Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@H:11]2[O:17][C@@H:16]([CH3:18])[C@:14](C(=O)C)([OH:15])[C@:12]2(C(=O)C)[OH:13])[C:9]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:8]=2[N:7]=1.C(O)C>CN(C=O)C>[CH:1]([NH:4][C:6]1[N:10]([C@H:11]2[O:17][C@@H:16]([CH3:18])[C@H:14]([OH:15])[C@@H:12]2[OH:13])[C:9]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)[C@@]1(O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)O[C@@H](C)[C@@]1(O)C(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](C)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Isopropylamine (5 mL) and 2-bromo-5,6-dichloro-1-(5-deoxy-2,3-diacetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.40 g, 0.86 mmol) were combined with absolute ethanol (20 mL) and stirred at 80° C. for 24 h. The reaction mixture was concentrated and purified by multiple cyclings on a chromatotron fitted with a 2 mm silica gel rotor, with 1:30 methanol:dichloromethane and 1:1 ethyl acetate:hexanes and 1:4 acetone:dichloromethane to give a white solid (0.18 g, 0.70, mmol, 60%); m.p. 103-105° C.; [α]20D=(+) 38.8 (c=0.5 DMF); UV λmax (ε): pH 7.0:303 nm (10,400), 276 (2,500), 260 (10,000); MS (CI): m/z (rel. intensity) 360 (14.26, M−); 1H NMR (DMSO-d6) d 7.39 (s, 1H, Ar—H), 7.31 (s, 1H, Ar—H), 6.57 (d, 1H, NH, J=7.6 Hz), 5.68 (d, 1H, H-1′, J=6.6 Hz), 5.23 (d, 1H, OH, J=4.8 Hz), 5.21 (d, 1H, OH, J=7.1 Hz), 4.31 (q, 1H, H-4′; J=6.7 Hz), 4.04-3.98 (m, 1H, isopropyl-CH), 3.95-3.87 (m, 1H), 3.81-3.76 (m, 1H), 1.36 (d, 3H, H-5′, J=6.5 Hz), 1.20 (d, 6H, cyclopentyl-CH2, J=6.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNC[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 21, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and (R)-(+)-β-methylphenethylamine.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C@H:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:23][C@H:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
371 mg of Z-Sta-OH (cf. stage 1.12), 240 mg of H-Ala-OC(CH3)3 and 184 mg of HOBt×H2O are dissolved in 10 ml of DMF. After cooling the solution to 0°, 133 mg of N-methylmorpholine and 321 mg of DCCI are added. The whole is stirred for 1 hour at 0° and for 14 hours at 25°, then the DCH formed is filtered off and the filtrate is concentrated to dryness by evaporation. The residue is taken up in ethyl acetate and the solution is extracted with saturated sodium bicarbonate solution. The organic phases are dried, concentrated by evaporation and the residue is flash-chromatographed over 80 g of silica gel (grain size 0.04-0.063 mm) [eluant: methylene chloride/ether (4:1), fractions of approximately 25 ml]. Fractions 24-40 are combined, concentrated by evaporation, the residue is dissolved in a small amount of methylene chloride, and the solution is filtered and concentrated by evaporation once more. After drying the residue in a high vacuum, Z-Sta-Ala-OC(CH3)3 is obtained as a slightly yellowish oil; Rf (methylene chloride/diethyl ether [4:1])=0.10.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.FC(F)(F)C(O)=O.CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl>[F:31][C:30]([F:32])([F:33])[C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:17]1[CH2:18][CH:2]2[C:1](=[O:6])[CH2:5][CH2:4][CH:3]2[CH2:16]1
Reactant: COCN(Cc1cccc(C(F)(F)F)c1)C[Si](C)(C)C
Reactant: O=C1C=CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12

