Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[C:1]1(=[O:19])[N:5]([CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH2:22])=[O:8])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C(N)=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-phthalimido-4-methylpentanoic acid (1.32 g, 5.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (0.81 g, 5.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 1 hour, then 1 mL of concentrated ammonium hydroxide is added. After 10 minutes, the reaction mixture is diluted with 50 mL water. The resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C., <1 mm) to afford 1.16 g (89%) of 2-phthalimido-4-methylpentanamide as a white powder: mp 173°-176° C.; 1H NMR (dmso-d6, 250 MHz) δ 7.95-7.79 (m, 4 H, Ar), 7.61 (br s, 1 H, CONH2), 7.22 (br s, 1 H, CONH2), 4.73- 4.60 (m, 1 H ), 2.30-2.10 (m, 1 H), 1.95-1.80 (m, 1H), 1.45-1.25 (m, 1H); 13C NMR (dmso-d6) δ: 170.4, 167.7, 134.4, 131.5, 123.1, 51.3, 36.4, 24.7, 23.2, 20.6. Anal. Calculated for C14H16N2O3. Theoretical: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.63; H, 6.11; N, 10.70.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:16]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 25 g (100.8 mmol) of 3-iodobenzoic acid in 250 mL of methanol under argon was added 1.2 mL (23.2 mmol) of concentrated H2SO4 and the mixture was heated to reflux for 24 h. The solution was concentrated to 150 mL, gravity filtered to remove any insoluble material, scratched with a glass rod, and allowed to cool slowly. After cooling to RT the flask was allowed to stand in the refrigerator for a few days. The solid was collected and washed with ice cold methanol and dried under high vacuum at RT for 2 days to provide 25.7 g (97%) of a light violet colored solid. mp 40°-41° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of veratrole (16.6 g, 0.120 mol) in tetrahydrofuran (130 mL) at −78° C. was added n-butyllithium (50.5 mL, of a 2.5 M solution in hexane, 0.126 mmol). The resulting mixture was allowed to warm to ambient temperature over 1 hour and then stirred at this temperature for 4 hours before recooling to −78° C. and treating the resulting slurry with a solution of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (30.71 g, 0.1128 mol) in tetrahydrofuran (180 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight and then recooled to 0° C. and quenched by the addition of saturated aqueous ammonium chloride solution (110 mL). The aqueous layer was extracted with ether (110 mL) and the combined organic extracts were washed with brine (220 mL), dried (MgSO4) and concentrated in vacuum to give the title compound (7).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[N:12][C:11]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:5][CH:4]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].Cl.C(N(CC)CC)C>CN1CCCC1=O.ClCCl>[F:16][C:14]1[CH:13]=[N:12][C:11]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:10]([CH:15]=1)[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[N:28]=[N:29][NH:30][N:2]=2)=[CH:27][CH:26]=1)=[O:25]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(F)cnc1Oc1ccc(F)cc1
Temperature: 150 °C
Yield: 51 %

