Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH:7]=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([O:18]C)=[O:17])[CH:2]=1.[OH-].[K+].C(O)C.O1CCOCC1>O>[CH:1]1[C:6]2[CH:7]=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([OH:18])=[O:17])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1N=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 269 mg. (1 mmole) of the ester of Example 9 to a solution of 132 mg. (2 mmole) of 85% aqueous potassium hydroxide in a mixture of 6.5 ml. of ethanol, 0.65 ml. of dioxane and 1.3 ml. of water. Stir at room temperature for 2 hours. Filter and evaporate the solution to a small volume. Dilute with 9 ml. of water and acidify with acetic acid. Filter wash the solids with water and dry. Dissolve the product in 9 ml. of hot tetrahydrofuran, filter and dilute with 9 ml. of methanol. Evaporate to a thick slurry, dilute with 2 ml. of methanol, filter and wash with methanol. Dry to obtain the title product, (m.p. sinters 289° C., m.p. 290°-291° C. dec.).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([O:48]CC)=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:25]1>>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([OH:48])=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:25]1
Reactant: CCOC(=O)c1sc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)O
Yield: 86 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(2-(1H-indol-3-yl)ethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 86% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.20 (s, 1H), 7.09-695 (m, 2H), 3.98 (t, J=6.0 Hz, 2H), 3.61-3.50 (m, 4H), 2.94 (t, J=6.0 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([N+:18]([O-])=O)[CH2:14][CH:13]=1)[C:6](=[O:10])[CH:7]([Cl:9])[Cl:8].Cl.[OH-].[NH4+]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([NH2:18])[CH2:16][CH:17]=1)[C:6](=[O:10])[CH:7]([Cl:8])[Cl:9]
Reactant: COCCN(CC1=CCC(Oc2ccccc2)([N+](=O)[O-])C=C1)C(=O)C(Cl)Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCN(CC1=CCC(N)(Oc2ccccc2)C=C1)C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
23 ml of a 15% solution of TiCl3 was added to 1.6 g of N-(β-methoxy-ethyl)-N-[4-phenoxy-(4'-nitro)-benzyl]-dichloroacetamide, in 30 ml of acetone; the pH was then adjusted to 3 with 23% HCl. The resulting mixture was stirred at room temperature for 24 hours and then, with cooling, brought to pH 9 with concentrated ammonium hydroxide. The resulting precipitate was removed by filtration and washed with water. The filtrated was extracted several times with chloroform. The combined organic extract was then dried on Na2SO4 and evaporated to dryness to give 1.2 g of N-(β-methoxy-ethyl)-N-[4-phenoxy-(4'-amino)-benzyl]-dichloroacetamide, m.p. 100°-102° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:35][CH:36]=5)=[CH:26][CH:27]=4)[CH2:22]C[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB(C2C=CC3C4C(=CC(B5OC(C)(C)C(C)(C)O5)=CC=4)C(=O)C=3C=2)[O:51]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[N:35][CH:36]=5)=[CH:26][CH:27]=4)[C:22](=[O:51])[C:30]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(=O)c2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1

Procedure:
Followed the procedure used to prepare compound 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 2,7-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-fluoren-9-one was used instead of 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane. m/z 650.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.O.[OH:22]P([O-])(O)=O.[Na+].OO.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>CC#N.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:22])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2F)cc1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 6-fluoro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde (106.0 mg, 0.39 mmol) in MeCN (5 mL) and water (3 mL) was added sodium phosphate monobasic hydrate (12.3 mg, 0.087 mmol), 25% hydrogen peroxide (56.3 mg, 0.41 mmol) and sodium chlorite (44.5 mg, 0.39 mmol). The reaction mixture was stirred for one hour at room temperature and additional MeCN (5 mL) and sodium chlorite (44.5 mg, 0.39 mmol) were added. The reaction mixture was heated to 50° C. for one hour, cooled to room temperature and stirred for another 16 hours. The reaction was quenched with sodium sulfite (405.0 mg, 3.15 mmol) and acidified with 3 N HCl (1 mL). The reaction solution was partially concentrated in vacuo, and extracted with EtOAc (10 mL). The organic layer was concentrated in vacuo and purified by reverse phase HPLC (Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 80:20 A:B linear to 40:60 A:B in 8.5 min to 100% B to 9.0 min, hold at 100% B from 9.0 to 10.0 min. Flow: 25 mL/min) to give the title compound (6.8 mg, 6% yield). MS (ES+) 286.2 (M+1)+. Retention time=2.73 minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:25][CH3:26])[C:10](=[O:24])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[C:16](=[O:23])[C:12]3=2)[C:7]1=[O:27].[H][H]>[Pd].C(O)C>[F:31][C:30]1[CH:2]=[CH:3][C:4]([CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([O:25][CH3:26])[C:10](=[O:24])[N:11]4[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[C:16](=[O:23])[C:12]4=3)[C:7]2=[O:27])=[CH:28][CH:29]=1
Reactant: COc1c2c(c3n(c1=O)CCCCN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c2c(c3n(c1=O)CCCCN(C)C3=O)CCN(Cc1ccc(F)cc1)C2=O

