420 mmol) of N-[3-{3,4-di(β-methoxyethoxymethoxy)phenyl}-2-propenoyl]-o-aminophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][C:19](=O)[CH:18]([CH3:22])[O:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CSC.B>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH3:22])[O:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:29][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)C(=O)N3)cc1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)CN3)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.45 g, 3.14 mmol) in THF (25 ml.) was added borane dimethyl sulfide (1M in THF) (0.343 g, 4.71 mmol, Aldrich) at 0° C. and reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was quenched with MeOH (15 mL) and the solvent was removed under vacuum. The residue obtained was diluted with MeOH and stirred at 25° C. for 1 h, then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in hexanes as the eluent to afford 1.3 g of N-(4-methoxybenzyl)-2-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE AE) as off white solid in 92% yield.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl>C(O)(C)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1cn(N)c2ccccc12
Reactant: Clc1ccncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Cc1cn(Nc2ccncc2Cl)c2ccccc12

Procedure:
The title compound was prepared from 3-methyl-1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 80° C. for 5 hours in substantially the same manner as in Example 1. Recrystallized from ethanol, m.p. 278°-280° dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.83 g), (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.69 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.54 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.65 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propenamide (0.86 g, yield 61%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 173–174° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=2)[CH:5]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[NH:4][C:3]1=[O:33].[H-].[Na+].[CH3:36]I>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:10]=2)[CH:5]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[N:4]([CH3:36])[C:3]1=[O:33]
Reactant: CI
Reactant: CN1C(=O)NC(Cc2c[nH]c3ccccc23)C1CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1C(=O)N(C)C(Cc2c[nH]c3ccccc23)C1CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
The compound of Example 1 (0.5 g) in tetrahydrofuran (5 ml) was treated with sodium hydride (43 mg of a 60% dispersion in oil) under a nitrogen atmosphere with stirring. After 5 minutes methyl iodide (0.28 g) was added and stirring continued for 2 hours. The reaction was diluted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether and crystallised from ethyl acetate-petroleum ether to give the title compound, mp 202°-205° C.; found: C, 59.88; H, 4.23; N, 8.42. C24H21F6N3O requires C, 59.88; H, 4.40; N, 8.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH:38]=[O:39])[CH2:34][CH2:33]2)[C:26]=1[CH3:40])=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][N:32]2[CH2:33][CH2:34][N:35]([CH:38]=[O:39])[CH2:36][CH2:37]2)[C:26]=1[CH3:40])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(C=O)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(C=O)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (178 mg) was condensed with 4-(5-formyl-2,4-dimethyl-1H-pyrrol-3-ylmethyl)-piperazine-1-carbaldehyde (125 mg) using piperidine (cat. amount) in ethanol at 80° C. for 4 hours to give the titled compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[NH4+:9].[OH-].[Na+]>O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:8])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following the examples of U.S. Pat. No. 4,839,461, a solution of 1.96 g (0.02 mole) maleic anhydride was dissolved in 1 ml water at 25° C. and stiffed for 30 minutes while allowing the mixture to cool to 25° C. To this colorless solution at 25° C. was added 2.4 g of 30% aqueous solution of ammonium hydroxide (0.022 mol NH3) to give a colorless solution. This solution was boiled to dryness over a period of 30 minutes at approximately 100°-120° C. and 10-20 Torr, to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 135°-140° C. for 8 hours to give a water insoluble, pinkish-tan brittle grasslike solid weighing 2.7 g. This solid was dissolved in 6.6 g of an aqueous solution containing 0.8 g of sodium hydroxide to form a clear orange solution, pH 7.0, containing 25% solids.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29](OCC)=O)[CH2:24][CH:25]=1>>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:22][CH:21]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc3ccccc3c2)CC1
Product: C1=C(c2ccc3ccccc3c2)CCN(CCCc2onc3c2CCCCC3)C1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[S:29][C:19]2[C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)[C:5]([OH:7])=O.[CH3:30][NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[S:29][C:19]2[C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)[C:5]([NH:31][CH3:30])=[O:7]
Reactant: CN
Reactant: O=C(O)c1ccc(-n2cnnc2-c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Product: CNC(=O)c1ccc(-n2cnnc2-c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(3-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4H-1,2,4-triazol-4-yl)benzoic acid and methylamine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 209. MS: (ESI+) 437.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].I[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH:15](O)[CH3:16].C[OH:19]>>[CH2:9]([OH:19])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(O)OCCOCCI
Reactant: NCCNCCN
Reactant: CO
Product: NCCNCCNCCOCCOCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of diethylene triamine (460 ml, 4.3 mole) and (2-iodoethoxy) ethoxyethanol (7.30 g, 28 mmole) was stirred-at room temperature for 1 hour. The excess of diethylenetriamine was removed by distillation under vacuum. The residue was then treated with aqueous Satd NaOH, extracted with CH2Cl2, dried over MgSO4/Na2CO3, filtered, and concentrated to give a yellow oil. This was purificated by column chromatography on silica with CH3OH/NH40H (10:1), then (5:1) to give 1.43 g (33%) of the title compound as a pale yellow oil. The reaction is shown schematically as follows:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]CC)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C.C(OCC)C>[CH3:1][C:2]1[C:3]([C:8]([NH:14][NH2:15])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncccc1C
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Cc1cccnc1C(=O)NN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 3-methylpyridine-2-carboxylate (2 g, 12.11 mmol, CAS [58997-10-7], commercially available e.g. from Beta Pharma) was dissolved in ethanol (40 mL) and treated with hydrazine monohydrate (0.706 mL, 14.53 mmol). The reaction mixture was stirred at room temperature for 15 mins before heating at reflux for 18 hours. The reaction mixture was cooled to room temperature, more hydrazine monohydrate (0.5 ml) was added, and the reaction mixture was heated at reflux for a further 24 hours. The reaction mixture was cooled to room temperature. The solvent was evaporated to near dryness, and the residue was azeotroped with ethanol (3×35 ml). The mixture was evaporated to dryness after the third time to afford a pale yellow solid. This solid was slurried in diethyl ether, filtered off and dried to afford the title compound as a white solid (0.575 g, 3.80 mmol).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=1>CN(C=O)C.CCOC(C)=O>[O:7]([C:11]1[C:16]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([C:22]([F:23])([F:25])[F:24])[N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 18 %

