Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:50][C:51]1[CH:59]=[CH:58][C:54]([CH2:55][CH2:56][NH2:57])=[CH:53][CH:52]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:57][CH2:56][CH2:55][C:54]3[CH:58]=[CH:59][C:51]([CH3:50])=[CH:52][CH:53]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1ccc(CCN)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and 1-hydroxybenzotriazole hydrate (34 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47 mg, 0.24 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, and 4-methylphenethylamine (30 mg, 0.23 mmol) was added. After stirring was at ambient temperature for a further 30 minutes, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (2 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless oil (96 mg, 96% yield).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.CN(C)CCCN=C=NCC.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].Cl>ClCCl.O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:18])=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
To a stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.52 g, 1.50 mmol) in dichloromethane (40 mL) and tetrahydrofuran (40 mL) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol), and 4-(dimethylamino)pyridine (0.42 g, 3.43 mmol). The reaction mixture was stirred at ambient temperature for 10 min, methanesulfonamide (0.22 g, 2.28 mmol) was added and stirring continued at ambient temperature for 36 h. 5% aqueous hydrochloric acid (10 mL) were added and then diluted with ethyl acetate (200 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (10% to 30% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (0.45 g, 70%): 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=16.2 Hz, 1H), 7.58 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.7 Hz, 1H), 3.56 (s, 2H), 3.41 (s, 3H), 2.09-2.00 (m, 4H), 1.81-1.58 (m, 12H), 0.99-0.91 (m, 2H), 0.70-0.62 (m, 2H); MS (ES−) m/z: 420.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:14])[CH:3]=1.[CH3:24][O:25][C:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:31]3[CH2:32][CH2:33][CH:28]([C:26]([O:25][CH3:24])=[O:27])[CH2:29][CH2:30]3)=[N:19][CH:18]=2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(Cl)nc2)cc(N)c1C#N
Reactant: COC(=O)C1CCNCC1
Product: CCOc1nc(C(=O)NCc2ccc(N3CCC(C(=O)OC)CC3)nc2)cc(N)c1C#N

Procedure:
A mixture of Example 185 (50 mg, 0.15 mmol) and piperidine-4-carboxylic acid methyl ester (0.75 mL) were heated to 140° C. for 20 min. in a microwave reactor. The reaction mixture was extracted with ethyl acetate (5 mL) and washed with 1M HCl (2×10 mL). The organic layer was concentrated in vacuo and purified by silica gel chromatography (50-100% ethyl acetate in hexanes) providing the title compound as an off white solid (34 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 8.92 (t, J=6.44 Hz, 1H), 8.05 (d, J=2.03 Hz, 1H), 7.47 (dd, J=8.82, 2.37 Hz, 1H), 7.30 (s, 2H), 7.06 (s, 1H), 6.80 (d, J=8.48 Hz, 1H), 4.48 (q, J=7.12 Hz, 2H), 4.31 (d, J=6.10 Hz, 2H), 4.14 (d, J=13.22 Hz, 2H), 3.60 (s, 3H), 2.82-2.98 (m, 2H), 2.56-2.67 (m, 1H), 1.85 (dd, J=13.56, 3.39 Hz, 2H), 1.43-1.62 (m, 2H), and 1.30 (t, J=7.12 Hz, 3H); MS (ESI) m/e positive ion 461 [M+Na]+, 439 [M+H]+; negative ion 437 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CC(C)([O-])C.[K+].Cl[CH2:19][CH2:20][CH2:21][OH:22].O>CS(C)=O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:19][CH2:20][CH2:21][OH:22])[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2cccnc12
Reactant: OCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCCOc1cccc2cccnc12
Temperature: 70 °C

