Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([C:11]2[CH:16]=[CH:15][C:14](SC)=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH:20]1C=C(Cl)C=C(C(OO)=O)C=1.[OH:31][S:32]([O-:34])=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[CH2:9][C:11]2[CH:12]=[CH:13][C:14]([S:32]([CH3:20])(=[O:34])=[O:31])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3) (15.00 g, 57.62 mmol) in methylene chloride (500 mL) at 5° C. (ice-bath) was added MCPBA (29.64 g, ca. 67% peroxide, ca. 113 mmol), portionwise over 30 minutes. The solution was warmed to room temperature. The reaction solution was stirred vigorously with NaHSO3 solution for 10 minutes to quench any unreacted MCPBA. The layers were separated and ethyl acetate was added to aid in dissolution of the precipitate which began to form. The partial suspension was filtered and the solid saved. The organic phase was washed successively with NaHCO3 solution and brine, dried over Na2SO4, and diluted with isooctane until a solid began to precipitate. Upon removal of most of the ethyl acetate and methylene chloride in vacuo more solid precipitated. All of the precipitates were combined yielding 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (14.5 g, 86%). mp 182°-183° C. 1H NMR (CDCl3) 300 mHz δ8.04 (dd, J=5.24, 8.46, 2H), 7.92 (d, J=8.26 Hz, 2H), 7.46 (d, J=8.46 Hz, 2H), 7.17 (t, J=8.46, 2H), 4.37 (s, 2H), 3.05 (s, 3H). MS: m/z 293 (MH+); HRMS A =1.6 mmu.
Reaction SMILES: BrC[CH2:3][C:4]1[C:5]([CH3:20])=[N:6][N:7]([CH2:18][CH3:19])[C:8]=1[S:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:10]([S:9][C:8]2[N:7]([CH2:18][CH3:19])[N:6]=[C:5]([CH3:20])[C:4]=2[CH2:3][NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]([Cl:17])[CH:13]=1
Reactant: Nc1cccnc1
Reactant: CCn1nc(C)c(CCBr)c1Sc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(CNc2cccnc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 7.5 %

Procedure:
A mixture of 227 mg of 4-bromoethyl-5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole, 62 mg of 3-aminopyridine and 36 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 15 minutes. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol for the elution to give 17 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-ylmethyl]-pyridin-3-yl-amine as a brown gum. 1H NMR (DMSO-d6) 1.19 (t, 3H), 2.27 (s, 3H), 4.05–4.11 (m, 4H), 6.03 (t, 1H), 6.87 (d, 1H), 6.99 (m, 1H), 7.04 (d, 2H), 7.44 (t, 1H), 7.72 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:27][C@@H:28]([CH3:37])[CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:8]([Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[C:1]#[C:2][CH2:27][C@@H:28]([CH3:37])[CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH3:9]
Reactant: C#C[Si](CC)(CC)CC
Reactant: C[C@H](CBr)COC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC[Si](C#CC[C@@H](C)COC1CCCCO1)(CC)CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of triethylsilyl acetylene (6.25 g, 8 mL, 44.7 mmol) in anhydrous tetrahydrofuran (150 mL) was mixed with a 2.5 M solution of n-butyl lithium (19.6 mL, 49.2 mmol) in hexane at −70° C. in argon. After stirring for 15 min at this temperature hexamethyl phosphoric triamide (19.4 g, 18.8 mL, 108 mmol) was added and the mixture stirred a further 15 min. A solution of 2-((S)-3-bromo-2-methylpropoxy)tetrahydropyrane (10.6 g, 44.7 mmol) in anhydrous tetrahydrofuran (40 mL) was added in drops to this solution and this was the slowly heated to room temperature. After adding saturated ammonium chloride solution (40 mL), the mixture was concentrated to low volume in a vacuum, the residue taken up in water (150 mL) and extracted with cyclohexane/diethyl ether (1:1.3×100 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (11 g) was purified by flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/cyclohexane (1:30).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([Cl:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(OCc2ccccc2)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 1-benzyloxy-2-chloro-4-fluoro-benzene (618, 5.8 g, 0.024 mol) in tetrahydrofuran (100 mL) was added 2.50 M of n-butyllithium (2.7 mL, 2.50 M in hexane, 0.029 mol) slowly at −78° C. over 15 minutes under nitrogen. The reaction mixture was stirred at −78° C. for 30 minutes. To the reaction mixture was then added N,N-dimethylformamide (4.2 mL, 0.054 mol). The reaction was allowed to warm to room temperature and was continued at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with hydrochloric acid (10%), water, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (619, 2.1 g, 32%). MS(ESI) [M+H+]+=265.08.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>>[C:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:7]
Reactant: CC(C)CCCCCCCO
Reactant: O=C(O)CCCCC(=O)O
Product: CC(C)CCCCCCCOC(=O)CCCCC(=O)OCCCCCCCC(C)C
Temperature: 220 °C

