Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:21]1([CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][NH:11][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][N:3]=3)[CH2:15][CH2:16]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1noc2ccccc12
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CN2CCC(CCNc3noc4ccccc34)CC2)cc1
Yield: 15.5 %

Procedure:
The procedure described in Example 21 was followed with 3-chloro-1,2-benzisoxazole (0.682 g, 4.44 mmol), 4-aminoethyl-1-phenylmethyl piperidine (0.970 g, 4.44 mmol), and K2CO3 (0.614 g, 4.44 mmol) in DMSO (30 mL). After purification, the title compound (0.231 g, 15%) was obtained as a pale yellow oil. 1H-NMR (CDCl3) δ 7.45-7.54 (m, 2H), 7.24-7.40 (m, 6H), 7.19 (t, 1H, J=7.8 Hz), 4.40 (brt, 1H, J=5.5 Hz), 3.52 (s, 2H), 3.45 (dt, 2H, J=7.4 Hz, J=6.0 Hz), 2.91 (brd, 2H, J=11.8 Hz), 1.99 (brt, 2H, J=11.2 Hz), 1.62-1.73 (m, 4H), 1.37-1.52 (m, 3H). 13C-NMR (CDCl3) δ 162.7, 158.6, 137.8, 129.8, 129.4, 128.2, 127.1, 122.1, 119.8, 116.3, 110.0, 63.3, 53.6, 41.5, 36.1, 33.4, 32.0. EIMS: 335 (M+), 244, 199, 186, 172, 91 (base). HRMS calc'd. for C21H25N3O: 335.1998. Found: 335.1909.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:47][C:48]#[N:49]>CN(C=O)C>[C:48]([CH2:47][O:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)#[N:49]
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4O)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OCC#N)nccc3c2)cc1
Temperature: 60 °C

Procedure:
To a vial charged with 1-(2-hydroxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (111 mg, 0.194 mmol) was added DMF (777 μl) and Cs2CO3 (190 mg, 0.583 mmol) and bromoacetonitrile (46.6 mg, 0.39 mmol) respectively. The mixture was heated to 60° C. overnight affording conversion to desired product fairly cleanly. The mixture was dried under reduced pressure and purified with a 25 g Interchim column (25 um silica) ramping EtOAc in heptane (0-100%, 10% DCM throughout) affording product as a light brown solid. m/z (ESI) 611.3 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](OCC)=[O:10])[CH2:3][CH2:2]1.ClCC(C1C=CC=CC=1)C(OCC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[OH:10][CH2:9][CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: CCOC(=O)C(CN1CCOCC1)c1ccccc1
Agent: CCOC(=O)C(CCl)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCOCC
Product: OCC(CN1CCOCC1)c1ccccc1
Yield: 118.8 %

Procedure:
Ethyl 3-morpholino-2-phenylpropionate (660 mg, 2.51 mmol) prepared in the above (1) in dry ether (5 ml) was dropwise added to a suspension of LiAlH4 (110 mg, 2.89 mmol) and dry ether (10 ml) while chilling with ice, and then stirred to cause reaction at room temperature for 2 hours. To the resulting solution, saturated aqueous sodium sulfate was added in order to decompose remaining excess LiAlH4. Subsequently, insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure to obtain 660 mg of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N+:9]([O-:11])=[O:10])[CH:19]=[CH2:18]
Reactant: O=[N+]([O-])c1c(O)cccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(Cl)c1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
4.7g of 3-chloro-2-nitrophenol in 30ml of acetone were treated with 3.7g potassium carbonate and then reacted with 3.25g allylbromide under reflux for 8 hours. The reaction mixture was cooled and filtered and the residue extracted into chloroform, washed once with water, dried using sodium sulphate and 6.5g of an oily residue obtained The crude product was then purified by flash chromatography to give 4.85g of 3-chloro-2-nitrophenyl allyl ether as a colourless oil (yield 84%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>>[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:31]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3cccc(F)c3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 13 μL (0.11 mmol) 3-fluorobenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH2:11](N)[CH3:12]>B([O-])([O-])[O-]>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH:6][CH2:11][CH3:12])=[O:7]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
Agent: [O-]B([O-])[O-]
Product: CCNC(=O)CC[C@H](N)C(=O)O