Procedure:
A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium tertbutoxide (28.0 g, 0.25 mole) in 80 ml of dimethyl sulfoxide was stirred for 1 hr at room temperature. 3-Chloro-1-propanol (242.0 g, 0.25 mole) was added and the solution was heated overnight at 70° C. The solution was poured into 500 ml of water. A brown solid/mass was obtained. The solid was washed with several portions of water and then triturated with acetone. The solid was filtered and dried in vacuo at 80° C. overnight to give 35.67 g (70.3%) of light brown solid, m.p. 126°-127° C.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.N1C=CC=CC=1.[CH2:18]([C:22]1[O:26][N:25]=[C:24]([CH2:27][NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][C:30]=2[NH2:39])[CH:23]=1)[CH2:19][CH2:20][CH3:21]>C(#N)C>[CH2:18]([C:22]1[O:26][N:25]=[C:24]([CH2:27][N:28]2[C:29]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:32]=[CH:31][C:30]=3[N:39]=[CH:1]2)[CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: CCCCc1cc(CNc2c(N)cnc3ccccc23)no1
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCc1cc(Cn2cnc3cnc4ccccc4c32)no1
Yield: 86.5 %

Procedure:
Triethyl orthoformate (0.80 mL, 4.80 mmol) and pyridine hydrochloride (0.092 g, 0.80 mmol) were sequentially added to a solution of N4-[(5-butylisoxazol-3-yl)methyl]quinoline-3,4-diamine (1.19 g, 4.00 mmol) in acetonitrile (100 mL), and the solution was heated gently at reflux overnight. An analysis by HPLC indicated the presence of starting material, and additional triethyl orthoformate and pyridine hydrochloride were added. The solution was heated at reflux for an additional 24 hours. The solvents were removed under reduced pressure, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 1.06 g of 1-[(5-butylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[NH2:11])=[O:12]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-amino-5-bromobenzoic acid methyl ester (460.1 mg) in degassed toluene was mixed with tetrakis(triphenylphosphine)palladium (0) (62.4 mg) and stirred at room temperature for 10 min. Then 4-chlorophenylboronic acid (344 mg) in ethanol (0.76 mL) and 2 M sodium carbonate solution (1.34 mL) were added, and the reaction mixture was heated at 100° C. overnight. The reaction was then mixed with ethyl acetate and water. The aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 261.71 (C14H12ClNO2) was obtained in this way; MS (ESI): 262 (M+H+).
Reaction SMILES: [F:1][C:2]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:3][CH2:4][CH2:5][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=3)[O:27][CH2:26][C:25]2([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH3:35])=[CH:20][CH:19]=1)(C(O)=O)[C:7]([OH:9])=[O:8].[Na+].[Cl-]>CS(C)=O>[OH:34][C:30]1[CH:29]=[C:28]2[C:33]([CH:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:6]([CH2:5][CH2:4][CH2:3][C:2]([F:47])([F:1])[C:43]([F:44])([F:45])[F:46])[C:7]([OH:9])=[O:8])=[CH:19][CH:20]=3)[C:25]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)([CH3:35])[CH2:26][O:27]2)=[CH:32][CH:31]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Yield: 67.6 %

Procedure:
A solution of (4,4,5,5,5-pentafluoropentyl)(4-(4-(7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl)phenyloxy)butyl)methane-1,1-dicarboxylic acid (0.19 g, 0.285 mmol) in dimethylsulfoxide (7.6 ml) was stirred at 125° C. for 3 hours. After the reaction was completed, the reaction mixture was treated with saturated NaCl solution and extracted with ethyl acetate:hexane=1:1. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (0.12 g, 67.6%) as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:10](=O)[NH:9]2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].[O-2].[Ca+2]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:10](=[S:28])[NH:9]2)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NC(c2ccc(Cl)cc2)c2ccccc2C1CCN1CCOCC1
Agent: [Ca+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: S=C1NC(c2ccc(Cl)cc2)c2ccccc2C1CCN1CCOCC1

Procedure:
20 millimoles of 1-(4-chlorophenyl)-4-[2-(morpholine-4-yl)-ethyl]-1,4-dihydro-2H-isoquinoline-3-one were introduced, while stirring, into a suspension of 8 millimoles of phosphorus pentasulfide and 32 millimoles of calcium oxide in 50 ml of toluene and the whole was heated for 7 hours under reflux until the reaction was completed. The reaction mixture was decanted off to remove the resinous residue and extracted twice with toluene. The combined organic solutions were concentrated and the product was recrystallized from isopropanol. M.p.: 228°-231°C (HCl)
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=[O:9])[S:4][N:3]=1.Cl.O.C([O-])(O)=O.[Na+].[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:10][CH2:18][CH3:19])=[O:9])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1snc(Cl)c1Cl
Yield: 83 %

