Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[I:10]I>ClC1C=CC=CC=1.[Cu](Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([I:10])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: II
Agent: Cl[Cu]Cl
Solvent: Clc1ccccc1
Product: CCc1cc(I)ccc1O

Procedure:
A solution of 119.9 ml of 2-ethylphenol in 500 ml of chlorobenzene was treatedwith 126.9 g of iodine and 134.5 g of copper(II) chloride and stirred under reflux for 5.5 hours. After cooling the reaction mixture was filtered and the residue was washed with methylene chloride. The combined filtrates were washed with aqueous sodium thiosulphate solution and ice-water. The organic phases were dried over sodium sulphate and concentrated. The residue was crystallized from hexane and gave 79.3 g of 2-ethyl-4-iodo-phenol. The mother liquor was chromatographed over silica gel and gave a further 41 g of 2-ethyl-4-iodo-phenol; MS (EI) m/z 248 (M).
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.N[N:10]1[C:14]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:13][N:12]=[C:11]1[SH:20].C([O-])([O-])=O.[Na+].[Na+]>O>[SH:20][C:11]1[N:10]=[C:14]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[NH:13][N:12]=1
Reactant: Nn1c(S)nnc1-n1cccn1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: Sc1n[nH]c(-n2cccn2)n1
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
Sodium nitrite (0.4 g) was added to 25 ml of conc HNO3 and 75 ml H2O (after R. A. Henry and W. G. Finnegan, J. Am. Chem. Soc., 76, 290 (1954) and C. A. Amsworth and R. G. Jones J. Am. Chem. Soc., 75, 4915 (1953). Solid 4-amino-3-mercapto-5-(1-pyrazolyl)-1,2,4-triazole (5 g) was added in small batches with stirriing while keeping the temperature below 40° C. After addition, the solution was stirred for 20 minutes and made basic by the addition of 15% aq. Na2CO3. The yellow solution was filtered and acidified with glacial acetic acid (25 ml). The tan precipitate was collected and boiled with ethanol to give 2.3 g of tan powder m.p. 245°-247°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](SC)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Al]>CC#N>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:16])([F:17])[F:15]
Reactant: C1COCCN1
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Agent: [Al]
Solvent: CC#N
Product: COc1cc(C=C2SC(N3CCOCC3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
A solution of 4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile (88 mg, 0.2 mmol) in CH3CN (1 mL) was treated with morpholine (0.4 mmol) and heated to 60° C. in an aluminum heating block for 10 h. The solvent was removed in vacuo and the crude reaction mixture was purified by silica gel chromatography (EtOAc/CH2Cl2) to afford the title compound. 1H NMR (400 Hz, CDCl3) δ 7.95 (d, 1H), 7.79 (s, 1H), 7.66 (dd, 1H), 7.19 (m, 3H), 6.76 (d, 1H), 4.10 (m, 2H), 3.84 (m, 4H), 3.78 (s, 3H), 3.64 (m, 2H); LC/MS (m/z) [M+1]+490.3 (calculated for C23H19F3N3O4S, 490.47).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:22][CH2:23][C:24](NC1SC(C2C=CN=C(NC3C=CC=C([N+]([O-])=O)C=3)N=2)=C(C)N=1)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:25]
Reactant: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine in a manner analogous to that described above for compound [60]. 1H-NMR (DMSO-d6) δ: 2.94 (s, 3H, CH3), 4.75 (s, 2H, CH2), 7.44(m, 3H, pyrimidinyl-H & Ph-H), 8.09 (m, 2H, Ph-H), 8.28 (s, 1H, NH), 8.80 (d, 1H, J=5.2 Hz, pyrimidinyl-H).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]2[CH2:11][CH2:12][CH2:13][C:2]1=2.C1C[O:17]CC1.O>C1COCC1>[O:17]=[C:13]1[C:2]2[NH:1][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cc2c([nH]1)CCC2
Reactant: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reaction time: 1.5 h

