Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[F:22][C:23]([F:29])([F:28])[S:24](O)(=[O:26])=[O:25]>C1(C)C=CC=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:26])=[O:25]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser, a calcium chloride tube and a stirrer, 190.0 g (0.904 moles) of dimethyl 5-hydroxyisophthalate, 3 liters of dehydrated toluene and 214.7 g (2.718 moles) of dehydrated pyridine were placed and the resultant mixture was cooled at −30° C. under stirring. To the cooled mixture, 510.2 g (1.808 moles) of anhydrous trifluoromethanesulfonic acid was slowly added dropwise with sufficient care so that the temperature did not exceed −25° C. It took 1 hour to complete the addition. After the addition was completed, the temperature of the reaction was elevated at 0° C. and the reaction was allowed to proceed for 1 hour. Then, the temperature was elevated to the room temperature and the reaction was allowed to proceed for 5 hours. The obtained reaction mixture was poured into 4 liters of ice water and separated into an aqueous layer and an organic layer. The aqueous layer was treated twice by extraction with 500 ml of toluene and the extract was combined with the organic layer. The obtained organic layer was washed twice with 3 liters of water and dried with 100 g of anhydrous magnesium sulfate. From the resultant mixture, anhydrous magnesium sulfate was removed by filtration and toluene was removed by distillation using a rotary evaporator. After drying under a reduced pressure, 294.0 g of dimethyl 5-trifluoromethanesulfonyloxyisophthalate was obtained as a light yellow solid substance (the yield: 95%). The crude product obtained above was recrystallized from hexane and white needle crystals were obtained. The obtained crystals were used for the next reaction.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:18]1>>[CH3:30][C:28]1[CH:27]=[CH:26][C:25]([C:31]([F:34])([F:32])[F:33])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][C@@H:17]([NH:16][C:2]3[CH:11]=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=4)[N:3]=3)[CH2:18]2)=[O:23])[CH:29]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)cnc2c1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3cnc4cc(C(F)(F)F)ccc4n3)C2)c1

Procedure:
In analogy to the procedure described for example 200, the title compound was prepared from 2-chloro-6-trifluoromethyl-quinoxaline and ((R)-3-amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13). (M+H+) 469.2.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH:31]([CH3:34])[C:32]#[N:33]>>[C:32]([CH:31]([CH3:34])[N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:28])=[O:27])#[N:33]
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: CC(Br)C#N
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1C(C)C#N)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 2-bromo-propionitrile. MS: ESI (negative): 408 (M−H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH2:14][C:15]1[CH:41]=[CH:40][C:18](/[CH:19]=[CH:20]/[C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:22]=2)=[CH:17][CH:16]=1)[CH3:13]>>[CH3:11][N:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[CH:20][C:21]2[C:29]3[C:24](=[CH:25][C:26](/[CH:30]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:27][CH:28]=3)[N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:39])[CH3:37])[N:22]=2)=[CH:40][CH:41]=1)[CH3:13]
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)Cc1ccc(/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)cc1
Product: CN(C)Cc1ccc(C=Cc2nn(COCC[Si](C)(C)C)c3cc(/C=C4/C(=O)Nc5ccccc54)ccc23)cc1

Procedure:
Synthesized according to the method of Example A19, utilizing indolin-2-one (10.4 mg, 0.0.78 mmol) and (E)-3-(4-((dimethylamino)methyl)styryl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazole-6-carbaldehyde (33.4 mg, 0.077 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a 1.5-2.0:1.0 (E:Z) mixture of isomers: a yellow solid (29.1 mg, 67%): 1H NMR (400 MHz, CD3OD) δ ppm 9.09-9.14 (s, 0.31H), 8.22 (d, J=8.28 Hz, 0.84H), 8.09 (d, J=8.53 Hz, 0.34H), 7.83-7.87 (m, 1.25H), 7.61-7.69 (m, 4.02H), 7.56-7.60 (m, 1.69H), 7.50 (s, 0.61H), 7.36-7.48 (m, 3.85H), 7.24 (t, J=7.78 Hz, 1.48H), 7.03 (t, J=7.28 Hz, 0.48H), 6.92 (d, J=7.53 Hz, 1.01H), 6.81-6.89 (m, 1.49H), 5.80 (s, 0.60H), 5.78 (s, 1.52H), 3.59-3.65 (m, 2.20H), 2.37-2.42 (m, 7.40H), 0.89 (t, J=8.28 Hz, 3.05H), −0.09 (s, 9H); MS ESI 551.4 [M+H]+, calcd for [C33H38N4O2Si+H]+ 551.8.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[CH2:33]([NH:40][C:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:20])[O:3][C:2]2([CH3:21])[CH3:1])[CH:13]=[N:14][CH:15]=1)=[O:19])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.100 g, 0.349 mmol) (Example 23) is dissolved in dichloromethane (2 mL). Catalytic amount of dimethylformamide (0.002 mL, 0.0262 mmol) is added to the reaction mixture and cooled to 0° C. Oxalyl chloride (0.076 mL, 0.874 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 2 h and then concentrated in vacuo. The residue obtained is redissolved in dichloromethane and benzylamine (0.114 mL, 1.04 mmol) is added. Reaction mixture is stirred at room temperature for 1 h. The mixture is washed with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichlormethane-methanol, 19:1) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid benzylamide; MS (ESI) m/z 376.