Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26]4/[C:27](=[O:32])[N:28]=[C:29]([NH2:31])[S:30]/4)[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl>[NH2:31][C:29]1[S:30]/[C:26](=[CH:25]\[C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[C:15]3[O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)/[C:27](=[O:32])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(/C=C4\SC(N)=NC4=O)cc23)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1=NC(=O)/C(=C/c2ccc3nccc(OC4CCNCC4)c3c2)S1

Procedure:
The suspension of 4-{6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.15 mmol) in dichloromethane (1 ml) was treated with hydrogen chloride (in 1,4-dioxane, 4M, 1 ml) for 1.5 hr at room temperature. After removing the solvent, the obtained solid was treated with either. Ion exchange extraction chromatography (Cation exchanger: benenesulfonic acid, 2 g/6 ml, 1M ammonia in methanol and dichloromethane) afforded the free base form of 2-Amino-5-[1-[4-(piperidin-4-yloxy)-quinolin-6-yl]-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 355 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[C:13]([OH:26])[CH:12]=1.[CH3:27][NH:28][CH2:29][CH:30]=[CH2:31].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:29]([N:28]([CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[C:13]([OH:26])[CH:12]=1)[CH:30]=[CH2:31]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(OCCCCCCCCBr)cc1O
Reactant: C=CCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C)CCCCCCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Yield: 43.2 %

Procedure:
To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1,3-dimethoxybenzene (788.5 mg, 5.8 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide a 1:1 mixture of(4-chlorophenyl)(2-hydroxy-4-methoxyphenyl)methanone and (4-chlorophenyl)(2,4-dimethoxyphenyl)methanone. Purification by silica gel chromatography provided methoxyphenyl)methanone (650 mg, 2.5 mmol) and (4-chlorophenyl)(2,4-dimethoxyphenyl)methanone(700 mg, 2.5 mmol). The combined molecules (2.7 g) were dissolved in AcOH (50 mL) and 49% HBr (50 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. Without purification this was subjected to alkylation with 1,8-dibromooctane (4.0 g, 14.7 mmol) and K2CO3 (2.0 g, 14.7 mmol) in DMF (50 mL). After 12 h the reaction mixture was diluted with water (150 mL) and the water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone(1.9 g, 4.4 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone (1.9 g, 4.4 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (938.1 mg, 13.2 mmol) and NaHCO3 (13.2 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone (1.8 g, 1.9 mmol); 1H-NMR (300 MHz, CDCl3) 12.6 ppm (s, 1H) , 7.64 (d, J=9.6 Hz, 2H), 7.60-7.48 (m, 3H), 6.59 ( s, 1H), 6.45 (d, J=9.6 Hz, 1H), 6.05-5.84 (m, 1H), 5.39-5.12 (m, 2H), 4.05 (t, J=7.7 Hz, 2H), 3.21-2.99 (m, 2H), 2.51-2.11 (m, 7H), 1.92-1.80 (m, 2H), 1.79-1.21(m, 8H); 13C-NMR (75 MHz, CDCl3) 196.3 ppm, 162.5, 138.1, 137.8, 134.2, 132.3, 131.7, 128.5, 110.9, 101.8, 68,8, 60.4, 57.0. 43.8, 29.6, 29.3, 27.3, 28.1; ESI-MS calcd for C25H33ClNO3 [M+H+]: 430.2. found 430.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1cccnc1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[CH2:22]([O:21][C:19]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=3)=[S:33])=[CH:3][CH:4]=2)[CH:18]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cc(Sc2ccc(N)cc2)nc2ccccc12
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: CCOC(=O)c1cc(Sc2ccc(NC(=S)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc2ccccc12
Yield: 89 %