Procedure:
To a solution of N-(4-cyanobenzyl)-5-fluoro-2-(4-fluorophenoxy)nicotinamide (step 1, 220 mg, 0.60 mmol) in 1-methyl-pyrrolidin-2-one (5 mL) were added sodium azide (117 mg, 1.8 mmol) and triethylamine hydrochloride (248 mg, 1.8 mmol) at room temperature. This mixture was heated at 150° C. for 18 h. The reaction mixture was diluted with dichloromethane (100 mL), and the solution was washed with saturated sodium dihydrogenphosphate solution (50 mL). The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography on silica gel (50 g) eluting with dichloromethane/methanol/acetic acid (100/5/0.5) to give off white solids. The solids were triturated with ethyl acetate to afford 125 mg (50%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 9.18 (1H, t, J=5.8 Hz), 8.14 (1H, d, J=2.8 Hz), 7.99 (1H, dd, J=8.2, 2.8 Hz), 7.90 (2H, d, J=8.2 Hz), 7.51 (2H, d, J=8.2 Hz), 7.22–7.15 (4H, m), 4.56 (2H, d, J=5.8 Hz); MS (ESI) m/z 409 (M+H)+, 407 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][CH2:13][C@H:14]([NH:21][C:22](=[O:44])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)[CH:24]=1)[C:15](=[O:20])[NH:16][CH2:17][CH2:18][OH:19])(C)(C)C>>[OH:12][CH2:13][C@H:14]([NH:21][C:22](=[O:44])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:42])([F:43])[F:41])=[CH:35][CH:34]=2)[CH:24]=1)[C:15](=[O:20])[NH:16][CH2:17][CH2:18][OH:19]
Reactant: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N[C@@H](CO)C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
Trifluoroacetic acid (1 mL) was added to 20 mg of N-[(S)-2-t-butoxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzamide and the mixture was stirred for 20 minutes at room temperature. After removal of the solvent, the resulting residue was purified using a micromass spectrometer (ZMD produced by Micromass) equipped with a gradient high-performance liquid chromatograph 996-600E produced by Waters. The resulting solid was dried under reduced pressure to obtain 9 mg (57%) of N-[(S)-2-hydroxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:41])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:40])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[C:30]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][C:32](=[O:33])[C:31]=1[CH3:39])\[CH3:27])\[CH3:22].Cl([O-])(=O)=[O:43].[Na+]>C(Cl)(Cl)Cl.O.II>[CH3:39][C:31]1[C:32](=[O:33])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=1/[CH:29]=[CH:28]/[C:26](/[CH3:27])=[CH:25]/[CH:24]=[CH:23]/[C:21](/[CH3:22])=[CH:20]/[CH:19]=[CH:18]/[CH:17]=[C:16](\[CH3:40])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:41])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][C:7](=[O:43])[C:2]=1[CH3:1]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1
Agent: II
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Temperature: -20 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
100 mg of echinenone are dissolved in 10 ml of chloroform under a nitrogen atmosphere and are oxidized with 100 mg of sodium chlorate in 1 ml of water after having added 2 mg of iodine dissolved in 1 ml of chloroform. After stirring for 24 hours at -20° C., 67 mg of canthaxanthin having an all-trans content of 81% are obtained.
Reaction SMILES: OC(CC)[C:3]([O:5][CH2:6]CCl)=[O:4].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].[C:17](C1C=CC=CC=1)(C)(C)[CH3:18]>C(OCC)C>[OH:13][CH:12]([CH2:17][CH3:18])[C:11]([O:15][CH2:16][C:3]([O:5][CH3:6])=[O:4])=[O:14]
Reactant: CC(C)(C)c1ccccc1
Reactant: COC(=O)CO
Reactant: CCC(O)C(=O)OCCCl
Solvent: CCOCC
Product: CCC(O)C(=O)OCC(=O)OC

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25M 2-chloroethyl 2-hydroxybutyrate, 0.25M methyl glycolate, and 0.125% tert-butylbenzene was added to 0.43 g Lipase AK. After mixing for 48 hr at room temperature, the conversion of 2-chloroethyl 2-hydroxybutyrate to the title compound was estimated (by GC, Method A) to be 43%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C6H8O5Tms (M-CH3) 233.0845, obsd 233.0878. In identical reactions substituting Lipase P30, Lipase G, or porcine pancreatic lipase for Lipase AK, the relative values for conversions at 48 hr (Lipase AK=100) were 81, 71, and 48, respectively.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:53])[CH2:49][C:50](Cl)=[O:51].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:50](=[O:51])[CH2:49][CH:48]([CH3:53])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 2.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.400 g, 0.66 mmol) in pyridine (4 mL) was added 3-methylbutanoyl chloride (0.100 mL, 0.80 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.43 (s, 1H), 10.08 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.69 (t, 3H), 7.49 (t, 1H), 2.24 (d, 2H), 2.18 (m, 1H), 0.96 (d, 6H); ES-MS (m/z) 361 [M+1]+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].Cl.O.CCOCC>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
Dissolve 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.47 g.) in hot methanol (25 cc.). Add 3N hydrochloric acid (15 cc.) and keep the mixture at 70° C. under nitrogen for 1 hour. Add water and work up with ether and chromatograph the resulting gum on activated alumina (40 g.). Elute with ether to give a fraction (0.2 g.) which on recrystallization from light petroleum gives 13β-ethyl-17β-hydroxy-gon-4-en-3-one; m.p. 153-5° C; ultra-violet absorption peak at 240 mμ (ε 16,300).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23](OC(C)(C)C)=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:30][C:31]1[CH:32]=[N:33]C(Cl)=[N:35][CH:36]=1.CCN(C(C)C)C(C)C>CCO>[Br:30][C:31]1[CH:36]=[N:35][C:23]([N:19]2[CH2:20][CH2:21][O:22][C@H:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:33][CH:32]=1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(C(=O)OC(C)(C)C)CCO4)c3n2)cn1
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reaction time: 9 h
Yield: 74.8 %