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.24 (s, 3 H), 1.53 (s, 3 H), 4.62 (s, 2 H), 6.98 (s, 1 H), 7.26-7.35 (m, 1 H), 7.35-7.46 (m, 5 H), 7.57 (d, J=7.6 Hz, 1 H), 7.64-7.73 (m, 2 H), 7.74-7.84 (m, 1 H), 8.26 (dd, J=7.8, 1.5 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][OH:11])[CH2:5]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>CCCCCCC.C1COCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:11][CH2:10][C@@H:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]3)=[O:26])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: CN1CCC[C@@H](CO)C1
Reactant: Cc1ccc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1ccc(N2CCN(C(=O)OC[C@@H]3CCCN(C)C3)CC2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
Sodium hydride (0.70 g, 60% dispersion in mineral oil, 17.5 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of (R)-(1-methylpiperidin-3-yl)methanol (0.75 g, 5.83 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (Intermediate 1; 2.19 g, 6.42 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with sat aq NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-25%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 min, filtered and concentrated in vacuo. The residue was further purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give [(3R)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate (619 mg, 32%) as a pale brown solid.
Reaction SMILES: NN.[NH2:3][C:4]1[C:5]([N+:31]([O-:33])=[O:32])=[CH:6][C:7]2[C:13](=[O:14])[N:12]([C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][N:21]4S(C)(=O)=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10][N:9]([CH2:28][CH3:29])[C:8]=2[CH:30]=1>C1COCC1.CO>[NH2:3][C:4]1[C:5]([N+:31]([O-:33])=[O:32])=[CH:6][C:7]2[C:13](=[O:14])[N:12]([C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][NH:21]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10][N:9]([CH2:28][CH3:29])[C:8]=2[CH:30]=1
Reactant: CCN1CCN(c2ccc3cnn(S(C)(=O)=O)c3c2)C(=O)c2cc([N+](=O)[O-])c(N)cc21
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc3cn[nH]c3c2)C(=O)c2cc([N+](=O)[O-])c(N)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Hydrazine (0.6 mL) was added to a solution of 8-amino-1-ethyl-4-(1-methanesulfonyl-1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (1.1 g, 2.5 mmol) in 1:1 THF/MeOH (20 mL). The solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 8-amino-1-ethyl-4-(1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one (815 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][Cl:6])[O:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24][C:22](=[O:23])[C@H:18]([CH:19]([CH3:21])[CH3:20])[NH:17][C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)COC(=O)OCCl
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Chloromethyl chloroformate (1.50 mL, 16.6 mmol) was added to a solution of the alcohol (2.74 g, 8.12 mmol) from step (a) and pyridine (4.9 mL, 61 mmol) in 40 mL dry CH2Cl2, in an ice bath. After stirring for 1 h, the mixture was diluted with CH2Cl2 and washed successively with water, saturated NaHCO3, and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated, coevaporating several times with toluene on a rotavapor. Flash column chromatography (silica, 2/1 petroleum ether—ethyl acetate) gave 3.31 g (95%) of the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH3-]C#N.[Na+].N>C(O)C.C(O)(=O)C>[CH:15]1([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC1CC1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
1 g (5 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate is dissolved in 40 mL of ethanol with 10% of acetic acid. 0.28 mL (4.2 mmol) of cyclopropylamine is added. After 30 minutes, 0.53 g (36 mmol) of NaBH3CN is added and the reaction medium is stirred for one hour at room temperature. The reaction is stopped by addition of aqueous ammonia solution and the organic products are then extracted with ethyl acetate. The organic phase is dried and then evaporated. The crude product obtained is chromatographed on silica gel (eluent: 55/45 heptane/ethyl acetate). 0.8 g of tert-butyl 4-cyclopropylamino-piperidine-1-carboxylate in the form of a colourless oil is obtained in a yield of 79%.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:18]([N:28]([CH3:36])[C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1COCC1>[C:18]([N:28]([CH3:36])[C@H:29]([C:33]([NH:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
To a solution of the thus obtained Tyr(3-tBu)-NH2 (1 g, 4.23 mmol), Z-N-Me-Val-OH (1.23 g, 4.63 mmol) and CMPI (1.2 g, 4.69 mmol) in THF (20 ml), TEA (1.8 ml) was added under cooling with ice and stirred at room temperature for 4 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1), giving Z-N-Me-Val-Tyr(3-tBu)-NH2 (1.7 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:32]1[CH2:31][CH2:30][C:29]([F:28])([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:26]