Procedure:
A standard 2-liter esterification apparatus was charged with 292 g adipic acid and 727 g isodecyl alcohol. The mixture was heated to reflux, removing water as formed. After 30 minutes of reflux the temperature was 215° C. and 40 ml of water was collected, at which time 0.9 g of catalyst compound ATC-I was added to the flask. The pressure was reduced as needed to maintain the reflux temperature at 220° C. After an additional 45 minutes the water of reaction was collected and the acid number of the residue was measured to be 0.01 mg KOH/g. Heating was discontinued and excess alcohol removed as the pressure was reduced to 20 torr. The reaction mixture was cooled to 170° C., the catalyst was hydrolyzed and the remaining alcohol removed by steam distillation using 100 ml water during 2 hours at 100 torr. The residue was filtered with a No. 1 Whatman paper coated with diatomaceous earth to yield a clear residue product diisodecyl adipate (DIDA) (nD25 =1.4502) having an acid number of 0.05 mg KOH/g and color of 15 APHA. The product remained clear after storage for six months at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
33.3 g (0.25 mol) of 5-aminoindane (a product of Tokyo Chemical Industry Co. Ltd.) was dissolved in 250 ml of glacial acetic acid, the resulting solution was heated to 50° C., and 51.0 g (0.5 mol) of acetic anhydride was added dropwise thereto. After completion of the dropwise addition, the resulting solution was stirred for 4 hours. After completion of the reaction, the reaction liquid was poured in 1,500 ml of ice water while stirring. Crystals precipitated were filtered off, and washed with 1,000 ml of water. The crystals obtained were dried to obtain 37.06 g of 5-(N-acetylamino)indane (yield: 84.6%, melting point: 100.5 to 103.5° C.).
Reaction SMILES: [CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:20][C:9](=[O:11])/[C:8](=[N:7]/[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 67 %

Procedure:
(E)-Cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid (prepared as in Example 18, 100 mg, 0.33 mmol), 2-aminobenzothiazole (50 mg 0.33 mmol) and N,N-diisopropylethylamine (173 μL, 0.99 mmol) were combined in methylene chloride (1.6 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-cyclopentyloxyimino-2-(3,4-dichloro-phenyl)-acetamide (96 mg, 67%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H17Cl2N3O2S [M+] 433.04, found 434 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 4.93 (m, 1 H, OCH), 7.34 (ddd, Jo=8.0, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.40 (dd, Jo=8.4, Jm=2.0 Hz, 1 H, Ar), 7.47 (ddd, Jo=8.3, Jo=7.3, Jm=1.3 Hz, 1 H, Ar), 7.53 (d, Jo=8.4 Hz, 1 H, Ar), 7.67 (d, Jm=2.0 Hz, 1 H, Ar), 7.83 (m, 2H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31](Cl)(=[O:33])=[O:32])=[CH:26][CH:25]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:31]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)(=[O:32])=[O:33])[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=S(=O)(Cl)Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)Nc4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=427.3 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-fluoro-phenylsulfamoyl chloride.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([CH:11](Br)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:12]([NH:4][CH2:3][CH2:1][OH:2])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCO
Reactant: CC(Br)c1ccccc1
Product: OCCNCCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of ethanolamine (10 g, 0.162 mol) and 1-phenylethyl bromide (5 g, 0.027 mol) was stirred at 120° C. for 3 h. The reaction mixture was partitioned between water and dichloromethane. Organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane to afford (2.5 g) of desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(C(C)C)CC)(C)C.[Cl:31][CH:32]=[CH:33][C:34](Cl)=[O:35].C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:34](=[O:35])/[CH:33]=[CH:32]\[Cl:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(Cl)C=CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)/C=C\Cl)cc2c1Nc1cccc(Br)c1
Reaction time: 0.67 h

Procedure:
To a solution of 0.5 g (1.47 mmol) of of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.24 g (1.8 mmol) of diisopropylethyl amine in 3 ml of terahydrofuran at 0° C. with stirring was added 0.21 g (1.7 mmol) of 3-chloro-acryloyl chloride (cis/trans mixture) in 2 ml of tetrahydrofuran. After 40 min at 0° C., the mixture was poured into a saturated solution of sodium bicarbonate and then extracted ether. The organic solution was dried over magnesium sulfate and the sovent was removed. The residue chromatographed on silica gel giving 0.16 g of N-[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-3-chloro-(E) acrylamide: mass spectrum (electrospray, m/e,): M+H 424.9, 427.0, and 0.12 g of N-[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-3-chloro-(Z) acrylamide acrylamide: mass spectrum (electrospray, m/e,): M+H 425.0, 427.0
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:21]=[N:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:21]=[N:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3c2)nn1

