Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Cyclohexanol (5.01 g, 50.0 mmol) and p-toluenesulfonyl chloride (10.6 g, 55.6 mmol) were charged into a 100 cc round-bottom flask, and then pyridine (20 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 8 hours while gradually elevating the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (100 ml×3). The organic layers were combined, washed successively with 2N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain substantially pure cyclohexyl p-toluenesulfonate as a white solid (12.7 g, 49.9 mmol, 99% yield).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH2:14])[CH2:4][CH2:3]1.C[C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1.[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([N:35]([CH3:43])[C:36](=[O:42])[CH:37]3[CH2:41][CH:38]32)=[CH:33][C:32]=1[CH:44]=O>>[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([N:35]([CH3:43])[C:36](=[O:42])[CH:37]3[CH2:41][CH:38]32)=[CH:33][C:32]=1[CH2:44][NH:14][CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[NH:7][CH:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Agent: C[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Product: COc1cc2c(cc1CNC1CCC(C)NC1c1ccccc1)N(C)C(=O)C1CC21

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-Methyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S,)-6-methyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-methyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde [or (1S,1aR)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde or (1R, 1aS)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:21][CH:20]([OH:22])[C:19]2[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CO2)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 16 g. (88 mmol) of 3,4-dimethyoxyphenylethylamine and 13.5 g. (88 mmol) of p-methoxystyrene oxide is heated with stirring under argon on a steam bath overnight. A sample is withdrawn from the reaction mixture and chromatographed on a silica column, eluting with benzene ethyl acetate to isolate the pure product in crystalline form. To the remainder of the reaction mixture is added 100 ml. of ethyl acetate-hexane (1:1) and seeded with the crystalline product, with stirring and chilling. Filtration furnishes the product N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-methoxyphenyl)ethylamine, m.p. 92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=[O:24])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)([OH:38])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]([OH:38])=[O:24])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a stirred solution of the product from Example 151 (58 mg, 0.11 mmol) in dichloromethane (3 mL) and water (3 mL) at 0° C. was added sulfamic acid (44 mg, 0.44 mmol) and sodium chlorite (30 mg, 0.33 mmol). The reaction was allowed to attain room temperature with stirring over 3 hours, the layers separated and the aqueous layer extracted with further dichloromethane (5 mL). The combined organic layers were dried (MgSO4) and evaporated to leave a residue which was filtered through a plug of silica eluting with ether:dichloromethane:iso-hexane 1:1:3, then purified by column chromatography on silica eluting with ethyl acetate:dichloromethane 1:1 +1% acetic acid to afford the desired compound (40 mg).
Reaction SMILES: [CH3:1][NH2:2].CO[C:5]([C:7]1[N:8]=[C:9]([CH:12]([OH:37])[CH2:13][CH:14]([N:18]([CH3:36])[C:19](=[O:35])[CH:20]([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]([CH3:17])[CH3:16])[S:10][CH:11]=1)=[O:6]>C1COCC1.CO>[OH:37][CH:12]([C:9]1[S:10][CH:11]=[C:7]([C:5](=[O:6])[NH:2][CH3:1])[N:8]=1)[CH2:13][CH:14]([N:18]([CH3:36])[C:19]([CH:20]([NH:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])=[O:35])[CH:15]([CH3:16])[CH3:17]
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)OC)cs1)C(C)C
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 100 °C
Yield: 51.9 %