Reactant: Fc1ccc(C2(F)CCNCC2)cc1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc12
Yield: 53.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (100 mg, 0.28 mmol) obtained in Example 88, step 2 and 4-fluoro-4-(4-fluorophenyl)piperidine hydrochloride (79 mg, 0.34 mmol), the title compound (80 mg, 54%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:29](=[O:30])[C@H:25]([CH:26]([CH3:27])[CH3:28])[NH:24][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2-methylpropan-1-ol (J. Am. Chem. Soc 113 (1991) p 8883) (4.73 g, 25 mmole), 4-dimethylamino-pyridine (0.61 g, 5 mmole) and N-benzyloxycarbonyl-L-valine (6.28 g, 25 mmole) in dichloromethane (70 ml) was added dicyclohexyl-carbodiimide (6.19 g, 30 mmole) and the mixture was stirred 2 days at room temperature. The mixture was cooled, the urethane was filtered and the solution evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with,sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 10.2 g=96%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C@H:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1.[H][H].[ClH:26]>C(O)C.[Pd].CCOCC>[ClH:26].[ClH:26].[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CN1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Reaction time: 48 h

Procedure:
A solution of 3.7 g of the free base of cis-1-methyl-4-(4-nitrophenoxy)-3-phenylpiperidine, of Example 7, in 100 ml of absolute ethanol is hydrogenated over 0.37 g of 10% Pd on carbon catalyst at 45 psi of hydrogen and room temperature. Uptake stops after 48 hours. The catalyst is filtered off and the filtrate is concentrated in vacuo to a gum. This material is chromatographed on silica gel using acetone and then 25% methanol/acetone as solvent. A purified free base is obtained and a portion of this material is dissolved in ether and is then added dropwise to a solution of dry HCl in ether. The resulting precipitate is filtered, washed with ether, and is then immediately suspended in boiling ether. Absolute ethanol is added until the mixture grows clear. Scratching of the cold solution causes crystallization to occur. The recrystallized solid is filtered, washed with cold acetone, then ether, and dried to afford a solid (m.p. 226°-227° C. dec.) of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine dihydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:14]O)=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18]>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:14][Br:18])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1CO
Solvent: ClCCl
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.3 g) and 1 g of triphenylphosphine polystyrene (1.2 mmol/g) were taken in anhydrous dichloromethane (6 mL) and cooled to 0° C., and carbontetrabromide (0.4 g) added. The mixture stirred for 1 h. at 0° C. room temperature for 2 h. Resin was filtered and washed with 5 mL of dichloromethane, filtrate was concentrated and dried in vacuum give (5-Bromomethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.3 g). This was used in the next reaction with no further purification. 1H NMR (400 MHz, Acetone-d6) 4.9 (s, 2H), 2.45 (s, 3H), 1.55 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:15])[F:1])=[CH:7][CH:8]=1)[CH3:13])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCCC(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCCC(F)(F)F)nc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.95 g, white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (0.82 g, 3.51 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]1.S(CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)C=C[C@H](C(C)C)CC)C1)[C@@H:37]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H:38]1O>>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH:20]=[CH:21][C@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:37][CH3:38])[CH2:10]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[C@H](C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Product: CC[C@H](C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of stigmasta-5,22-dien-3β-yl 6-iodohexyl ether, there was prepared 6-(stigmasta-5,22-dien-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data and Rf values are given in the above Table.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].F[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[C:41]([C:40]1[CH:43]=[CH:44][C:37]([N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]3[N:5]([CH3:26])[C:6]4[C:15]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[N:9]([CH2:16][C:17](=[O:24])[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:8](=[O:25])[C:7]=4[C:3]=3[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]2)=[CH:38][CH:39]=1)#[N:42]
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(C(=O)NC2CCN(c3ccc(C#N)cc3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 19.9 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.64 mmol), 4-fluorobenzonitrile (115 mg, 0.95 mmol) and potassium carbonate (176 mg, 1.3 mmol) in N-methylpyrrolidone (3.0 mL) was stirred at 120° C. for 16.5 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (73 mg, 20%) as a pale-yellow solid.