Procedure:
Phenol (57 mg, 0.60 mmol) and sodium hydride (32 mg, 0.8 mmol) were added in DMF (15 mL). The reaction mixture was stirred for 10 mins and then 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol) was added into the reaction mixture. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/1) to give the title product (15 mg).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14]>O1CCCC1.CO>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ccccc1N
Yield: 100 %

Procedure:
Isatoic anhydride (10.0 g) was suspended in tetrahydrofuran (200 ml) and treated dropwise with 40% solution of methylamine in methanol (10.0 ml) with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to give the title compound (10.3 g, about 100%). Melting point: 78.0 to 79.0° C. (recrystallized from ethyl acetate-n-hexane).
Reaction SMILES: B.CSC.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[O:10][CH:11]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:12][CH:13]=[CH2:14].O.B1([O-])O[O:30]1.O.O.O.O.[Na+]>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[O:10][CH:11]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH2:14][OH:30]
Reactant: [O-]B1OO1
Reactant: C=CCC(Oc1ccc(OC)c(OC)c1)c1ccc(C#N)cc1
Agent: B
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC(CCCO)c2ccc(C#N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was added dropwise to a cooled (−5° C.) solution of 4-[1-(3,4-dimethoxy-phenoxy)-3-butenyl]benzonitrile (from step (a) above; 17.6 g, 56.8 mmol) in dry THF (15 mL) over a period of 15 minutes (during which time the reaction temperature rose to 0° C.). The resulting mixture was stirred at between 0 and 10° C. for 1.5 h, before being allowed to warm to rt. Stirring was continued for a further 3.5 h at this temperature before water (22 mL) and sodium perborate tetrahydrate (11 g, 66 mmol) were added. The biphasic mixture was stirred for 2 h at rt before the water layer was separated and extracted with ether. The combined organic layers were washed with brine, dried and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with IPA:ethyl acetate:heptane (5:25:76) to yield 14.5 g (77%) of the sub-title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[C:4]1[CH3:14])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O-:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1.[Cl:24][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N+:3]([CH2:1][CH3:2])=[C:4]([CH3:14])[CH:5]=1
Reactant: CCn1c(C)cc(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC[n+]1c(C)cc(Cl)c2ccccc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
The starting material was prepared by reaction of 1-ethyl-2-methyl-4-quinolone with toluene-p-sulphonyl chloride to give 4-chloro-1-ethyl-2-methylquinolinium toluene-p-sulphonate.