Procedure:
0.3 M glutamine and 1.5 M ethylamine were allowed to react at 30° C. for 22 hours in borate buffer (Na2B4O7—NaOH, pH 11) in the presence of 0.3 U glutaminase, to give 225 nmol of L-theanine. In addition, a by-product glutamic acid was 20 nmol. The purification of theanine from the reaction mixture was carried out by subjecting the reaction mixture to column chromatography using Dowex 50×8 column and Dowex 1×2 column, and thereafter treating the resulting product with ethanol.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([O-])([O-])=[O:9].[K+:12].[K+]>CO>[C:4]([O:9][CH3:8])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[K+:12]
Reactant: O=C1C=CC(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]
Yield: 177.1 %

Procedure:
46.5 grams (0.46 mole) maleic anhydride is dissolved in 500 mls methanol. 36 g K2CO3 is added to a pH of 8.5-8.6, the solution is filtered and evaporated to dryness. 77.6 grams of product is obtained. Purity=96.4% by NMR analysis.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[O:9][C:10]2[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([Br:27])=[CH:17][C:11]=2[C:12]=1[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(=O)[CH3:2].CCN(CC)CC>C(Cl)Cl>[Br:27][C:18]1[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]2[O:9][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=2[CH:17]=1
Reactant: CNC(=O)c1c(C(=O)NNC(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2nnc(C)o2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Yield: 99.8 %

Procedure:
A mixture of compound 2-(2-acetylhydrazinecarbonyl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.33 mmol), p-TsCl (124 mg, 0.66 mmol) and Et3N (108 mg, 0.98 mmol) in CH2Cl2 (6 mL) was refluxed for 5 h. After concentration in vacuo, the residue was purified with prep-TLC (DCM:MeOH=100:1) to give the product 5-bromo-N-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (146 mg, yield: 63%). 1H-NMR (CDCl3, 400 MHz) δ 9.80 (br s, 1H), 8.96 (s, 1H), 7.77 (s, 1H), 3.36 (s, 3H), 3.13˜3.06 (m, 6H), 2.75 (s, 3H). MS (M+H)+: 443/445.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[Cl:35][C:36]1[N:37]=[C:38]([CH3:44])[NH:39][C:40]=1[C:41](O)=[O:42]>CN(C=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:41]([C:40]2[NH:39][C:38]([CH3:44])=[N:37][C:36]=2[Cl:35])=[O:42])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
EDC (0.060 g, 0.311 mmol) and HOBT (0.042 g, 0.311 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.111 g, 0.311 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.050 g, 0.311 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc and saturated sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated. Rerverse phase HPLC (acetonitrile:water with 0.1% formic acid) gave the title compound (0.019 g, 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.86 (br. s., 1H), 8.17 (br. s., 1H), 7.77-7.88 (m, 1H), 7.57-7.66 (m, 1H), 7.46-7.55 (m, 1H), 7.44 (br. s., 1H), 7.22-7.35 (m, 1H), 4.37-4.70 (m, 2H), 2.28 (s, 3H). LCMS: m/z 497, 499.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[O:5].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]4[O:13][CH2:14][O:15][C:9]=4[CH:8]=3)=[O:5])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCCl)Nc1ccc2c(c1)OCO2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCN1CCN(c2ccccc2)CC1)Nc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 109.5 %