Procedure:
In a sealed tube, 10.0 mL of a 2.0 M solution of methylamine (5.00 mmol) in THF was added to a 0.02 M solution of 23 (27.0 mg, 0.0529 mmol) in MeOH (2.50 mL). The reaction solution was heated to 100° C. for 21 h. After the solution cooled to rt, the solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN/H2O) followed by lyophilization provided compound 25 (14.0 mg, 52%) as an amorphous solid. The 1H NMR corresponds to a 6:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.9 (c=1.0, MeOH). 1R: 1070, 1499, 1551, 1646, 2876, 2961 cm−1. 1H NMR (500 MHz, MeOD): δ 0.83 (d, 3H, J=6.5 Hz), 0.90 (t, 3H, J=7.5 Hz), 0.966 (d, 3H, J=6.5 Hz), 0.974 (d, 3H, J=6.5 Hz), 1.15-1.25 (m, 1H), 1.25-1.32 (m, 1H), 1.48-1.66 (m, 4H), 1.72 (d, 2H, J=10.5 Hz), 1.81-1.99 (m, 3H), 2.00-2.10 (m, 1H), 2.16 (s, 3H), 2.19-2.37 (m, 1H), 2.53-2.58 (m, 1H), 2.87-2.94 (m, 1H), 2.92 (s, 3H), 3.17 (s, 3H), 4.16-4.58 (br s, 1H), 4.64 (dd, 1H, J=2.3, 10.3 Hz), 4.72 (d, 1H, J=9.0 Hz), 8.06 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.1, 20.5, 20.6, 24.4, 25.9, 26.3, 26.4, 31.3, 31.7, 37.8, 38.8, 44.8, 55.4, 56.7, 70.0, 70.6, 124.2, 151.0, 164.4, 175.3, 175.7, 179.4. HRMS (FAB) calcd for C25H44N5O4S (M+H): 510.3114. Found: 510.3098.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccco1
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Compound 454 (556 mg, 2.00 mmol) and DMAP (24.4 mg, 0.200 mmol) were suspended in pyridine (8 mL), and 2-furoyl chloride (0.394 mL, 4.00 mmol) was added thereto, followed by stirring at 50° C. for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by recrystallizing from ethanol to afford the entitled Compound 511 (491 mg, 66%) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:24][CH2:25][CH2:26][CH3:27])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCBr
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (100 mL). To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, n-butyl bromide (3.4 mL, 0.042 mol) was added dropwise. Ater the dropwise addition, the reaction was conducted at 70° C. for 6 h. After completion of the reaction, the reaction solution was poured into water (600 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate f (8.2 g) in a yield of 81.4%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH3:20][N:21]([CH3:35])[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:25]1([OH:28])[CH2:26][CH2:27][C:22]([N:21]([CH3:20])[CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2occc2c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Yield: 23.9 %

Procedure:
A solution of benzo[b]furan (1.50 g, 12.7 mmol) in dry THF (50 ml) was cooled to −8° C. under a stream of argon. Tert-butyllithium (15.2 mmol, 10.2 ml of a 1.5 molar pentane solution) was added dropwise in such a way that a reaction temperature of −5° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2½ hours at −5° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (2.76 g, 12.7 mmol) in dry THF (15 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 4 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 1.02 g 1-benzofuran-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 134–137° C. were obtained.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: O=C(NC1CCN(CCO)CC1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(NC1CCN(CCCl)CC1)c1ccccc1

Procedure:
1 Gram of 1-(2-hydroxyethyl)-4-benzamidopiperidine suspended in 2 milliliters of dry benzene was treated with 0.62 gram of thionyl chloride. The stirred mixture was refluxed for 3 hours., then cooled and filtered to give the title compound as a light grey solid. Crystallisation from ethanol-ether of this hydrochloride gave 0.8 grams (62%) of pale yellow needles, melting point 238.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[C:10]([F:39])[CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:66][CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Yield: 31.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 47 (0.33 g, 0.55 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.26 g, 1.1 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.2 g, 1.7 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 0.1 g, 31%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([C:16]2[CH:17]=[N:18][C:19]([N:22]([CH3:24])[CH3:23])=[N:20][CH:21]=2)[CH:7]=1)=O)C.C(OC(C1[N:35]2[N:36]=C(N)N=C2C=C(Br)C=1)=O)C.CN(C)C1N=CC(B(O)O)=CN=1>>[NH2:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:16]3[CH:21]=[N:20][C:19]([N:22]([CH3:24])[CH3:23])=[N:18][CH:17]=3)[CH:7]=[C:6]([C:4]([NH:35][NH2:36])=[O:3])[N:11]2[N:12]=1
Reactant: CCOC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(N)nn12
Reactant: CCOC(=O)c1cc(Br)cc2nc(N)nn12
Agent: CN(C)c1ncc(B(O)O)cn1
Product: CN(C)c1ncc(-c2cc(C(=O)NN)n3nc(N)nc3c2)cn1