Procedure:
Cyclopent-2-enone (3.31 g, 40.4 mmol) and trifluoroacetic acid (0.031 mL, 0.404 mmol) were combined in dichloromethane (40 mL). 1-Methoxy-N-(3-(trifluoromethyl)benzyl)-N-((trimethylsilyl)methyl)methanamine (12.33 g, 40.4 mmol) from Step B was added as a solution in 10 mL of dichloromethane dropwise via addition funnel over 45 minutes at room temperature under nitrogen. The reaction was quenched with aqueous sodium bicarbonate and extracted with 2×100 mL of dichloromethane. The organic washes were combined and washed with brine. The solvent was removed in vacuo to give 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one: 1H NMR (300 MHz, CDCl3) δ ppm 7.54-7.34 (m, 4H), 3.66 (d, J=13.4, 1H), 3.52 (d, J=13.4, 1H), 3.04 (dd, J=1.8, 8.9, 1H), 2.91 (ddd, J=2.8, 7.4, 11.7, 1H), 2.72-2.65 (m, 1H), 2.62 (d, J=8.9, 1H), 2.52-2.23 (m, 4H), 2.15 (ddd, J=8.1, 12.9, 17.1, 1H), 1.85-1.70 (m, 1H).
Reaction SMILES: [CH3:1][C:2]12[CH2:25][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:27])([CH3:26])[CH2:3]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[N:58]1([C:22]([CH:19]2[CH2:20][CH2:21][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([N:7]4[CH2:27][C:4]5([CH3:26])[CH2:5][CH:6]4[CH2:25][C:2]([CH3:1])([CH3:8])[CH2:3]5)=[O:10])=[CH:16][CH:15]=3)[CH2:18]2)=[O:23])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1
Reactant: C1COCCN1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N3CCC(C(=O)O)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N3CCC(C(=O)N4CCOCC4)C3)cc2)C1
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of 1-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid (300 mg, 0.81 mmol, prepared as described in ex-ample 1) and HOBT (131 mg, 0.97 mmol) in dry THF (20 ml) was added EDAC (186 mg, 0.97 mmol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (219 μl, 1.22 mmol) and morpholine (85 μl, 0.97 mmol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. The resulting residue was purified by preparative HPLC (Gilson) and pure fractions were collected and evaporated to dryness and dried in vacuo at 50° C. affording 250 mg (70%) of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>>[CH3:25][C:21]1[N:22]=[CH:23][NH:24][C:20]=1[CH2:19][S:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOc1cc(Cl)nc2ccccc12
Product: CCOc1cc(NCCSCc2[nH]cnc2C)nc2ccccc12
Yield: 30.3 %

Procedure:
2-Chloro-4-ethoxyquinoline (3.72 gms) and 5-(2-aminoethyl)thiomethyl-4-methylimidazole (3.1 g.) were heated together at 150°-160° C (oil-bath temperature) for 3 hours. The residue, on cooling, was washed with water and dried. Purification was effected by column chromatography (silica gel column, ethyl acetate-5% methanol eluant) and crystallisation from acetone to give 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline (1.86 gms) m.p. 152.5°-153.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[N+](C1C=CC([O:24][C:25]([O:27][CH2:28][C:29]2[O:33][N:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=2)=O)=CC=1)([O-])=O>>[CH2:37]([O:36][C:34]([C:31]1[CH:30]=[C:29]([CH2:28][O:27][C:25]([NH:1][CH2:2][C:3]2([F:16])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]2)=[O:24])[O:33][N:32]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Product: CCOC(=O)c1cc(COC(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)on1
Yield: 25.5 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.70 g (3.01 mmol) of tert-butyl 4-aminomethyl-4-fluoropiperidine-1-carboxylate (commercial) and 1.11 g (3.31 mmol) of ethyl 5-(4-nitrophenoxycarbonyloxymethyl)isoxazole-3-carboxylate, obtained in step 14.1., 0.33 g of pure product is obtained in the form of an orange-coloured oil.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([C:11]1[CH:15]=[C:14]([NH2:16])[N:13]([CH2:17][CH3:18])[N:12]=1)([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].C(N(CC)C(C)C)(C)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:7]([C:11]1[CH:15]=[C:14]([NH:16][C:35](=[O:36])[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:13]([CH2:17][CH3:18])[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCn1nc(C(C)(C)C)cc1N
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 76.8 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-ethyl-1H-pyrazol-5-amine oxalate (350 mg, 1.36 mmol), potassium carbonate (280 mg, 2 mmol) and N,N-diisopropylethylamine (170 mg, 1.3 mmol) in dichloromethane (3 mL) at rt, was added dropwise, phenyl chloroformate (220 mg, 1.4 mmol) and the reaction mixture was stirred for a further 3 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford phenyl 3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (300 mg, 77%) as a colorless solid. LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=O.C=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C1(=O)CCCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: C=Cc1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O=C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C=Cc2ccccc2)cc(OC)c1OC
Yield: 17.5 %