Procedure:
3,4-Dichloro-5-isothiazolecarboxylic acid (55 g; 0.278 mol) was dissolved in 500 ml of ethanol. The solution was saturated with hydrochloric acid and then refluxed for 3 hrs. The ethanol was distilled on a rotary evaporator leaving a residue which was then charged into 200 ml of water and neutralized with NaHCO3. The water layer was extracted with 2x200 ml of Ch2CL2. The extracts were combined, dried over MgSO4, filtered and the solvent distilled. The remaining liquid was distilled to yield 52.3 g (83%) of ethyl 3,4-dichloroisothiazol-5-carboxylate by 92° (3.0 mm).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.S(Cl)(Cl)=O.[O:15]1[CH2:20][CH2:19][NH:18][C:17]2[CH:21]=[N:22][CH:23]=[CH:24][C:16]1=2.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[O:15]1[CH2:20][CH2:19][N:18]([C:6]([C:5]2[CH:4]=[N:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])[C:17]2[CH:21]=[N:22][CH:23]=[CH:24][C:16]1=2
Reactant: c1cc2c(cn1)NCCO2
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(O)nc1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
In a 25 ml flask, 6-hydroxy-nicotinic acid (102 mg, 0.73 mmol) was dissolved in N,N-dimethyl acetamide (2.7 ml) and then cooled to −15□. Thionyl chloride (0.06 ml) was added thereto and the temperature was slowly raised up to −5□ and then stirred at −5□ for 30 minutes. The mixture was cooled again to −15□ and then 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and potassium carbonate (127 mg, 0.82 mmol) were added thereto and stirred for 10 minutes. The temperature was raised up to room temperature and then stirred for 14 hours. Ethyl acetate was added to the reaction mixture, and the mixture was neutralized with saturated solution of sodium hydrogen carbonate and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=50:1. The fractions containing the product were collected and evaporated to obtain the target compound 32 as white solid (86 mg, 45%).
Reaction SMILES: [CH3:1][N:2]([CH:4]([N:8](C)C)[N:5](C)[CH3:6])C.C1(=O)[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(=O)(O)O.NC(N)=N.Cl>C1(C)C=CC=CC=1.CO>[O:17]=[C:14]1[CH2:15][CH2:16][C:6]2[N:5]=[C:4]([NH2:8])[N:2]=[CH:1][C:12]=2[CH2:13]1
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: O=C1CCC(=O)CC1
Agent: Cl
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ncc2c(n1)CCC(=O)C2

Procedure:
A solution of tris(dimethylamino)methane, 25.0 g (172 mmol), in 100 ml toluene is added dropwise, under nitrogen, to a solution of the monoethylene ketal of 1,4-cyclohexanedione, 25.0 g (160 mmol), in 300 ml of toluene. The resulting solution is evaporated in-vacuo and the residue is dissolved in 600 ml of methanol along with 38.72 g (320 mmol) of guanidine carbonate. The pH of the solution is adjusted to 9 with 15% hydrochloric acid and the mixture is refluxed for 16 hours. The solvent is evaporated and the yellow residue is washed with cold water and recrystallized from absolute ethanol to yield 11.0 g of 5,6,7,8-tetrahydro-6-ketoquinazolin-2-amine, ethylene ketal as yellow prisms; mp 214°-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 99.9 %

Procedure:
Using 6-bromonicotinic acid (808 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (765 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.5 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:22](=[O:23])[CH2:21][CH:20]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:19][C:18]1=[O:30].C(N(CC)CC)C>ClCCl>[O:23]=[C:22]1[CH2:21][CH:20]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:19][C:18]([O:30][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[C:17]1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(CC3CCOC3)CC2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(CC3CCOC3)CC2=O)c(C)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of trimethylacetyl chloride (55 mg, 0.457 mmol) in dichloromethane (2 ml) is added dropwise to a solution of 2-(2,4,6-trimethylphenyl)-5-(tetrahydrofuran-3-ylmethyl)-cyclohexane-1,3-dione (120 mg, 0.38 mmol) in dichloromethane (2 ml) and the mixture is cooled in an ice bath and stirred at 0° C. for 2 minutes. A solution of triethylamine (46 mgs, 0.457 mmol) in dichloromethane (1 ml) is added, and once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate solution (3×20 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 2,2-dimethylpropionic acid 3-oxo-5-(tetrahydrofuran-3-ylmethyl)-2-(2,4,6-trimethylphenyl)cyclohex-1-enyl ester as a white solid, m.p. 108-110° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[OH:11][C:5]1[CH:6]=[C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: Sc1ccccc1
Reactant: CC(=O)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1ccc(Sc2ccccc2)cc1O
Temperature: 110 °C
Yield: 101.9 %