Procedure:
(S)-tert-butyl 2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine-4-carboxylate (16.4 g, 54.69 mmol) was dissolved in EtOH (500 ml), and 5-bromo-2-chloropyrimidine (12.7 g, 65.62 mmol) and DIPEA (47.6 g, 273.45 mmol) were added, followed by 50° C. for 9 hours. After the completion of the reaction, the reaction mixture was recrystallized with EtOH to give (S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (18.7 g, 75%).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:40])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[CH:15]=1>C(O)C>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[C:16]3[CH:15]=[C:14]([C:13](=[O:40])[NH:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=4)[CH:19]=[CH:18][C:17]=3[N:20]=[C:21]2[CH3:22])=[CH:27][CH:28]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 89.8 %

Procedure:
Four milliliters of acetic acid and 8 ml of ethanol were added to 0.434 g of N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide, and the mixture was stirred at 90° C. for 7 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and ether were added to the residue for crystallization. The crystals were separated through filtration, and were dried to give 0.375 g of 1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (242).
Reaction SMILES: [CH2:1]1[S:10](=[O:12])(=[O:11])[NH:9][CH2:8][CH:7]2[CH2:13][CH2:14][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].CN(C=O)C.[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24]([CH2:23][N:9]1[CH2:8][CH:7]2[CH2:13][CH2:14][C:2]([C:4]2([CH3:6])[CH3:5])([CH3:3])[CH2:1][S:10]1(=[O:12])=[O:11])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC12CCC(CNS(=O)(=O)C1)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC2CCC(C)(CS1(=O)=O)C2(C)C
Reaction time: 8 h

Procedure:
Camphorsultam (3 g, 14 mmole) in DMF (25 mol) was mixed with NaH (1.1 equiv.) for 15 minutes, then tert-butyl bromoacetate (2.5 ml) was added and the reaction mixture was stirred overnight. The solvent was evaporated to dryness and the residue was partitioned between aq-citric acid and EtoAc. The organic layer was washed with sat. aq. NaHCO3, and water, dried and evaporated to give the ester. (3.5 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH:9]1[CH2:20][N:21]([C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:20][N:21]([C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)C(F)(F)F)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
695 mg of tert-butyl {[4-(2-fluorophenyl)-1-(trifluoroacetyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was dissolved in 5 mL of THF-2 mL of methanol, and 1 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and chloroform was added to the obtained residue, followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 636 mg of a colorless foamy substance of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH:9]=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:9][NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNCCc1cccs1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCc1cccs1
Temperature: 7 °C
Reaction time: 0.17 h
Yield: 31.3 %

Procedure:
At 7° C., a solution of N-(2-(2-thienyl)ethyl)formamide (9,98 g, 63.8 mmol) in tetrahydrofuran (200 ml) was added to a suspension of sodium borohydride (2.89 g, 76.5 mmol) in tetrahydrofuran (200 ml). The mixture was stirred for 10 min. A solution of iodine (8.09 g, 31.9 mmol) in tetrahydrofuran (200 ml) was added dropwise. The reaction mixture was stirred for 30 min at 7° C. and 30 min at room temperature. It was heated to reflux for 16 h. The reaction mixture was cooled to 7° C. Methanol (500 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in 20% aqueous sodium hydroxide solution (500 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×200 ml). The combined organic layers were dried over magensium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (220 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 2.82 g of N-methyl-N-(2-(2-thienyl)ethyl)amine.
Reaction SMILES: N1C=CC=C1.COC(O)[C:9]([F:12])([F:11])[F:10].Cl.[CH:15]1[CH:19]=[C:18]([CH2:20][C:21]2[NH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH:16]=1>O1CCCC1>[NH:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:20]([C:18]1[NH:17][CH:16]=[CH:15][CH:19]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: c1c[nH]c(Cc2ccc[nH]2)c1
Reactant: COC(O)C(F)(F)F
Agent: Cl
Solvent: c1cc[nH]c1
Solvent: C1CCOC1
Product: FC(F)(F)C(c1ccc[nH]1)c1ccc[nH]1