Procedure:
A solution of the ethyl 1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (1.0 g, 5.58 mmol) in THF/Water (10:1, 11 mL) at 0° C. was deoxygenated by passing a stream of dry nitrogen gas for 10 min. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzochinone (DDQ) in THF (4 mL) was added dropwise over 5 min. After stirring for 1.5 h, the cooling bath was removed and stirring was continued at rt. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-60% EtOAc/Heptane) to afford ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate as a taupe solid (270 mg, 25%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (t, J=7.13 Hz, 3H), 2.87-2.95 (m, 4H), 4.39 (q, J=7.13 Hz, 2H), 6.78 (d, J=1.66 Hz, 1H), 9.86 (s, 1H); LCMS-MS (ESI+) 193.9 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4]1[CH:5]=[CH:6][C:7]([N+:33]([O-])=O)=[C:8]([CH:32]=1)[C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:10])[CH3:2]>O=[Pt]=O>[NH2:33][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:36][CH3:37])[CH2:1][CH3:2])=[CH:32][C:8]=1[C:9]([NH:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17][CH2:18]1)=[O:10]
Reactant: CCN(CC)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Agent: O=[Pt]=O
Product: CCN(CC)c1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Reaction time: 3 h

Procedure:
Step 2): To a solution of 5-diethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (1.0 g, 1.99 mmol) was added PtO2 (30 mg). The solution was stirred under H2 atmosphere (3 kg/cm2) for 3 hours. The catalysts were filtered off and the filtrate was evaporated to give 2-amino-5-diethylamino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 930 mg(100%): mp 161°-163° C.
Reaction SMILES: Cl.[CH3:2]O.[C:4]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na].Cl>CC(C)=O>[OH:11][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([O:17][CH3:2])=[O:16])[CH:13]=1
Reactant: CO
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25 ml of 10% hydrogen chloride-methanol was added to 1.95 g (8.62 mmol) of 3-benzoylbenzoic acid and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a sodium hydrogencarbonate aqueous solution and brine, and dried (MgSO4). The solvent was distilled off and the residue was dissolved in 20 ml of methanol. Under ice-cooling, 0.32 g (8,41 mmol) of sodium boronhydride was added thereto and the mixture was stirred for 30 minutes. After acetone and 1N hydrochloric acid were added, the reaction mixture was extracted twice with chloroform, the extract was washed with a sodium hydrogencarbonate aqueous solution, and dried (MgSO4). The solvent was distilled off to obtain 2.04 g (8.42 mmol) of methyl a-hydroxy-a-phenyl-m-toluate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[C:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:12]=[C:13]3O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O.N>>[Cl:25][C:13]1[C:14]2[C:9](=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[N:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=1
Reactant: Oc1cc(-c2ccccc2)nc2nn(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1cc(-c2ccccc2)nc2nn(-c3ccccc3)cc12
Reaction time: 1.5 h