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (52 mg, 0.12 mmol) and 10% palladium on charcoal (70 mg) in ethanol (6 mL) was stirred at room temperature under a balloon of hydrogen overnight. The reaction mixture was filtered and concentrated under vacuum. ES MS M+1=480
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][C:30]=1[CH3:31])[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[CH3:31][C:30]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:15][N:14]=2)=[CH:4][C:3]=1[OH:2]
Reactant: COc1cc2c(cc1C)-c1noc(-c3noc(-c4ccccc4)c3C(F)(F)F)c1CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(cc1O)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a stirred solution of 7-methoxy-8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 64B, 0.130 g, 0.305 mmol) in dichloromethane (5 mL) at 0° C. was added boron tribromide (1.52 mL, 1.52 mmol). The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between dichloromethane (25 mL) and water (25 mL). The dichloromethane extract was washed with a saturated aqueous solution of sodium bicarbonate (2×25 mL), washed with brine, dried over sodium sulfate, and concentrated. This crude product was filtered through a short silica gel pad, and the filtrate was concentrated to give 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (0.121 g, 0.293 mmol, 96%) as a tan solid. The product had an HPLC ret. time=4.08 min (condition B). LC/MS M+1=413.30.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19]>C1C(O)=CC=CC=1C>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)=[NH:19]
Reactant: CN(C)C#N
Reactant: Cc1cccc(-c2ccccc2N)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(-c2ccccc2NC(=N)N(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-3'-methylbiphenyl hydrochloride (1 g), N,N-dimethylcyanamide (0.67 ml) in m-cresol (1 ml) was heated at 100° C. for 3 hours to give N,N-dimethyl-N'-(3'-methyl-2-biphenylyl)guanidine (m.p. 116° C.) which was crystallised from hexane.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Br[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (200 mg) in N,N-dimethylformamide (5 mL) is added tert-butyl 2-bromoethylcarbamate (270 mg) and Cs2CO3 (810 mg). The mixture is stirred for 20 hours at room temperature. tert-Butyl 2-bromoethylcarbamate (110 mg) and Cs2CO3 (325 mg) are added and the mixture is stirred for 4 hours. Again tert-butyl 2-bromoethylcarbamate (110 mg) and Cs2CO3 (325 mg) are added and the mixture is stirred for 12 hours. The mixture is partitioned between water and diethylether. The organic phase is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20) to give the title compound. Yield: 320 mg; LC (method 8): tR=0.66 min; Mass spectrum (ESI+): m/z=344 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:16]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:25]([O:29][C:30](=[O:42])[NH:31][C:32]1([C:40]#[CH:41])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.O>[C:25]([O:29][C:30](=[O:42])[NH:31][C:32]1([C:40]#[C:41][C:2]2[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:16]=2)[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCCCCCOc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Compound 34-3 (10.5 g), (2,2-dimethyl-5-ethynyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (6.46 g) synthesized by a known method (for example, Tetrahedron vol. 57 (2001) 6531-6538), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (725 mg), bis(acetonitrile)palladium(II) dichloride (131 mg) and cesium carbonate (21.4 g) in acetonitrile (150 ml) was stirred at 80° C. for 12 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object (11.7 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=O.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>>[OH:15][C:14]1[N:1]=[C:2]2[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]2=[CH:9][C:13]=1[C:11]#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: Cc1nn(C)c(N)c1C=O
Product: Cc1nn(C)c2nc(O)c(C#N)cc12
Temperature: 25 °C

Procedure:
A solution of 5-amino-1,3-dimethylpyrazole-4-carbaldehyde (6.15 g) in ethyl cyanoacetate (10 mL) was stirred at 185° C. for 3 hrs. The reaction mixture was allowed to cool to room temperature. The precipitated solid was filtered, washed with ethyl acetate, and dried under high vacuum to give 6-hydroxy-1,3-dimethylpyrazolo-[5,4-b]pyridin-5-carbonitrile as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:27][C:28](=O)OCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].CC(O)C.Cl>C1COCC1.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[NH:27][CH3:28]
Reactant: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1cc(F)cc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1cc(F)cc(Cl)c1
Reaction time: 8 h

