Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: COc1cc(C=O)ccc1C#N
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(C2CO2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 ml). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched by drop-wise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (J=2.5 Hz, 1H); LC/MS (IE, m/z) 176.33 [M+1]+; tR=2.55 min.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1.C([O:32][B:33](OC(C)C)[O:34]C(C)C)(C)C.Cl>C1COCC1>[CH3:27][CH:26]([C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([B:33]([OH:34])[OH:32])=[CH:8][CH:9]=3)[CH2:16][CH2:17]2)[O:25][N:24]=1)[CH3:28]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(B(O)O)cc3)CC2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
n-Butyllithium (2.5M in hexanes, 0.56 mL, 1.4 mmol) was added dropwise to a solution of 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 380 mg, 1 mmol) in THF (5 mL) at −78° C. The mixture was stirred at −78° C. for 2 h, and was then charged with a cooled solution (−78° C.) of triisopropylborate (0.46 mL, 2 mmol) in THF (3 mL) at −78° C. The reaction mixture was allowed to warm up to ambient temperature and stirred at ambient temperature overnight. The reaction mixture was charged with 1N HCl (20 mL) and stirred at ambient temperature for 1 h. The mixture was then extracted with Et2O, and the organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 7% MeOH/CH2Cl2 to give 120 mg (35%) of the {4-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]phenyl}boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 2H), 7.69 (d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=8.8 Hz), 4.04-3.92 (m, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.15-3.05 (m, 2H), 2.84-2.73 (m, 1H), 2.04-1.94 (m, 1H), 1.88-1.78 (m, 2H), 1.37-1.22 (m, 2H), 1.16 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 346 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Yield: 56.7 %

Procedure:
267 (220 mg, 0.47 mmol) and LiOH (56 mg, 2.37 mmol) were suspended in THF (2 mL) and H2O (2 mL) and stirred overnight at room temperature. The THF was removed, the mixture was diluted with H2O, and acidified to pH=5 with 1M HCl. The crude product was purified via HP-LC to provide 268 (120 mg, 56% yield) as a white solid. LC-MS (M+H=451, obsd.=451).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:12]=1)=[O:5])[CH3:2].[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][NH:42][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH2:13][N:11]2[CH:12]=[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:10]2)=[CH:15][CH:16]=1)=[O:20]
Reactant: Cc1oc(-c2ccccc2)nc1CN
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2)nc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 82.8 %

Procedure:
A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (500 mg), (5-methyl-2-phenyl-4-oxazolyl)methylamine (260 mg), 1-hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained yellow crystals were collected by filtration, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg, yield: 87%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 190–191° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2[C:30]([N:35]([CH3:37])C)=[CH:31][CH:32]=[CH:33]C=2)CCCCC1.N1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:35]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:37]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: C1CCNCC1
Product: c1ccc(COc2cccc(N3CCCCC3)c2)cc1
Temperature: 110 °C
Reaction time: 21 h
Yield: 708.5 %

Procedure:
To a solution of 1-(benzyloxy)-3-bromobenzene (1.00 g) in 1,2-dimethoxyethane (15 mL) were added tris(dibenzylideneacetone)dipalladium(0) (180 mg), 2′-[dicyclohexylphosphino]-N,N-dimethylbiphenyl-2-amine (150 mg), piperidine (500 μL), and tripotassium phosphate (2.5 g) at room temperature, and the mixture was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, insolubles were separated by filtration and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-85/15) to obtain 1-[3-(benzyloxy)phenyl]piperidine (722 mg).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].O.C(OC([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][CH2:35][CH2:36][OH:37])[CH:25]=[N:26][CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][CH2:35][CH2:36][OH:37])[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccccc2CCCO)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCCCc1ccccc1-c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82 %