Procedure:
5.5 g. of 2,6-diphenyl-2H-pyrazolo[3,4-b]pyridin-4-ol (0.019 mol.) and 27.5 ml. of phosphorus oxychloride are refluxed with stirring for 90 minutes. The cooled mixture is poured onto crushed ice, then made alkaline with concentrated aqueous ammonia while adding ice. The collected 4-chloro-2,6-diphenyl-2H-pyrazolo[3,4-b]pyridine is washed with water and dried at 80°; m.p. 175°-177°. A sample, recrystallized from ethanol, melts at 176°-178°; yield: 5 g. (86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Solvent: c1ccncc1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (400 mg, 1.6 mmol) in pyridine (5 mL) was added 2,4-difluorobenzenesulfonyl chloride (407 mg, 1.9 mmol) slowly, the reaction mixture was stirred at room temperature overnight, the solvent was evaporated in vacuo, and the residue was treated with brine (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was evaporated in vacuo, and the residue was purified by column chromatography using petroleum ether:EtOAc=5:1 as eluent to afford the desired product 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide as white solid in 59% yield (400 mg). m/z 427 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].C1C(=O)N([Br:16])C(=O)C1.O>CN(C=O)C>[Br:16][C:5]1[S:1][C:2]([CH2:6][C:7]#[N:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1cccs1
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of 2-(thiophen-2-yl)acetonitrile (1.23 g, 10 mmol, 1.0 eq) in DMF (10 mL), NBS (1.96 g, 11 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture. After extraction with EtOAc (3×), the organic layers were washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (petroleum/EtOAc from 100:1 to 10:1) to affords 2-(5-bromothiophen-2-yl)acetonitrile (738 mg, 60%). LC-MS (m/z)=202 [M+H]+
Reaction SMILES: ClCCl.[CH2:4]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C(Cl)=O.[C:32]([O:42][CH3:43])(=[O:41])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)O>N1C=CC=CC=1>[CH2:4]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH:33]([C:32]([O:42][CH3:43])=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:24])=[CH:18][CH:17]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)C(O)c1ccccc1
Reactant: CCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCOc1ccc(CC(=O)OC(C(=O)OC)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a dichloromethane (20 ml) solution of 4-undecyloxyphenylacetic acid (2 g, 7 mmol.) was added dropwise oxalyl chloride (1 ml). The reaction solution was stirred at 50° C. for one hour, which was then cooled, followed by concentration under reduced pressure The concentrate was dissolved in dichloromethane (10 ml), and the solution was added dropwise to a dichloromethane (10 ml) solution of methyl mandelate (1.1 g, 6.5 mmol.). To the reaction solution was added pyridine (2 ml), and the mixture was stirred at room temperature for two hours, to which was then added water (50 ml), followed by extraction with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (developing solvent: IPE) to give methoxycarbonylphenylmethyl 4-undecyloxyphenylacetate (2-g, 1.4 g, 43%).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[O:17][C:16]([SH:18])=[N:15][N:14]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[O:17][C:16]([S:18][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=4)=[N:15][N:14]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COCn1ncc2cc(-c3nnc(S)o3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1ncc2cc(-c3nnc(SCc4cccc(C(F)(F)F)c4)o3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
A suspension of 5-[1-(methoxymethyl)-1H-indazol-5-yl]-1,3,4-oxadiazole-2-thiol (525 mg, 2.00 mmol), 3-(trifluoromethyl)benzyl chloride (0.372 mL, 2.40 mmol), and potassium carbonate (415 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water, the precipitate was collected by filtration, purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (821 mg, yield 98%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=[O:14])[CH:8]=2)[O:3]1.[CH3:27]O.Cl>O1CCOCC1>[CH3:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:27])=[O:14])[CH:8]=2)[O:3]1
Reactant: CO
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(C(=O)O)ccc2O1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 22 g of 2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman-6-carboxylic acid (prepared as described in Preparation 42), 100 ml of methanol and 200 ml of a 4N solution of hydrogen chloride in dioxane was allowed to stand overnight at room temperature. At the end of this time, the solvent was stripped from the reaction mixture by evaporation under reduced pressure. The residue was then dissolved in benzene, and the resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, eluted with a 20:1 by volume mixture of benzene and ethyl acetate, to afford 16.1 g of the title compound, melting at 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][C:14](=O)[CH3:15].[BH4-].[Na+].C([OH:22])(C)C>CO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([CH2:14][CH3:15])[OH:22]
Reactant: CC(C)O
Reactant: CC(=O)Cc1c(C)nc2ccccc2c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)c1c(C)nc2ccccc2c1N
Temperature: 25 °C

Procedure:
A mixture prepared from 1-(4-amino-2-methyl-3-quinolinyl)-propanone (8 g), sodium borohydride (3 g), 75 ml of isopropanol and 25 ml of methanol was stirred twenty hours at ambient temperature. The reaction mixture was concentrated and stirred with water, and the product which separated was collected and dried to 8 g of solid, mp 220°-230°. This material was recrystallized from absolute ethanol to give 4.6 g of crystals, mp 240°-241°.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[CH2:7][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCCCN
Product: CCCCNCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature of 30°-70° C. The reaction mixture was held at 70° C for an additional one hour. At the end of this period, the excess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 17.0 g (90.0 percent) of N-butylglycine tert-butyl ester, B.P. 76° C/4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](N(OC)C)=[O:12])=[CH:5]2.[CH2:17]([Li])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5]2
Reactant: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [Li]CCCCCC
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution (100 mL) of 5-chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide (9.14 g) synthesized above in tetrahydrofuran was added a 2.3M solution (50.0 mL) of hexyllithium in hexane at −78° C., and the mixture was stirred under nitrogen atmosphere for 1.5 hr. A 2.3M solution (38.3 mL) of hexyllithium in hexane was additionally added, and the mixture was stirred at −78° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (6.90 g, 68%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=O)[CH3:5])[CH3:2].[P:7]([OH:10])([OH:9])[OH:8].Cl>>[CH2:1]([NH:3][C:4]([P:7]([OH:10])(=[O:8])[OH:9])([P:7]([OH:10])(=[O:9])[OH:8])[CH3:5])[CH3:2]
Reactant: OP(O)O
Reactant: CCNC(C)=O
Agent: Cl
Product: CCNC(C)(P(=O)(O)O)P(=O)(O)O

Procedure:
Into a mixture of 87 gm of N-ethylacetamide and 82 gm of phosphorous acid, hydrogen chloride was introduced for 8 hours. During this time the mixture was stirred and the temperature was held at 150° - 160° C. The reaction mixture was then treated analogously to Example 1, and the N-ethyl-1-aminoethane- 1,1 -diphosphonic acid product was obtained. The yield was 36.5 gm.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([C:22](OC)=[O:23])=[CH:15][C:13]=2[N:14]=1.[BH4-].[Li+].O1CCCC1>C(OCC)C>[C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH2:22][OH:23])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c2sc(Nc3c(C)cc(C)cc3C)nc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(Nc2nc3cc(CO)cc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.4 %