Procedure:
2-Amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester, was prepared analogously to Example 28, Step 3, except 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (10.0 g, 35.1 mmol) was used as the starting material (which may be prepared as described in Example 6) and 2-dimethylamino-pyrimidin-5-boronic acid was used in place of 3-pyridyl-boronic acid to give 2-amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid hydrazide. MS (APCI+): m/z 328.3.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([N:24]1[CH2:25][C@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:22]([CH2:21][N:13]([C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1

Procedure:
A 309 mg portion of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was dissolved in 7 ml of acetic anhydride and 14 ml of pyridine and stirred at room temperature for 13Hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 224 mg of tert-butyl {[(3R,4S)-1-acetyl-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless amorphous substance. FP: 473.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2([CH3:26])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH:14]2[CH3:25])[CH:10]=[CH:11][CH:12]=1)=O.O.[NH2:29]N>CO.O>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]([CH3:26])([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[CH:4]=[CH:3][NH:2][N:29]=3)[CH:8]=2)[CH:14]([CH3:25])[CH2:15]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCN1CCC(C)(c2cccc(C(=O)C=CN(C)C)c2)C(C)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCCCCCN1CCC(C)(c2cccc(-c3cc[nH]n3)c2)C(C)C1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-(3-dimethylaminopropenoyl)phenyl)-1-hexyl-3,4-dimethylpiperidine (Preparation 38, 117 mg, 0.32 mmol) in a mixture of methanol (5.0 mL) and water (1.0 mL) was added hydrazine hydrate (0.1 mL, 3.2 mmol). The mixture was heated at reflux for 2 h and then cooled to room temperature. The mixture was concentrated in vacuo and saturated aqueous sodium hydrogencarbonate (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL), the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane:0.88 ammonia (90:10:1). The title compound was isolated as clear oil (85 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1.Br[C:12]1C=CC(I)=C(CC)C=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH2:10][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: C=Cc1ccc(Br)cc1C
Agent: C=C[Si](C)(C)C
Product: C=Cc1ccc(Br)cc1CC
Yield: 77 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 4-bromo-2-ethyl-1-iodobenzene (2.1 g, 6.9 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 175° C. for 45 min to yield 36A (1.1 g, 77%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 (t, J=7.58 Hz, 3 H) 2.51 (q, J=7.66 Hz, 2 H) 5.15 (dd, J=10.99, 1.14 Hz, 1 H) 5.47 (dd, J=17.31, 1.14 Hz, 1 H) 6.74 (dd, J=17.43, 11.12 Hz, 1 H) 7.08-7.20 (m, 3 H).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[C:25]1([C:30](Cl)=[O:31])[S:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:30]([C:25]1[S:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cccs1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (200 mg) in tetrahydrofuran (3 mL) were added triethylamine (100 μL) and 2-thenoyl chloride (100 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (273 mg, yield 92%) as colorless crystals. melting point 250° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)ccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.241 g, 5.85 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.234 g, 5.85 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.358 mL, 5.85 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.259 g, 61%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.88-2.13 (m, 4H), 2.63-2.83 (m, 2H), 2.99-3.10 (m, 1H), 3.23-3.34 (m, 1H), 3.45 (s, 3H), 3.88-4.00 (m, 1H), 4.35-4.46 (m, 1H), 5.85 (d, 1H), 6.88-7.06 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][C@H:15]2[CH2:16][CH2:17][C@H:18]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:19][CH2:20]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (5.6 g, 26.7 mmol) in methanol (50 mL), acetic acid (1.2 g, 20.57 mmol) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (1.6 g, 26.74 mmol) was added at 0° C. and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography twice eluting with ethyl acetate:hexane to afford (4 g, 44%) of less polar cis isomer and (3 g, 33%) of the pure more polar trans isomer.