Procedure:
A mixture of CF3COOH, H2O, and CH2Cl2 (10:1:50, 2.44 mL) was added to a 10 mL round-bottom flask containing 3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-1-propanol (99.5 mg, 0.25 mmol). The flask was capped with a glass stopper, and the reactants were stirred at room temperature for 14 h. The reaction mixture was concentrated with a rotary evaporator (bath up to 35° C.) and was further dried on an oil pump (35° C.). The residue was dissolved in water (1 mL), and the aqueous solution was lyophilized. The resulting oil was purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 8% to 25% CH3CN in water within 20 min, from 25% to 100% in another 20 min, then 100% CH3CN for 20 min, both solvents containing 0.1 vol % CF3COOH; tR 19.6-23.7 min). Partial evaporation to remove CH3CN, followed by lyophilization, gave the product as a yellowish oil (121 mg, 82%). 1H NMR (CD3OD, 500 MHz) δ 8.85 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 7.45 (d, 2H, J=4.6 Hz), 7.38-7.33 (m, 1H), 7.29 (d, 1H, J=7.6 Hz), 4.98-4.95 (m, 1H), 4.61-4.52 (m, 2H), 4.21-4.09 (m, 2H), 3.48 (t, 2H, J=6.2 Hz), 2.72 (t, 4H, J=6.2 Hz), 1.78-1.69 (m, 2H). Anal. Calcd. for C18H22N2O2.2.41CF3COOH.1.04H2O (FW 591.9): C, 46.30; H, 4.51; N, 4.73; F, 23.21. Found: C, 46.31; H, 4.40; N, 4.71; F 23.18.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl[C:12]([C:14]12[N:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2)=O.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:12]([C:14]34[N:20]([C:21]([O:23][CH2:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[O:22])[CH:17]([CH2:16][CH2:15]3)[CH2:18][CH2:19]4)=[N:1][C:2]=2[CH:6]=1
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)Cl)CC2
Reactant: NC(=O)c1sc(Br)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1C2CCC1(c1nc3cc(Br)sc3c(=O)[nH]1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, the crude product (2.0 mmol) of benzyl 1-(chlorocarbonyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate produced above and tetrahydrofuran (10 mL) was added N-ethyl-N-(1-methylethyl)propan-2-amine (0.70 mL) at room temperature. After stirring for 1 hr, the reaction system was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added ethanol (10 mL) and 2M sodium hydroxide (2.5 mL), and the mixture was stirred at 100° C. overnight. The reaction system was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (313 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[N:12]O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(C=NO)c[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(CN)c[nH]c2c1

Procedure:
To a mixture of 6-methyl-1H-indole-3-carbaldehyde oxime (0.66 g) and NiCl2.6H2O (0.97 g) in methanol (60 ml) was added at 22° C. sodium borohydride (3.04 g) in portions. The suspension was filtered and the filtrate evaporated. The residue was partitioned between aqueous NH3 (1%) and ethyl acetate, the organic layer was dried and evaporated to the give crude C-(6-methyl-1H-indol-3-yl)-methylamine as a yellow semi solid (0.68 g).
Reaction SMILES: [C:1]([N:4]=[C:5]([N:10]1[CH2:14][CH2:13][S:12][CH:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:26][CH2:25]1)[O:6]C(=O)C)(=[O:3])[CH3:2].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[C:1]([NH:4][C:5]([N:10]1[CH2:14][CH2:13][S:12][CH:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:28][CH2:29]1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N=C(OC(C)=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
0.59 g of N,O-diacetyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboximidic acid is dissolved in a mixture of 15 ml of ethanol and 5 ml of tetrahydrofuran, and 1.34 ml of 10% aqueous sodium hydroxide solution is added thereto under ice-cooling. The mixture is stirred for 15 minutes, and the mixture is neutralized with 10% hydrochloric acid. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with ethyl acetate, and the extract is washed with an aqueous sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and ether. 0.49 g of N-acetyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.[Cl:16][CH2:17][C:18]([CH3:22])(O)[CH:19]=[CH2:20]>ClC1C=CC=CC=1.CCCCCC.C(OCC)C>[Cl:16][CH:17]([C:8]1[C:2]([CH3:1])=[C:3]([OH:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[OH:7])[C:18]([CH3:22])=[CH:19][CH3:20]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: CC=C(C)C(Cl)c1c(C)c(O)c(C)c(C)c1O
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Trimethylhydroquinone (2.01 g, 14 mol) was suspended at room temperature in a mixture of chlorobenzene (10 ml) and hexane (5 ml). Boron trifluoride diethyl ether complex (3.60 ml of a 48 percent strength solution of boron trifluoride in diethyl ether, 1.95 g of boron trifluoride, 28 mmol) was then added in the course of 15 min. 1-Chloro-2-methylbut-3-en-2-ol (2.42 g, 20 mmol) was then added dropwise in the course of 15 min. After 30 min., the reaction mixture was filtered, and the filtrate was washed with chlorobenzene (10 mol) and dried at 40° C./20 mbar for 8 hours. 2.24 g (62.9 percent) of 2-(1-chloro-2-methylbut-2-en-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene were obtained. The melting point of the product Was 118 to 122° C. (decomposition). Other data regarding the product was:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.O.[OH-].[Na+]>CC1CCCNC1>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][CH2:4][CH2:3][N:9]3[CH2:8][CH2:7][CH2:6][CH:15]([CH3:14])[CH2:10]3)=[CH:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Agent: CC1CCCNC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1CCCN(CCNc2ccnc3cc(Cl)ccc23)C1
Yield: 64.3 %