Procedure:
To a solution of methyl 2-mesitylamino-7-nitro-1,3-benzothiazole-5-carboxylate (350 mg, 0.942 mmol) in ethyl ether (6 ml) was added 2.0 M solution of lithium borohydride in tetrahydrofuran (THF) (1.41 ml, 2.82 mmol). The mixture was stirred at room temperature for 15 h. The reaction was quenched with saturated NH4Cl solution. The aqueous phase was extracted with ethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 189 mg of the title compound.
Reaction SMILES: [SH:1][C@@:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[CH3:10][S:11][C:12]#[N:13].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH:6]([C@:2]1([CH3:9])[S:1][C:12]([S:11][CH3:10])=[N:13][C:3]1=[O:4])([CH3:8])[CH3:7]
Reactant: CSC#N
Reactant: CC(C)[C@](C)(S)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSC1=NC(=O)[C@](C)(C(C)C)S1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
(S)-2-Mercapto-2,3-dimethylbutanoic acid (1.5 g, 0.01 mol) was dissolved in toluene (15 mL) under an atmosphere of nitrogen. Activated 3A sieves (1.5 g) and MeSCN (1.1 mL, 0.015 mol) were added and the resultant mixture was warmed to 110° C. The mixture was stirred for 2 h and cooled to 23° C. The mixture was treated with saturated aqueous NaHCO3 (20 mL), the phases were separated and the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatographic purification (10 g silica gel, 20-30% EtOAc/Hexanes) of the residual material yielded (S)-5-isopropyl-5-methyl-2-(methylthio)thiazol-4(5H)-one. This material was dissolved in MeOH (15 mL) and (S)-exo-aminonorbornane (1.35 g, 0.015 mol, 99.3% ee) was added under an atmosphere of nitrogen. The solution was stirred for 4 h and concentrated. Chromatographic purification (10 g silica gel, 10-40% EtOAc/Hexanes) of the residual material yielded 1.73 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3, 90.15/9.85 mixture of diastereomers, signals for the major diastereomer) δ 3.33-3.40 (m, 1H), 2.36-2.45 (m, 2H), 2.21 (septaplet, 1H, J=8 Hz), 1.84-1.91 (m, 1H), 1.60-1.83 (m, 1H), 1.42-1.68 (m, 3H), 1.62 (s, 3H), 1.13-1.30 (m, 4H), 1.05 (d, 3H, J=8 Hz), 0.90 (d, 3H, J=8 Hz); 13C NMR (100 MHz, CDCl3, 90.15/9.85 mixture of diastereomers, signals for the major diastereomer) δ 191.1, 180.9, 70.9, 59.5, 43.0, 38.5, 35.9, 35.7, 35.6, 28.2, 26.6, 25.6, 19.0, 18.4; IR (neat): 3168, 2959, 2869, 1696, 1585, 1440, 1327, 1256, 1090, 1017, 829 cm−1; Exact Mass (C14H22N2OS+H): calculated=267.1526, measured=267.1525. Chiral LC: 90.15/9.85 dr.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[CH:5]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:4]2[NH:3]1>Cl.O1CCOCC1.O>[NH:16]1[CH2:17][CH2:18][CH:13]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C@H:5]4[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:4]4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)NC4CCCCC43)CC2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
tert-butyl 4-(2-oxooctahydro-1H-benzimidazol-1-yl)-1,4′-bipiperidine-1′-carboxylate (1.2 g, 2.95 mmol) was dissolved in a mixture of 4M HCl in dioxane (15 mL) and water (5 mL). The mixture was stirred at rt for 1 hour then concentrated in vacuo to provide the title compound as a white solid (0.7 g). 1H NMR (400 MHz, CHLOROFORM-D) free base: δ ppm 1.22-1.53 (m, 5H), 1.49-1.69 (m, 1H), 1.69-1.88 (m, 7H), 1.94 (m, 1H), 2.04-2.52 (m, 6H), 2.60 (t, J=11.33 Hz, 2H), 2.82-3.09 (m, 4H), 3.17 (d, J=12.89 Hz, 2H), 3.59-3.88 (m, 1H), 4.47-4.68 (m, 1H). MS (M+1): 307.3.