Procedure:
To N-(3-chloropropionyl)-3,4-methylenedioxyaniline (2.0 g) dissolved in N,N-dimethylformamide (20 ml) were added N-phenylpiperazine (1.6 g) and triethylamine (3 ml) and the mixture was stirred at 80° C. for 20 hours in a nitrogen atmosphere. The reaction mixture was evaporated in vacuo and to the residue were added ethyl acetate and 2N sodium hydroxide solution. After the aqueous layer was removed, the ethyl acetate layer was washed twice with water and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off and the residual solid was recrystallized from ethanol to give N-[3-(4-phenyl-1-piperazinyl)propionyl]-3,4-methylenedioxyaniline (3.4 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37]CC)=[O:36])=[C:21]([CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[N:22]=2)[CH2:14][CH2:13]1)=[O:10].[Li+].[OH-:41]>C1COCC1.O>[C:32]([C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:25]([NH:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[S:19][C:20]=1[C:35]([OH:37])=[O:36])=[O:34])([OH:41])=[O:33]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)c4ccccc4C(=O)O)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate (Example 277; 194 mg, 0.32 mmol) in anhydrous THF (2 ml) was added 2 N LiOH (0.82 ml). The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH 3 and the precipitate that formed was diluted with water and extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the title compound (160 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].[N-]=C=O>Cl>[Cl:11][C:10]1[C:2]([NH:1][C:17]([NH:16][CH2:15][CH2:14][CH2:13][Cl:12])=[O:18])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C=NCCCCl
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NCCCCl)Nc1c(Cl)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A 250 mL round bottom flask is charged with 2-amino-3-chlorobenzoic acid (5.00 g, 29.1 mmol) and 100 mL of 5% aqueous KHCO3. The slurry is cooled to 0° C., and 3-chloropropylisocyanate (6.0 mL, 58 mmol) is added. The mixture is then allowed to warm to room temperature over 16 hours. HPLC analysis shows some starting material remaining, so the solution is recooled to 0° C. and an additional portion of the isocyanate (3.0 mL, 29 mmol) is added. After 2 h, the solution is acidified with 1 N HCl (ca. 40 mL), and the resulting yellow solid is filtered, rinsing with 1 N HCl. The resulting solid (35.5 g) is recrystallized from 80 mL of hot ethanol, to provide the product as a white solid: 4.22 g, 14.5 mmol, 50% yield. M.p. 124.4-124.8° C. 1H NMR (CD3OD): 7.84 (d, J=8,1H), 7.64 (d, J=8,1H), 7.24 (t, J=8,1H), 3.68 (t, J=7, 2H), 3.37 (t, J=6, 2H), 2.01 (m, 2H). MS (CI): 289 (M-H, 100), 196 (M-ClCH2CH2CH2NH, 25).
Reaction SMILES: [NH:1]1[CH:8]=[C:7]([CH2:9][C:10]([O:12]CC)=[O:11])[C:5](=[O:6])[NH:4][C:2]1=S.ClCC(O)=[O:18].Cl>O>[NH:1]1[CH:8]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[C:5](=[O:6])[NH:4][C:2]1=[O:18]
Reactant: CCOC(=O)Cc1c[nH]c(=S)[nH]c1=O
Reactant: O=C(O)CCl
Agent: Cl
Solvent: O
Product: O=C(O)Cc1c[nH]c(=O)[nH]c1=O

Procedure:
Ethyl (2-thiouracil-5-yl)acetate (33, 7.8 g, 36 mmol) was mixed with chloroacetic acid (1.9 g, 20 mmol) and water (47 ml) and refluxed for 2 hours. Concentrated hydrochloric acid (22 ml) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered and the precipitate was washed once with water and dried. The procedure was repeated with the precipitate in place of 8 yielding 4.19 g (68%) of the title compound as a white solid. 1H-NMR (DMSO-d6/TMS): 2=3.13 (s, 2H, CH2COO); 7.35 (d, 1H, J=6.5 Hz, H-6); 10.74 (m, 1H, H-1); 11.09 (s, 1H, H-3); 12.20 (br, 1H, COOH). 13C-NMR (DMSO-d6/TMS): δ=31.3 (CH2COO); 106.6 (C-5); 139.7 (C-6); 151.2 (C-2); 164.0 (C-4); 171.9 (COOH).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C@H:3]1[CH2:7][CH2:6][N:5](C(OCCCC)=O)[CH2:4]1.[ClH:16]>C(Cl)Cl>[ClH:16].[CH3:1][N:2]([CH3:15])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CCCCOC(=O)N1CC[C@H](N(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: CN(C)[C@H]1CCNC1
Reaction time: 3 h

Procedure:
In a dried reaction flask, the crude (S)-butyl 3-(dimethylamino)pyrrolidine-1-carboxylate (2.0 g) obtained in the above step was added to CH2Cl2 (30 mL). HCl gas was passed thereto for 3 hr. The solution was concentrated under reduced pressure to obtain a crude yellow viscous material (1.6 g).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].I[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[C-]#N.[K+]>[Cu]I.O1CCCC1>[CH:1]([O:4][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: Ic1cccs1
Agent: [Cu]I
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1cccs1
Temperature: 90 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a mixture of 10 mL anhydrous isopropanol and 5 mL anhydrous tetrahydrofuran under argon at room temperature was added sodium metal (350 mg, 15.22 mmol). The resulting mixture was stirred vigorously at 35° C. until all the sodium metal was consumed (ca. 20 minutes). Copper(I) iodide (386 mg, 2.03 mmol) and 2-iodothiophene (2.13 g, 10.14 mmol) were added and the resulting suspension heated to 90° C. and stirred vigorously for 16 h. After cooling to room temperature, 20 mL of 0.5 M potassium cyanide aqueous solution was added and the resulting mixture stirred for 30 minutes. Organics were extracted with hexanes (2×75 mL), washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography on silica gel (100% hexanes) to give 2-isopropoxythiophene (250 mg, 16%). Used without further characterization.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[N:4]1S(C1C=CC(C)=CC=1)(=O)=O.[Mg]>CO>[OH:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[C:5](=[O:16])[NH:4]1
Reactant: Cc1ccc(S(=O)(=O)N2C(=O)N([C@H](C)c3ccccc3)C[C@@H]2CO)cc1
Agent: [Mg]
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@H](CO)NC1=O
Reaction time: 24 h