Procedure:
The synthesis was performed starting from ethyl 1-(3-chloro-5-fluorobenzyl)-7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (synthesized in analogy to example 3), which was dissolved in THF (50 ml), after which LiAlH4 was added at room temperature and the mixture was stirred for 8 h under reflux. Addition of 2N aqueous NaOH, extraction with CH2Cl2, washing of the organic layers with saturated NaHCO3 solution and saturated NaCl solution and evaporation of the solvent gave a residue that was treated with iPrOH/HCl after which the product precipitated. After filtration a white salt (134 mg, 39%) was obtained.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[O:7])CCC.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:21])[CH3:22])[CH:12]=2)=[O:7]
Reactant: COCCN
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O
Product: COCCNC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-methoxy-ethylamine in analogy to example B-5; MS-(−)-ion: M−1=337.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 590.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=2)[CH2:15][CH:16](O)[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:42])CC)C>ClCCl>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][CH:16]([F:42])[C:17]([F:18])([F:19])[F:20])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:32])[F:33])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Solvent: ClCCl
Product: FC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol (474 mg, 0.00094 mol) in 4.5 mL of dichloromethane at 0° C. was added (diethylamino)sulfur trifluoride (378 mg, 0.0023 mol). The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with water and extracted with dichloromethane. The organic layers were combined, dried over MgSO4, and concentrated in vacuio. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 240 mg (50%) of the desired N-(3-phenoxyphenyl)-N-(3,3,3,2-tetra-fluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine product as a yellow oil. HRMS calcd. for C24H19F8NO2: 506.1366 [M+H]+, found: 506.1368. 1H NMR (CDCl3) 67 7.26 (m, 3H), 7.20 (m, 5H), 6.87 (d, 2H), 6.62 (d, 1H), 6.50 (s, 1H), 6.49 (d, 1H), 5.87 (t, 1H), 4-89 (d, 1H), 4.77-4.52 (m, 1H), 4.73 (d, 1H), 4.60 (s, 2H). 19F NMR (CDCl3) δ −69.83 (t, 3F), −88.63 (s, 2F), −137.19 (dt, 2F), −228.82 (1F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:27]=[CH:26][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]([NH:28][OH:29])=[NH:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: NO
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 57) (355 mg, 1 mmol) in EtOH (60 mL) was added at 23° C. over 6 h 50% aqueous hydroxylamine solution (3.48 mL, 60 mmol) in 6 portions. The mixture was cooled in the ice-bath, diluted with H2O (100 mL) and stirred for 1 h. The precipitate was collected by filtration, washed with water and Et2O, and triturated with ethyl acetate to give the title compound as light yellow solid (336 mg).
Reaction SMILES: [N:1]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=[N:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14](C=O)[CH2:13][CH2:12]1.Cl>C(O)C>[N:11]1([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]3[N:1]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=CN1CCN(c2nc3cccccc-3n2)CC1
Agent: Cl
Solvent: CCO
Product: c1ccc2nc(N3CCNCC3)nc-2cc1
Reaction time: 18 h

Procedure:
A solution of 4-(cycloheptimidazol-2-yl)-1-piperazinecarboxaldehyde (38 g) in a solution of 500 ml of 2 N hydrogen chloride in ethanol was refluxed for 6 hr and allowed to stand at room temperature for 18 hr. The precipitate was collected and dried to give the title compound as the hydrochloride salt (31 g): mp>280° C. and nmr (DMSO-d6) δ 3.37 (t, 4H), 4.3 (t, 4H), 8.4 (m, 5H) and 10.0 (s, 2H).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[ClH:30].[ClH:1].[Cl:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[S:22][C:23]=2[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 4N solution of hydrochloric acid-dioxane was added 4-(6-chlorobenzothiazole-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.50 g; 4.239 mmol). The mixture was stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was washed with ethyl acetate to give 4-(6-chlorobenzothiazole-2-yl)piperazine dihydrochloride as colorless crystal (1.40 g; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](C(F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.C1(N=C=O)CCCCC1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: O=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NC1CCCCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol), diisopropyl(ethyl)amine (125 mg, 0.97 mmol), and cyclohexyl isocyanate (121 mg, 0.97 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.