Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(O)C.[OH-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by stirring a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 4-nitrobenzaldehyde (96 mg, 0.633 mmol), ethanol (5 ml) and saturated NaOH (50 ul) at room temperature for 4 h. The mixture was diluted with ethyl acetate (100 ml), washed with water and saturated NaCl. The crude was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography using hexane:ethyl acetate (4:1, 3:1) to give a yellow solid (33 mg, 12%). 1H NMR (CDCl3): 8.26 (d, J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 7.72 (d, J=16.2 Hz, 1H), 7.61 (d, J=15.6 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.49-4.35 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[Cl:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[F:48]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:44]3[CH:45]=[CH:46][C:47]([F:48])=[C:42]([Cl:41])[CH:43]=3)=[CH:2][CH:32]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(F)c(Cl)c2)cc1
Yield: 81.6 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (0.123 mg, 0.69 mmol) by following general procedure D to afford title compound (89 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]([CH2:21][CH2:22]Br)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:22][CH2:21]2)[CH:6]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCBr
Reactant: Fc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1(n2cc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-fluoropyrazole (125 mg, 1.45 mmol) in tetrahydrofuran (4 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 116 mg, 2.90 mmol). The mixture was stirred at 0° C. for 40 min before benzyl 2,4-dibromobutyrate (0.30 mL, 1.50 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography to afford benzyl 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarboxylate as a clear oil (115 mg, 30.4%). 1H NMR (400 MHz, CDCl3) δ 1.64-1.70 (m, 2H), 1.81-1.86 (m, 2H), 5.14 (s, 2H), 7.22-7.26 (m, 2H), 7.31-7.36 (m, 3H), 7.40 (td, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH2:27][O:28]C)=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].B(Br)(Br)Br>>[CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH2:27][OH:28])=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COCC1c2ccccc2CCN1c1nc(Nc2ccc(F)cc2)nc(C)c1C
Agent: BrB(Br)Br
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2CO)c1C
Yield: 39.6 %

Procedure:
The same procedures as in Example 32 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methoxymethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine(0.4 g, 1.0 mmol) and boron tribromide(1M-dichloromethane solution, 4.0 ml, 4.0 mmol) to afford 150 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[NH2:25][NH2:26]>C(O)(C)C>[CH3:22][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([NH:25][NH2:26])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[C:6]=1[OH:24])([CH3:21])[CH3:23]
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Reactant: NN
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-c2nnc(NN)s2)cc(C(C)(C)C)c1O
Yield: 73.1 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]-phenol (4.1 g, 0.0111 mole) in isopropyl alcohol (30 ml) is added hydrazine (5.0 g, 0.10 mole). The resulting mixture is heated at reflux for four hours. The mixture is cooled and concentrated in vacuo. The residue is dissolved in 1:1 ethyl acetate/ether and washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration in vacuo provides a solid which is recrystallized from ethanol/water to give 2.6 g of 2,6-bis(1,1-dimethylethyl)-4-(5-hydrazino-1,3,4-thiadiazol-2-yl)phenol after drying in vacuo (3.6 g theor., 73%), mp 109°-122° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:11]([OH:15])[C:12](=[NH:14])[OH:13])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[O:17]1CCC[CH2:18]1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:11]2[O:15][C:18](=[O:17])[NH:14][C:12]2=[O:13])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1ccc(Cl)c(C)c1C(O)C(=N)O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(C)c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 27, 1-(3-chloro-6-methoxy-2-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride (1.0 g., 3.4 mmoles) in 50 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-chloro-6-methoxy-2-methylphenyl)oxazolidine-2,4-dione (470 mg. 54%; m.p. 193°-195° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:32]([CH2:36][CH2:37][O:38]C3CCCCO3)[N:33]=[CH:34][CH:35]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[N:32]([CH2:36][CH2:37][OH:38])[N:33]=[CH:34][CH:35]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3CCOC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnn3CCO)c1)=N2

Procedure:
The title compound was prepared from (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-pyrazol-3-yl}-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M69) (237 mg, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (48 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22]Cl)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:39])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22][N:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN(C(=O)CCl)C1Cc2ccccc2C1)OCc1ccccc1
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Yield: 69.5 %