Procedure:
Pyrrole (150 mmol) and trifluoroacetaldehyde methyl hemiacetal (75 mmol) in tetrahydrofuran are heated at reflux with catalytic amounts of hydrochloric acid for 2 hours under an inert atmosphere. GC analysis of the reaction mixture indicated the presence of the desired dipyrromethane in greater than 80% yield. Neutralization of the acid followed by work up and chromatography gave the pure bis(pyrrol-2-yl)-trifluoromethylmethane 3 (R3 =CF3)). MS:m/z=214. This preparation has been disclosed in Wijesekera U.S. patent application Ser. No. 08/143,261 filed on Oct. 26, 1993.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:38](=O)[CH3:39])OC(=O)C)(=O)C.[Na+].[C:42](O)(=O)C>ClC(Cl)C.CC(C)=O.ClCCl>[CH:38]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=3[Cl:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:39])[CH3:42]
Reactant: CC(=O)O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCN(C(C)C)C(c4ccccc4)C3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in a 2:1 mixture of dichloroethane and acetone, 2 equiv. of sodium triacetoxyborohydride would be added followed by 30 μL of acetic acid. The reaction would be stirred at room temperature under nitrogen overnight. The reaction would be diluted with 5 mL of dichloromethane. The reaction mixture would be washed with 1M aqueous sodium hydroxide solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].N#N.[CH2:17]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][NH2:22])[CH3:18].[OH:30][P:31]([OH:34])([OH:33])=[O:32].C>C1COCC1.CCO>[P:31]([OH:34])([OH:33])([OH:32])=[O:30].[CH2:17]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][NH:22][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1)[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCN(CC)CCN
Agent: N#N
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
Dissolve 5.66 g (0.024 moles) 4-[(methylsulfonyl)amino]benzoyl chloride in 40 ml THF. Chill the solution on an ice/MeOH bath under a stream of N2. Add dropwise 4.5 g (0.024 moles) N-ethyl-N-heptyl-1,2-ethanediamine to the room temperature for about 24 hours. Follow the progress of the reaction by thin layer chromatography on silica gel (Acetonitrile:MeOH:Ammonia, 85:10:5). At the completion of the reaction, remove the solvents in vacuo. Dissolve the resulting oil in 10% K2CO3 solution and extract with 5×100 ml Et2O. Dry the organics over Na2SO4. Evaporate the solvents to provide an oil. Crude wt: 3.38 g. Dissolve the oil in 25 ml EtOH and acidify with 1.02 g 85% H3PO4. Treat the solution with activated charcoal, filter and evaporate the solvents to provide the title compound. Recrystallize the product from EtOH/Et2O.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14][C:13]2([CH3:25])[CH3:24].O>ClCCl>[C:5]([C:18]1[CH:19]=[C:10]([Br:9])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14][C:13]2([CH3:24])[CH3:25])(=[O:7])[CH3:6]
Reactant: CCC1(CC)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC1(CC)CC(C)(C)c2cc(Br)cc(C(C)=O)c2O1
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
A stirred, cooled (ice bath) suspension of aluminum chloride (1.1 g, 8.38 mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl chloride (0.6 mL, 8.38 mmol). After 5 minutes, a solution of 6-bromo-2,2-diethyl-4,4-dimethyl chroman (Intermediate 25, 1.66 g, 5.59 mmol) in dichloromethane was added. The reaction mixture was stirred for 1 h. The reaction mixture was then poured into water and extracted with diethyl ether (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.6 g, 84%).