Procedure:
2.5 g of N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride in 25 ml of 3-methylpiperidine were held at 100° C. in a sealed tube for 24 hours. Thereafter, 100 ml of water were added, the mixture is adjusted to pH 12 by means of concentrated sodium hydroxide solution and extracted three times with 50 ml of ethyl acetate each time. The combined extracts were washed with a small amount of water and concentrated. The residue was recrystallized from 80 ml of acetone. 0.88 g of colourless crystals, m.p.: 148°-151° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:15][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)c(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of methyl 4-bromo-3-hydroxy-2-nitrobenzoate (5.41 g, 19.6 mmol) and potassium carbonate (5.42 g, 39.2 mmol) in N,N-dimethylformamide (30 mL, 387 mmol) was treated with benzyl bromide (3.26 mL, 27.4 mmol) and stirred at 60° C. for 1 h. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude tan oil. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (6.99 g, 97%) as a yellow solid. LCMS calculated for C15H16BrN2O5 (M+NH4)+: m/z=383.0, 385.0. found: 383.0, 385.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)N1CCCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCCC1.CN(C)C=O.CCOCC>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[O:20])[S:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)N1CCCC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)N1CCCC1=O

Procedure:
3-(4-Nitro-phenyl)-5-[(2-oxo-pyrrolidine-1-carbonyl)-amino]-isothiazole-4-carboxylic acid amide (10.2 g,) and 10% palladium on carbon (2 g) in tetrahydrofuran (300 mL) and dimethylformamide (50 mL) was hydrogenated at 80 psi over 24 hr in metal bomb. The catalyst was removed by filtration through celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give an off white solid, which was stirred in ether (150 mL) and filtered to give the title compound as a off white solid (8.7 g, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27]CC)=[O:26].CC(C)([O-])C.[K+].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:24][C:25]([OH:27])=[O:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (100 g) and ethyl bromoacetate (100 ml) in tetrahydrofuran (500 ml) was added a solution of potassium t-butoxide (100 g) in tetrahydrofuran (500 ml) in a nitrogen stream at -15°~-10° C. for 2 hours and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added 2N aqueous sodium hydroxide (500 ml) at 0°-10° C. and the mixture was stirred at ambient temperature for 18 hours. The organic solvent was evaporated under reduced pressure to give an aqueous solution. To the aqueous solution was added water (500 ml), adjusted to pH 10 with 4N aqueous sodium hydroxide and washed with ethyl acetate (500 ml×2). The aqueous solution was adjusted to pH 4 with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml×2). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-(carboxymethyloxymethyl)-4-methanesulfonyloxypyrrolidine (94.0 g).
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:15].[Cl:1][C:9]1[CH:8]=[CH:7][C:6]2[O:2][CH2:3][CH2:4][C:5]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NCCCc1cccc2c1CCO2
Agent: Cl
Solvent: CC(=O)O
Product: NCCCc1c(Cl)ccc2c1CCO2
Yield: 91.3 %

Procedure:
A solution of of 3-(2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride (150 mg) and N-chlorosuccinimide (100 mg) in acetic acid (50 ml) was stirred at room temperature overnight. The solution was evaporated to dryness and the residue taken up in water, basified with 2N sodium hydroxide and extracted with dichloromethane. The extracts were dried and evaporated and the residue disolved in a solution of hydrogen chloride in methanol. Evaporation gave the the title compound (159 mg) as an off-white powder after trituration with ether.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH:1]1([C:14]([OH:20])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Cl[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1ccccc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
A solution of cyclopentylmagnesium chloride in diethyl ether was added dropwise to a solution of 23.5 g of ethyl phenylglyoxylate in 200 ml of tetrahydrofuran under cooling with ice, and this mixture was stirred at the same temperature for 30 minutes. After the addition of a saturated aqueous solution of ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 20/1) to obtain 11 g of ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate. This was dissolved in 40 ml of methanol, and 20 ml of a 4N aqueous solution of sodium hydroxide was added thereto at room temperature. This mixture was stirred at the same temperature for 2 hours and then at 50° C. for an hour. After the methanol was distilled off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting solid was washed with diethyl ether/hexane (=1/1) to obtain 8.7 g of the title compound.