Procedure:
537 mg (R)-4-Hydroxymethyl-1-((R)-1-phenyl-ethyl)-3-(toluene-4-sulfonyl)-imidazolidine-2-one (I.25) was placed in 9.45 mL methanol at ambient temperature, then 348 mg magnesium turnings were added. The reaction was shaken for 24 h and then filtered. The solvent was removed from the filtrate under reduced pressure and the crude material was then partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 10 g (40.1 mmol) trans-4-Hydroxy-cyclohexylcarbamic acid benzyl ester in 40 ml DMF, 4.09 g (60.1 mmol, 1.5 eq) imidazole and 6.65 g (44.1 mmol, 1.1 eq) TBDMSCl in 20 ml DMF were added at 0° C. The mixture was warmed to 50° C. and stirred at that temperature for 2 h. A saturated solution of NaHCO3 was added, the mixture was concentrated and redissolved in ether/water. The phases were separated and the inorganic phase was extracted with ether. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified on silica gel with hexane:EtOAc 5:1 as eluent yielding 11.8 g (81%) trans-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid benzyl ester as colorless gum, MS: 348 (M−CH3).
Reaction SMILES: [CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([C:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([Mg]C2C=CC=CC=2)[CH2:30][CH2:29]1)[CH2:26][CH3:27].[Cl-].Cl>O1CCCC1>[CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([C:12]2([C:17]3[CH2:16][CH2:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:16][C:15]([C@H:31]3[CH2:30][CH2:29][C@H:28]([CH2:25][CH2:26][CH3:27])[CH2:33][CH2:32]3)=[CH:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2=CCC(=O)CC2)CC1
Reactant: CCC[C@H]1CC[C@H]([Mg]c2ccccc2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCC[Si]1(c2ccccc2)CCC(C2(C3=CC=CCC3)C=CC([C@H]3CC[C@H](CCC)CC3)=CC2)CC1
Reaction time: 5 h

Procedure:
34.1 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-3-cyclohexenone was dropped in 250 ml of a tetrahydrofuran solution of 0.5 moles of trans-(4-n-propylcyclohexyl)phenylmagnesium chloride, followed by agitation at room temperature for 5 hours. The resultant mixture was charged into diluted hydrochloric acid and extracted with ether. The resultant ether solution was washed with brine, dried and concentrated, followed by addition, to the resultant residue, of 300 ml of benzene and 800 mg of p-toluenesulfonic acid monohydrate and removal of generated water under reflux. When the generation of water stopped, the benzene solution was washed with brine, dried and concentrated, followed by purification through column chromatography to obtain 36.8 g of 1-(4-n-pentyl-4-phenyl-4-silacylohexyl)-4-(trans-4-n-propylcyclohexyl)phenyl-1,3-cyclohexadiene at a yield of 70%. The results of 1H-NMR analysis of the compound are shown below. 1H-NMR (CDCl3) δ:0.50-2.75(41H, m), 5.62-5.90(1H, m), 6.18-6.36(1H, m), 7.05-7.70(9H, m) ppm
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.ICC>>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Solvent: CCI
Product: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
A mixture of (−)-1-benzyl-3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (0.66 g, 2.16 mmol) and iodoethane (4 mL, 50.2 mmol) was refluxed for 4 h. The mixture was evaporated and tert-butyl methyl ether (20 mL) was added. The solvent was decantated off, morpholine (5 mL) was added and the mixture was heated under microwave irradiation at 120° C. for 30 minutes. The mixture was evaporated and purified twice by flash chromatography on silica gel (methanol/ethyl acetate, 7:3 to 3:7 and isocratic 1:1) to give the title compound (0.26 g). [α]D=−21.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 117-118° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 23), 157, (78), 130 (82), 129 (95), 71 (bp).