Procedure:
The procedure described in Example 1 is followed, except that 23.07 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride, 13.02 g (0.125 mol) of styrene, 12.93 g (0.125 mol) of ethyl diisopropylamine and 0.3046 g (0.001 mol) of bis-(acetylacetonato)-palladium(II) are used. After a reaction time of 3 hours at 130° C., in 50 ml of cyclohexanone as the solvent, 4.7 g (0.0175 mol) of 3,4,5-trimethoxystilbene, corresponding to a yield of 17.5% of theory, are obtained in the form of white needles; melting point 108° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[Li]CCCC.[B:22]([O:31]C(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[C:13]([S:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][C:7]=1[O:23][B:22]([OH:31])[OH:27])(=[O:12])=[O:11])([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1ccc(NS(=O)(=O)C(C)(C)C)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(NS(=O)(=O)C(C)(C)C)c(OB(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-ethylphenyl-t-butylsulfonamide (6.44 g, 26.7 mmoL) in anhydrous THF (60 mL) cooled to -20° C. under N2 was added 2.5M n-BuLi solution (27 mL, 2.5 equiv). The mixture was warmed to rt and stirred for 2 h. To the mixture, containing the bright orange dianion at 0° C., was added B(OiPr)3 (9.3 mL, 1.5 equiv). The reaction was allowed to warm to rt and stirred overnight. The next day 2N HCl (3 mL) was added and the mixture was stirred for 1 h. The solvent was removed under reduced pressure and the residue was extracted with EtOAc. The organic was washed with 2N HCl, H2O and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. Rf=0.5 (1:1 EtOAc/Hex). The material was used in subsequent steps without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:42]=[CH:41][N:8]([C@@H:9]2[O:40][C@H:14]([CH2:15][O:16][C:17]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:7](=[O:43])[N:6]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:53]([CH2:55][CH2:56][O:57][CH2:58]Cl)#[N:54].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:42]=[CH:41][N:8]([C@@H:9]2[O:40][C@H:14]([CH2:15][O:16][C:17]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C@@H:12]([OH:13])[C@H:10]2[O:11][CH2:58][O:57][CH2:56][CH2:55][C:53]#[N:54])[C:7](=[O:43])[N:6]=1)(=[O:3])[CH3:2]
Reactant: N#CCCOCCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 32.7 %

Procedure:
N4-Acetyl-5′-O-(4,4′-dimethoxytrityl)cytidine (588 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added thereto, and then 365 mg of dibutylstannyl dichloride (1.2 mmol) was further added. The reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was added into an aqueous saturated sodium bicarbonate solution, and was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N4-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) cytidine (219 mg, yield 35%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][I:13]>CO>[I-:13].[CH3:12][N+:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CI
Reactant: C1CCC(N2CCCC2)CC1
Solvent: CO
Product: C[N+]1(C2CCCCC2)CCCC1
Product: [I-]
Reaction time: 8 h
Yield: 86 %

Procedure:
N-cyclohexylpyrrolidine prepared in Example 1 (1 molar equivalent) was dissolved in methanol to 0.5M concentration in a three neck reaction flask equipped with a mechanical stirrer and reflux condenser. To the methanolic solution of cyclohexylpyrrolidine, 2 molar equivalents of methyl iodide were added, and the resulting mixture was left to stir overnight. The mixture was heated to reflux and left to stir at reflux for 4 hours. The reaction was cooled down and left to stir overnight. The reaction was complete. The reaction mixture was concentrated on a rotary evaporator. The resulting tan-colored solids were dissolved in isopropyl alcohol and then precipitated out from solution by adding diethyl ether. The precipitate was filtered out and dried on a rotary evaporator at reduced pressure and in hot water bath at 80° C. to give the desired N-methyl-N-cyclohexylpyrrolidinium iodide in 86% yield. N-Methyl-N-cyclohexylpyrrolidinium iodide was converted to the hydroxide by ion-exchanging the iodide ion with hydroxide ion. In a polyethylene plastic bottle, N-methyl-N-cyclohexylpyrrolidinium iodide salt was dissolved in deionized water (1 mmol salt/10 ml H2O). Then Bio-Rad AG 1-X8 resin (1.1 g resin/mmol salt) was added and the slurry-like mixture was gently stirred overnight. The exchange solution was then filtered and a small aliquot was titrated with 0.1N HCl to give 92% yield of the N-methyl-N-cyclohexylpyrrolidinium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([NH:17][NH2:18])=[O:16])=[C:12]([CH3:14])[N:13]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C>[OH:19][C:20]1[CH:21]=[C:22]([CH:23]=[N:18][NH:17][C:15]([C:11]2[S:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:13][C:12]=2[CH3:14])=[O:16])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(C=O)cc1O
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)sc1C(=O)NN
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2sc(-c3ccc(Cl)cc3Cl)nc2C)cc1O
Yield: 85.6 %