Procedure:
2-(4-aminophenylthio)-4-ethoxycarbonylquinoline (6.0 moles, 2.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (6.0 mmoles, 1.4 g) were reacted according to procedure C to yield 3.0 g, 89% of the title compound. Mass Spec (FD) 561. Calculated for C26H19ClF3N3O2S2 : C, 55.56; H, 3.41; N, 7.48. Found: C, 55.38 H, 3.38; N, 7.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:15])([CH3:14])[NH:12][C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH3:15])([CH3:14])[N:12]([CH3:37])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)N(C)C2(C)C)cc1
Reaction time: 4 h
Yield: 30.8 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (150 mg, 0.35 mmol) in DMF (10 mL) were added NaH (15 mg, 0.7 mmol) and CH3I (100 mg, 0.7 mmol) at 0° C. under an inert atmosphere. The mixture was then stirred for 4 h, diluted with cold water and filtered. The resulting residue was dried to afford 4-(4-methoxyphenyl)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (50 mg, 37%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.04 (d, J=7.2 Hz, 1 H), 8.02-7.98 (m, 2 H), 7.81-7.78 (m, 1 H), 7.62-7.58 (m, 2 H), 7.31-7.28 (m, 2 H), 7.19-7.16 (m, 2 H), 6.99-6.84 (m, 4 H), 5.36 (s, 2 H), 3.89 (s, 3 H), 2.96 (s, 3 H), 1.24 (s, 6 H). MS: M+H: m/z=465.2; M+Na: m/z=487.2. HPLC: 92%, (Condition-I).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Cl[CH2:16][CH:17]([OH:28])[CH2:18][N:19]([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:27][N:19]([CH2:18][CH:17]([OH:28])[CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(Cc1ccccc1)CC(O)CCl
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 3 h
Yield: 22.6 %

Procedure:
To a solution of 6-hydroxycarbostyril (1.6 g) and sodium hydride (50% oily) (1 g) in dimethylformamide (30 ml), 1-chloro-2-hydroxy-3-(N-methyl-N-benzylamino)propane (2.2 g) is added dropwise at room temperature. After the addition, the mixture is heated with stirring at 70°-80° C. for 3 hours. The reaction mixture is poured into water and extracted with chloroform, and the extract is dried over magnesium sulfate. Chloroform is distilled off and the resulting residue is purified by silica gel column chromatography (solvent; methanol:chloroform=1:100-1:25) and recrystallized from ethanol to give 6-[3-(N-methyl-N-benzylamino)-2-hydroxypropoxy]carbostyril (0.76 g), as white powder, m.p. 129°-132° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH2:1]([NH:3][C:4]([NH:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[CH3:2]
Reactant: CCN=C=S
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CCNC(=S)NCc1ccccc1
Yield: 94.4 %