Procedure:
N-Chloroacetyl-N-(indan-2-yl)glycine benzyl ester (3 g) and 2 g of N-benzylglycine ethyl ester are dissolved in 50 ml of methyl ethyl ketone, 10 g of potassium carbonate is added, and the mixture is refluxed for 24 hours with stirring. After cooling, the insoluble matter is filtered off, and the filtrate is distilled under reduced pressure to give an oil. This is purified by silica gel column chromatography to give 3 g of N-ethoxycarbonylmethyl-N-benzylglycyl-N-(indan-2-yl)glycine benzyl ester as an oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([O:33][CH3:34])[CH:20]=3)=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][N:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[C:21]([O:33][CH3:34])[CH:20]=3)=[CH:17][O:18][C:14]=2[C:13]([I:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(-c2coc3ccnc(N)c23)ccc1NC(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
N-Iodosuccinimide (0.333 g, 1.48 mmol) was added to a solution of tert-butyl 4-(4-aminofuro[3,2-c]pyridin-3-yl)-2-methoxyphenylcarbamate (0.439 g, 1.24 mmol) in N,N-dimethylformamide (10 mL) at ambient temperature. The reaction suspension was stirred for 18 hours, at which time no starting material remained. An aqueous solution of 10% sodium thiosulfate (10 mL) was added to the suspension and stirred for 30 minutes. The precipitate was collected by vacuum filtration and washed with water. The solid was dried in vacuo to give the title compound (0.501 g, 84%) as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (s, 1H), 8.07 (s, 1H), 8.06 (s, 1H), 7.85 (d, 1H), 7.13 (d, 1H), 7.04, (dd, 1H), 5.73-5.80 (bs, 2H), 3.86 (s, 3H), 1.48 (s, 9H); RP-HPLC (Conditions d) Rt 8.49 min.; MS: MH+ 482.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH2:17][C:18]([Cl:20])=[O:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:21]=1.[CH2:22]1[O:37][C:36]2[CH:35]=[CH:34][C:26]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:25][C:24]=2[O:23]1>>[ClH:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH2:17][C:18]([N:31]3[CH2:32][CH2:33][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][C:36]5[O:37][CH2:22][O:23][C:24]=5[CH:25]=4)[CH2:29][CH2:30]3)=[O:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:21]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccc(F)cc21
Product: Cl
Product: O=C(CC1(c2ccccc2)C(=O)Oc2ccc(F)cc21)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
This compound was prepared according to the process described in Example 9, starting with 2-(5-fluoro-2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride and 4-(3,4-methyenedioxybenzyl)piperazine.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[Cl:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([C:37]2[N:41]([CH3:42])[CH:40]=[C:39]([CH:43]=[O:44])[CH:38]=2)=[O:36])=[CH:33][CH:32]=1.O>C(Cl)Cl.CCOCC>[Cl:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([C:37]2[N:41]([CH3:42])[CH:40]=[C:39]([CH:43]([OH:44])[C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:6]=3)[CH:38]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cn1cc(C=O)cc1C(=O)c1ccc(Cl)cc1
Agent: CC[Mg]Br
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cn1cc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1C(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 138.9 %

Procedure:
To 4.4 g (0.01 mole) 4-iodo-1-tritylimidazole in 80 mL of CH2Cl2 was added dropwise 3.3 mL of 3.0 M ethylmagnesium bromide in Et2O. After stirring for 1 h, a solution of 1.0 g (0.004 mole) of 5-(4-chlorobenzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde in 10 mL of CH2Cl2 was added dropwise. The resulting reaction mixture was stirred for 2.5 h after which it was poured into water. The solid was filtered off through celite. The organics from the filtrate were separated off, washed with water, brine and dried (Na2SO4). The solvent was evaporated in vacuo to give 3.1 g of (4-chlorophenyl)-{4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-1-methyl-1H-pyrrol-2yl}-methanone: CI-MS m/z=559 (M++H). 1HNMR (CDCl3) δ 7.7 (m, 5H) 7.4-7.0 (m, 16H); 6.5 (m, 1H); 3.75 (s, 3H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH3:20])=[N:17]2)=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH2:20][Cl:1])=[N:17]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc2ccc(Cl)cc2n1