Procedure:
To a solution of 4-fluoro-2-hydroxyacetophenone (3.083 g, 20 mmol) in NMP (50 mL) were added thiophenol (2.054 ml, 20 mmol) and K2CO3 (8.293 g, 60 mmol). The reaction was heated at 110° C. overnight. Upon cooling the mixture was poured into water, acidified by addition of HCl (diluted) and extracted with Et2O. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-hydroxy-4-phenylsulfanyl-phenyl)-ethanone (4.980 g of oil) that was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16](=S)[C:15]3[CH:25]=[CH:26][CH:27]=[N:28][C:14]2=3)=[O:12])[CH2:6][CH2:5]1.[C:29](OCC)(=[O:32])[NH:30][NH2:31]>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]3[C:29](=[O:32])[NH:30][N:31]=[C:16]3[C:15]3[CH:25]=[CH:26][CH:27]=[N:28][C:14]2=3)=[O:12])[CH2:6][CH2:5]1
Reactant: CCOC(=O)NN
Reactant: O=C(CN1CCN(CCO)CC1)N1c2ccccc2NC(=S)c2cccnc21
Product: O=C(CN1CCN(CCO)CC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-[[4-(2-hydroxyethyl)-piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]#[N:13].N>[Ni].CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][NH2:13]
Reactant: N#Cc1cc2cccnc2cc1F
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc2cccnc2cc1F
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To 7-fluoroquinoline-6-carbonitrile (1.00 g, 5.813 mmol), methanol saturated with ammonia (13.5 ml) and Raney-Ni (1.27 g) were added and hydrogenated at 50-60 psi for 4 h. The reaction mixture was filtered and concentrated to afford the title compound as a brown oil (0.80 g, 78%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.85 (d, J=2.3 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.06 (d, J=9.5 Hz, 1H), 7.68 (d, J=11.8 Hz, 1H), 7.49 (t, J=3.8 Hz, 1H), 3.92 (s, 2H), 1.90 (br s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:29]([C:30]([O:32]C)=[O:31])=[C:22]2[N:23]=[C:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:21]2=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:29]([C:30]([OH:32])=[O:31])=[C:22]2[N:23]=[C:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:21]2=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:35]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(nc3n2CCC3)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(nc3n2CCC3)c1C(=O)O
Yield: 22.5 %

Procedure:
A mixture of methyl 6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (Intermediate 53, 0.16 g) and lithium hydroxide monohydrate (0.526 g) in dioxane (10 mL) and water (2.5 mL) was irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was azeiotroped with a mixture of toluene and ethanol and the residue was triturated with 20% methanol in DCM and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with DMAW-60. The resultant solid was further purified by HPLC (C18) to give 6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylic acid (0.035 g).
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[C:3]#[N:4].Cl.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.C(=O)(O)[O-].[Na+]>C1C(O)=CC=CC=1C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([N:2]([CH3:1])[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[NH:4])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C#N)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(O)c1
Product: CN(C(=N)Nc1ccccc1-c1ccccc1)c1ccc(OCc2ccccc2)cc1

Procedure:
N-Methyl-4-benzyloxyphenylcyanamide (3.6 g) was added to a suspension of 2-aminobiphenyl hydrochloride (3 g) in m-cresol (8 ml) and the mixture was heated at 90°-95° C. for 3 hours and then added to water. The aqueous layer was basified with solid sodium bicarbonate and extracted with ether. The extract was dried (Na2SO4) and the solvent removed to give a residue which was extracted into boiling hexane to yield N-(4-benzyloxyphenyl)-N'-(2-biphenylyl)-N-methylguanidine.