Procedure:
To a mixture of 1.74 grams (0.02 mole) of ethyl isothiocyanate and 25 milliliters of benzene was added 2.14 grams (0.02 mole) of benzylamine. The temperature rose from 25° C. to 41° C. The reaction mixture was then refluxed on a steam bath for about 20 minutes to bring the reaction to completion. The mixture was evaporated under vacuum to give 3.67 grams of 1-ethyl-3-benzyl thiourea.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Cl:15])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][SH:27].O>CN(C)C=O>[Cl:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][S:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: CN(C)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25° C., poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil is crystallized from toluene-hexanes (3:1) to yield a pale yellow crystalline solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:30]1C[CH2:33][CH2:32][CH2:31]1.C(Cl)(=O)C=C>CCOCC>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:13][CH2:14]1)(=[O:30])[CH:32]=[CH2:33]
Reactant: OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 3.5 g of 1-[trans-4-(7-hydroxyheptyl)cyclohexyl]-2,3-difluorobenzene, 1.3 g of triethylamine, and 45 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.1 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Ether was added to the reaction mixture. An ether layer was washed with water and dried over anhydrous sodium sulfate. A solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=3/7 to 4/6) and recrystallized from hexane to obtain 2.23 g of 1-[trans-4-(7-propenoyloxyheptyl)cyclohexyl]-2,3-difluorobenzene (Y: 54%). The compound thus obtained had a purity of 99.6% by GC, 99.5% by HPLC, and of 1 spot by TLC. Furthermore, the compound had an m.p. of 34.0° C. to 35.3° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][N:11]2[N:10]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:17][C:14]1[CH:15]=[CH:16][N:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[N:18]=[C:12]2[CH:13]=1
Reactant: COc1ccccc1-c1nc2cc(N)ccn2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccn2nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (2.3 g, 9.6 mmol) (Example 102, step c) in DCM (60 ml) was added a solution of BBr3 (1 M in DCM, 28.7 ml, 28.7 mmol). The mixture was allowed to warm up to 25° C. and stirring was continued for 2 h. Volatiles were removed under reduced pressure and the crude residue was extracted with DCM and washed with aq. NaHCO3 solution. The organic layer was washed with brine, dried over Na2SO4 and concentrated to get the crude product which was washed with 10% DCM in hexane to afford the title compound as off-white solid (1.3 g, 60%). LC-MS: m/z=227.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=1[NH2:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:19]([C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])[C:18]1[C:17]([F:20])=[CH:16][N:15]=[CH:14][C:13]=1[F:12])=[O:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1c(F)cncc1F
Solvent: c1ccncc1
Product: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1c(F)cncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
2,6-Dichlorobenzoyl chloride (13.7 mL, 95.6 mmol) was added dropwise, over 10 minutes, to a solution of 3,5-difluoropyridin-4-ylamine (10.37 g, 79.7 mmol) in pyridine (160 mL) at a temperature of between 3 and 5° C., under argon. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the resultant residue was treated with HCl (1N, 120 mL). The resultant suspension was stirred at room temperature for 45 minutes and the precipitate was collected by filtration, washing with water. A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide and of 2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-benzamide (22.0 g) was obtained. A suspension of this mixture (22.0 g) in 1N NaOH (200 mL) and MeOH (200 mL) was heated at 65° C. for 7 hours then slowly cooled to room temperature. The pH of the mixture was adjusted to 4-5 by dropwise addition of 12N HCl, controlling the exotherm by the use of an ice-bath. The residue was left standing at room temperature for 18 hours and then the resultant solid was collected by filtration, washing with water, to afford the title compound as an off-white solid (14.65 g, 61% yield over two steps). LCMS (Method D): RT=2.93 min, m/z: 303 [M+H+].
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.N([O-])=O.[Na+].[F:29]B(F)F.F>O>[F:29][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Reactant: FB(F)F
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(F)cc1N[C@H]1CCCC[C@@H]1N1CCCC1

Procedure:
Ethyl 4-amino-2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoate was allowed to react with sodium nitrite (NaNO2) and trifluoroborane-hydrogen fluoride complex (BF3.HF) in water at 10° C. for 10 minutes. By post-treating the reaction liquid, ethyl 4-fluoro-2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoate was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13]>C(#N)C>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.4 %

Procedure:
41.3 g of 4-nitrophenylhydrazine and 33 g of phthalide were dissolved in 330 ml of acetonitrile. The solution was heated under reflux with stirring over 4 hours. The reaction solution was allowed to stand for cooling to room temperature. The resulting solid was then filtered off, and recrystallized from acetonitrile to obtain 15.1 g of 1-(2'-hydroxymethylbenzoyl)-2-(4-nitrophenyl) hydrazine (yield of 21.0%).
Reaction SMILES: C(C1C=C(OC)C(F)=C(C=1)C=O)C.[CH2:14]([O:16][C:17]1[C:18]([F:29])=[C:19]([CH:25]([OH:28])[C:26]#[N:27])[CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=1)C>>[CH2:23]([C:21]1[CH:22]=[C:17]([O:16][CH3:14])[C:18]([F:29])=[C:19]([CH:25]([OH:28])[C:26]#[N:27])[CH:20]=1)[CH3:24]
Reactant: CCOc1cc(CC)cc(C(O)C#N)c1F
Agent: CCc1cc(C=O)c(F)c(OC)c1
Product: CCc1cc(OC)c(F)c(C(O)C#N)c1