Procedure:
N-Chlorosuccinimide (3.0 g, 22.5 mmol) was added in portions over 1 hour to a stirred solution of 7-chloroquinaldine (3.3 g, 18.5 mmol) and dibenzoyl peroxide (0.1 g) in carbon tetrachloride (100 ml) under reflux. The mixture was heated under reflux for 24 hours adding further N-chlorosuccinimide (0.5 g and 1.0 g) after 3 hours and 20 hours. The mixture was cooled and filtered and the filtrate was extracted with 2M hydrochloric acid (5×40 ml). The extract was basified and re-extracted with dichloromethane and the extract was dried and evaporated to give the product contaminated with 7-chloroqinaldine.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>>[N:17]1[C:18]2[C:13](=[CH:12][C:11]([N:9]3[CH:10]=[C:6]([CH2:4][OH:3])[N:7]=[CH:8]3)=[CH:20][CH:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccc3ncccc3c2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCc1cn(-c2ccc3ncccc3c2)cn1

Procedure:
Following the general method described in example 388, 1-quinolin-6-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with diisobutylaluminum hydride. After hydrolytic workup and chromatography the title compound was obtained as a light brown crystalline solid. Mp. 183-187° C. (AcOEt/hexane), MS: m/e=226 (M+H+).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](OC)(=[O:22])[CH2:20][SH:21].[NH2-].[Li+]>C1(C)C=CC=CC=1>[C:19]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)(=[O:22])[CH2:20][SH:21]
Reactant: COC(=O)CS
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)CS)CC(C)(C)N1OC1CCCCC1

Procedure:
1-Cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol a (25.5 grams, 0.1 mol) and methyl thioglycolate (10.6 grams, 0.11 mol) are dissolved in toluene. Lithium amide (0.09 mol) is added and the reaction mixture is heated under reflux and the distillate collected in a Dean-Stark trap. After heating under reflux overnight, the toluene is removed under reduced pressure. Acetic acid is added to neutralize the basic catalyst. The crude reaction product is purified by liquid chromatography to afford the title compound.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].I[CH2:7][CH2:8][C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:18][C:9]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[CH2:8][CH2:7][C:2]([CH2:7][CH2:8][C:9]([C:10]([F:11])([F:12])[F:13])([F:18])[C:14]([F:17])([F:16])[F:15])([C:1]#[N:5])[C:3]#[N:4]
Reactant: FC(F)(F)C(F)(CCI)C(F)(F)F
Reactant: N#CCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCC(F)(C(F)(F)F)C(F)(F)F)CCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 0.9 %

Procedure:
0.66 g of malononitrile and 9.7 g of 1-iodo-3,4,4,4-tetrafluoro-3-trifluoromethylbutane were dissolved in 10 ml of ethylene glycol dimethyl ether, 4.1 g of potassium carbonate was added, and the mixture was stirred at room temperature for 15 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.04 g of 2,2-bis(3,4,4,4-tetrafluoro-3-trifluoromethylbutyl)malononitrile (hereinafter, referred to as the present compound (56)).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:3]1.[Li+].[OH-]>O1CCCC1>[CH3:1][C:2]1([CH3:31])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccccc2)CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCN(c2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 8.7 mg (0.02 mmol) of ethyl 4-(2-(4,4-dimethyl-1,2,3,4-tetrahydro-N-phenylquinolin-7-yl)ethynyl)benzoate (Compound 9) in 1.0 mL in tetrahydrofuran was added 0.5 mL (0.1 mmol) of 0.2M aqueous LiOH. The resulting solution was stirred at room temperature for 20 hours. The mixture was then concentrated in vacuo. Water was added, and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound as a yellow solid. PNMR (300 MHz, DMSO) d 1.31 (6 H, s), 1.81 (2 H, t, J=5.9 Hz), 3.58 (2 H, t, J=5.9 Hz), 6.61 (1 H, s), 6.87 (1 H, d, J=8.0 Hz), 7.19 (1 H, t, J=7.1 Hz), 7.26-7.33(3 H, m), 7.43 (2 H, t, J=7.1 Hz), 7.55 (2 H, d, J=8.2 Hz), 7.89 (2 H, d, J=8.2 Hz).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[C:3](/[C:7]#[N:8])\[C:4]([NH2:6])=[S:5].CO.OO>C(Cl)(Cl)Cl>[NH2:6][C:4]1[S:5][N:1]=[C:2]([CH3:9])[C:3]=1[C:7]#[N:8]
Reactant: C/C(N)=C(\C#N)C(N)=S
Agent: OO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nsc(N)c1C#N
Reaction time: 0.5 h