Procedure:
In ethanol (5 ml), 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acid hydrazide (34 mg) and 3-hydroxy-4-methoxybenzaldehyde (19 mg) was heated under reflux for 25 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration to give the title compound (42 mg, 86%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1CCOCC1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and benzyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13](C2C=CC=CC=2N)=[CH:12][C:11]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[O:9][C:39]1[C:40]([CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[C:41]([CH2:7][CH2:8][CH2:28][CH2:29][CH3:30])[C:42]([NH:37][C:32](=[O:33])[O:34][CH2:35][CH3:36])=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:38]=1[CH2:12][CH2:11][CH2:10][CH2:15][CH3:14])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:1]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:37][C:32](=[O:33])[O:34][CH2:35][CH3:36])=[CH:12][C:11]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)Cl
Reactant: CCCCCc1cccc(Oc2ccc(-c3ccccc3N)cc2CCCCC)c1
Reactant: c1ccncc1
Product: CCCCCc1cccc(Oc2c(CCCCC)c(CCCCC)c(NC(=O)OCC)c(CCCCC)c2CCCCC)c1
Product: CCCCCc1cccc(Oc2ccc(NC(=O)OCC)cc2CCCCC)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
[4-(3-Pentylphenoxy)-3-pentylphenyl]benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(3-pentylphenoxy)-3-pentylphenyl]carbamate.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1CCCC1.[Br:34][C:35]1[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[CH:37][C:36]=1[CH2:43]Br>CC1CCCO1.O>[Br:34][C:35]1[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[CH:37][C:36]=1[CH2:43][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CC(C)n1ncc(CBr)c1Br
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cnn(C(C)C)c2Br)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (14.5 g, 56.3 mmol) in 2-methyl tetrahydrofuran (120 mL) was added, dropwise, 1 M LiHMDS in tetrahydrofuran (57 mL, 56.3 mmol) at −78° C. under argon. After 20 min, 5-bromo-4-(bromomethyl)-1-isopropyl-1H-pyrazole (12.2 g, 43.3 mmol) in 2-methyltetrahydrofuran (10 mL) was added. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water (200 mL) and the mixture was separated. The organic phase was washed with 10% citric acid solution (2×100 mL), then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by flash column chromatography (10-30% ethyl acetate in heptane) to give 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (9.3 g). Also isolated from the column was a 7.1 g mixed fraction of starting ester and desired product. This was stirred with 1 equivalent of sodium hydroxide in 90% ethanol/methanol for 2 hours at room temperature. The solvent was removed in vacuo and ethyl acetate (100 mL) was added. The mixture was washed with 2 N sodium hydroxide (2×50 mL) and then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give a second crop of 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (5.1 g). The combined yield is 14.4 g (72%). +ESI (M+H) 404.0; 1H NMR (400 MHz, CDCl3, δ): 4.62 (m, 1H), 4.12 (q, 2H), 3.90 (br. s., 2H), 2.82 (m, 2H), 2.63 (s, 2H), 2.08 (d, 2H), 1.66 (m, 2H), 1.42 (s, 9H), 1.21 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])[CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7](=[O:14])[NH:6][N:5]=1.O[Li].O>O1CCCC1.O>[CH3:1][CH:2]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])[CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7](=[O:14])[NH:6][N:5]=1
Reactant: COC(=O)c1cccc(C(C)Cc2n[nH]c(=O)c3c2CCCC3)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1n[nH]c(=O)c2c1CCCC2)c1cccc(C(=O)O)c1

Procedure:
A solution of EXAMPLE 266 (50 mg, 0.16 mmol) in tetrahydrofuran (10 ml) was treated with a solution of LiOH.H2O (100 mg, 4 mmol) in water (4 ml) at 50° C. overnight. The mixture was concentrated, and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 313 (M+H)+.