Procedure:
119B was prepared from 119A using a procedure similar to that used in the preparation of 118E. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.47 Hz, 3H) 2.64 (q, J=7.62 Hz, 2H) 3.89 (s, 3H) 5.76 (s, 1H) 6.86 (dd, J=7.91, 2.20 Hz, 1H) 6.98 (dd, J=5.93, 1.98 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Cl-].[Na+]>O1CCCC1>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
0.230 g of sodium hydride (60%) is suspended in 6 ml of tetrahydrofurane under nitrogen at −30° C. 1.01 g of (E)-3-(1H-pyrrol-3-yl)acrylic acid tert-butyl ester (compound D1) are added to the suspension and warmed slowly to room temperature and stirred for 30 minutes. Afterwards it is recooled to −30° C. and 1.19 g of p-toluenesulfonylchloride are added and stirred for 2.5 hours. The suspension is warmed slowly at room temperature and 40 ml of saturated aqueous sodium chloride solution are added. The mixture is extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate (Na2SO4). Afterwards it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of hexane-ethyl acetate from 9:1 to 1:1 to give 1.60 g of the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[Cl:33]>C(OCCO)C>[Cl:33][C:27]1[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3Cl)c2cc1OC
Yield: 84.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 270.1 mg (1.5 mmol) of 4-amino-3-chlorophenol to give 299.2 mg (84.3%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 355.8, 357.8.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([C:22](OCC)=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].O>C1(C)C=CC=CC=1.O1CCCC1>[OH:11][CH2:10][C:9]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]([CH:27]([CH3:28])[CH3:29])=[C:7]([CH2:22][OH:23])[C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.8 ml (80 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 4.6 g (11.4 mmol) of the compound from Example 3 in 100 ml of dry tetrahydrofuran at -10° C. to -5° C. The mixture is stirred overnight at room temperature and then warmed to 40° C. for 5 h. After cooling again to 0° C., 100 ml of water are cautiously added dropwise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ 3.5 cm, using ethyl acetate/petroleum ether (6:4)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:83]1[CH2:88][CH2:87][O:86][CH2:85][CH2:84]1>CN(C=O)C.[Pd]>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:83]3[CH2:88][CH2:87][O:86][CH2:85][CH2:84]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH:14]=1
Reactant: O=C(c1cccnc1)c1cc(F)c(F)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccnc1)c1cc(F)c(F)cc1NS(=O)(=O)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4,5-difluoro-2-(pyridine-3 -carbonyl)-phenyl]-benzenesulfonamide 0.2 g (0.44 mmol), potassium phosphate tribasic monohydrate 0.607 g (2.64 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.082 g (0.06 mmol), morpholine 0.30 g (2.2 mmol) and Pd (dba)3 0.06 g (0.06 mmol) in 2 ml DMF. HPLC purification gave yellow title compound.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([N:6]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:8][C:7]1=[O:14])=[O:5].[CH2:15]([N:22]([CH2:26][Si](C)(C)C)[CH2:23]OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:23][C@@H:2]([CH3:1])[C@H:3]([C:4]([N:6]2[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:8][C:7]2=[O:14])=[O:5])[CH2:26]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1C(C)C
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Yield: 90.8 %

Procedure:
3-(trans-3-Methyl-2-propenoyl)-4-(S)-isopropyl-2-oxazolidinone (197 mg, 1.00 mmol, Aldrich) was reacted with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (238 mg, 1.00 mmol) according to the procedure of Example 1d, to afford the title compound (300 mg). The diasteromers were separated as in Example 1d, and the (3R,4R)-isomer was taken to the next step. MS m/z 331 (M+H)+. The (3S,4S)-isomer was taken to Example 4. MS m/z 331 (M+H)+.