Procedure:
A 3 liter multi-neck flask was equipped with dropping funnel, air stirrer, thermometer and condenser. To the flask was charged 3-amino-2-cyanothiocrotonamide 1 (40 g, 0.283 mole) and methanol (2 liters). A dark, almost homogeneous solution resulted. Hydrogen peroxide (80 ml, 100 vol, 0.7 mole) was then added dropwise over a period of 10 minutes. On completion of the addition the reaction mixture was slowly heated to reflux over a period of 30 mins and refluxing continued for 30 mins. TLC indicated complete reaction (silica, CHCl3). The hot solution was treated with activated carbon and then filtered through kieselguhr. The filtrates were then concentrated by evaporation to a volume of about 300 ml. The concentrated slurry was poured into ice-water (1400-1500 g) and the resultant product filtered-off, washed with water (2×150 ml), pulled as dry as possible on the filter and finally dried in a vacuum oven at 55° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[OH:14][CH2:13][C:12]([NH:11][S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Yield: 77.2 %

Procedure:
Prepared by general procedure III from commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and 2-amino-2-methyl-1-propanol (1.23 g, 13.8 mmol) to give the title compound (0.96 g, 77%) as a white solid. MS (ISN) 268.1 [(M−H)−], mp 112° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C@H:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9][C@@H:10]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:8])[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[Cl:29][CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[O:32].C(OCC)C>C(OCC)(=O)C>[Cl-:29].[S:1]1[CH:5]=[C:4]([C@H:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9][C@@H:10]2[CH:15]3[CH2:16][CH2:17][N+:12]([CH2:30][C:31](=[O:32])[C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)([CH2:13][CH2:14]3)[CH2:11]2)=[O:8])[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@@H](Nc1ccccc1)c1csc2ccccc12
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@@H](Nc1ccccc1)c1csc3ccccc13)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of (S)—((R)-quinuclidin-3-yl) 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (diastereomer 2 of C19) (62 mg, 0.16 mmol) in ethyl acetate (3 ml), was added 2-chloro-1-(thiophen-2-yl)ethanone (25.4 mg, 0.16 mmol), and the reaction mixture was stirred at r.t. overnight. Diethyl ether (10 ml) was added, and the precipitate was filtered and dried under vacuum to obtain (R)-3-((S)-2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (75 mg, 86% yield).
Reaction SMILES: [ClH:1].[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CC(O)=[O:14].O>[Zn]>[CH3:3][CH:2]([OH:14])[CH3:11].[ClH:1].[CH2:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: CC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: c1ccc2c(c1)CCCC2
Solvent: O
Product: CC(C)O
Reaction time: 0.08 h

Procedure:
To 7-nitro-2-((phenylmethyl)(methyl)amino)-(1,2,3,4-tetrahydronaphthalene hydrochloride (0.89 g, 2.7 mmol) in 85% AcOH/H2O (75 ml) was added zinc metal (3.5 g, 54.0 mmol). The mixture was stirred for 5 min, filtered through celite, and evaporated to an oil. The oil was dumped into basic water and extracted with chloroform (3×20 ml). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated to an oil. Treatment with IPA/HCl yielded 7-amino-2-((phenyl)methyl)(methyl)amino)-1,2,3,4-tetrahydronaphthalene: (0.81 g, 88%); MS. (M+H)+ =267.