Procedure:
Followed the two step procedure described for Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and methyl 6-chloropyridazine-3-carboxylate. 1H-NMR (DMSO-d6 500 MHz): 10.16 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 8.51-8.48 (m, 1H), 8.30-8.23 (m, 2H), 7.97-7.86 (m, 2H), 7.23-7.19 (m, 2H). MS (ESI): m/z 267.0 [M+1]+.
Reaction SMILES: C[Si:2](C(O)C)(C)C.[CH3:8][C:9](C)([O-:11])C.[K+].C1([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])C=CC=CC=1>C1COCC1>[SiH3:2][CH2:8][CH2:9][O:11][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Nc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: CC(O)[Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)NOCC[SiH3]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a stirred solution of trimethylsilyl ethanol (1.2 mmol, 0.14 g) in THF (3.8 mL) under argon at room temperature is added 1M solution of potassium tert- butoxide in THF (1.2 mL, 1.19 mmol) The reaction mixture is stirred for 40 minutes and then added dropwise over 5-10 minutes to a stirred solution of the above phenyl urethane (0.45 g, 1.1 mmol) in THF (3.8 ml) at 5° C. The reaction mixture is stirred at this temperature for 20 minutes and then warmed to room temperature for 16 hours. After refluxing for 40 minutes the reaction is cooled to room temperature and partitioned between ethyl acetate and water; the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried (Na2SO4) and concentrated. The residue is purified by flash chromatography (10% ethyl acetate/hexane) to give the intermediate silylethoxy urethane (0.22 g, 48%); Rf=0.56 (20% ethyl acetate/hexane). MS (El) m/z (419 M+).
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].[OH-].[K+].[O:13]=[C:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH:15]1[C:25](OCC)=[O:26]>O>[NH2:9][C:8]1[O:13][C:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][C:15]=2[C:25](=[O:26])[N:10]=1
Reactant: CCOC(=O)C1CCC(c2ccccc2)C1=O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(o1)C(c1ccccc1)CC2
Yield: 61.2 %

Procedure:
2-Methyl-2-thiopseudourea sulfate (1.336 g, 9.61 mmol) was dissolved in water (10 mL) and KOH (1.128 g, 20.10 mmol) was added. Under stirring, ethyl 2-oxo-3-phenylcyclopentanecarboxylate (2.03 g, 8.74 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and ether, and dried over anhydrous sodium sulfate to afford 2-amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-one (1.22 g, 5.35 mmol, 61.2% yield) as white solid. LC-MS (M+H)+=229.1. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 7.57-7.85 (2H, m), 7.08-7.47 (5H, m), 4.25-4.38 (1H, m), 1.72-2.73 (3H, m), 1.09-1.31 (1H, m).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:24][OH:25]>C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:9](=[O:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:25]1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C(=O)ON(Cc2ccccc2F)C1=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
The procedure of Example III was utilized with 10.2 ml (0.128 mole) pyridine, 10.2 grams (0.060 mole) dimethylmalonyl chloride and 120 ml methylene chloride in solution under argon at -72° C., to which 8.5 grams (0.060 mole) of N-(2-fluorophenylmethyl)hydroxylamine (Intermediate F) in 25 ml methylene chloride was added in a single portion, raising the temperature immediately to -25° C., and stirring was continued at 0° C. for two hours. Gas chromatography on a sample of the reaction mixture showed only one major peak. The reaction mixture was washed with 2 N hydrochloric acid and water, the methylene chloride layer was separated and dried over sodium sulfate, and after removal of sodium sulfate by filtration, the solvent was removed under reduced pressure, leaving 13.0 grams of a yellow viscous liquid (91% yield). The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: COC1C=CC(C2CCCC3C=C(OC)C=CC=3C2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH2:68]3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][N:58]([CH2:57][CH3:56])[C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH2:68]3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc2c(c1)CCCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc(C2CCCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1CCCc2cc(OC)ccc2C1

Procedure:
Synthesized from 5-methoxy-2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (485 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (459 mg). This compound (457 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (394 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[N:19]#[C:20][NH2:21].[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:20]([NH2:21])=[NH:19]
Reactant: N#CN
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=N)N

Procedure:
To 36 g. (0.315 mole) of 2,6-dimethylaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g. (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml. of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 2,6-dimethylphenylguanidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[F:25].[I:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:3]1[CH:4]=[C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:7][C:2]=1[NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[I:26]
Reactant: O=C(Cl)c1ccccc1I
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1F
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)c(F)c2)c2ccc3ccccc3c2N1
Yield: 37.3 %

Procedure:
By using 5-(4-amino-3-fluorophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.09 mmol) synthesized in the same manner as that of Example 1, (3), and 2-iodobenzoyl chloride (0.134 mmol), the title compound (19 mg, yield 38%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[CH2:22]([OH:24])C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([CH:14]=1)[CH:22]=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
The starting material is prepared as follows: 4-Benzyloxyphenol (20 g, 0.1 mol) is dissolved in 24 ml of ethanol and 120 ml of 20% aqueous sodium hydroxide (24 g NaOH, 0.6 mol), and heated at 70° C. To this is added chloroform (23.9 g, 0.2 mol) dropwise and the mixture is stirred for 3.5 hours at 70° C. The mixture is cooled and evaporated. The residue is then treated with conc. HCl until the pH of the solution is 1 to 3. The mixture is extracted with ether three times, and the combined organic layer is dried (MgSO4), evaporated and purified by silica gel chromatography (5% ethyl acetate/hexane) to give 5-benzyloxy-2-hydroxybenzaldehyde as a pale yellow, crystalline solid, m.p. 94°-96° C.