Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH2:9][NH2:10])[CH2:2][O:3][CH2:4][CH2:5][NH2:6].[O:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18]>CC#N>[NH2:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:7][CH2:8][CH2:9][NH:10][C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]([OH:18])=[O:11]
Reactant: NCCOCCOCCN
Reactant: O=C1COCC(=O)O1
Solvent: CC#N
Product: NCCOCCOCCNC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of 2,2′-(ethane-1,2-diylbis(oxy))diethanamine (1.4830 g, 10.0 mmol) in CH3CN (15 mL) was added dropwise a solution of 1,4-dioxane-2,6-dione (1.1560 g, 10.0 mmol) in CH3CN (5 mL) over 5 minutes and the mixture was stirred for 5 hours at room temperature. A colorless supernatant was discarded by decantation. 5 mL of CH3CN was added and the mixture was vortexed for 30 seconds. The supernatant was decanted. The remaining residue was dissolved in 1M HCl (20 mL) and chromatographed with Dowex 50W 8 ion-exchange resin (15 mL resin, H+-form). The mono-acid product was eluted with water and followed by 0.15M of NH4OH. The reaction afforded 37% yield of the mono-acid product as light yellow gum (JL01). 1H-NMR (400 MHz, DMSO-d6) δH 9.69 (t, J=5.20 Hz, 1H), 8.27 (br, 3H), 3.87 (s, 2H), 3.73 (s, 2H), 3.66 (t, J=5.40 Hz, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.48 (t, J=5.00 Hz, 2H), 3.27 (m, 2H), 2.91 (t, J=5.40 Hz, 2H); 13C-NMR (101 MHz, DMSO-d6) δC 174.17, 170.48, 72.94, 72.27, 69.89, 69.81, 69.39, 66.98, 48.63, 38.54; MS (ESI) m/z 265 (M+).
Reaction SMILES: Br[CH:2]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1)[C:3]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[F:13])=O.[NH2:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[S:28]>CN(C=O)C>[CH:23]([C:20]1[N:18]2[N:19]=[C:14]([C:2]3[S:28][C:27]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:26][C:3]=3[C:5]3[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=3[F:13])[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3cc(F)c(F)cc3F)nn12
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3-c3cc(F)c(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
A mixture of 2-bromo-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4,5-trifluorophenyl)ethanone (0.90 g, 2.2 mmol; prepared using General Procedure J from Preparation #F.1 and Preparation #G.1, General Procedure K with H2SO4, and General Procedure A.2), tert-butyl 4-(aminocarbothioyl)tetrahydropyridine-1-(2H)-carboxylate (Maybridge, 0.8 g, 3.3 mmol) and DMF (20 mL) was stirred at ambient temperature for about 24 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with Et2O (300 mL). The organic layer was dried over Na2SO4, decanted, and concentrated. The crude material was loaded onto a silica gel column and eluted with a gradient of 0-10% MeOH in DCM to give the title compound (0.41 g, 34%): LC/MS (Table 1, Method a) Rt=4.18 min; MS m/z: 559.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:34])[C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[NH:8][C:9](=[O:21])[CH:10]([CH2:16][S:17][C:18](=[O:20])[CH3:19])[CH2:11][S:12][C:13](=[O:15])[CH3:14])(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:13]([S:12][CH2:11][CH:10]([CH2:16][S:17][C:18](=[O:20])[CH3:19])[C:9]([NH:8][C@H:7]([C:6]([OH:34])=[O:5])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:21])(=[O:15])[CH3:14]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 1 h

Procedure:
Nα -[2-(acetylthiomethyl)-3-(acetylthio)propanoyl]-Nε -tert.butyloxycarbonyl-L-lysine tert.butyl ester (3 g.) is dissolved in a mixture of trifluoroacetic acid and anisole, and the mixture is stored at room temperature for one hour. The trifluoroacetic acid is removed in vacuo, the residue is distributed between ether and water and the aqueous layer is applied to a column of Dowex 50. After washing the acidic material with water, the Nα -[2-(acetylthiomethyl)-3-(acetylthio)propanoyl]-L-lysine is eluted with a buffer of pyridine-acetic acid at pH 6.5.
Reaction SMILES: [OH:1][CH2:2][C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:18][C:19]1[C:20]([NH:28][C@@H:29]2[CH2:34][O:33][CH:32]([CH2:35][C:36]#[N:37])[CH2:31][CH2:30]2)=[C:21]2[S:27][CH:26]=[CH:25][C:22]2=[N:23][CH:24]=1>C1COCC1.C(O)C>[OH:1][CH2:2][C:3]1[N:28]([C@@H:29]2[CH2:34][O:33][C@@H:32]([CH2:35][C:36]#[N:37])[CH2:31][CH2:30]2)[C:20]2=[C:21]3[S:27][CH:26]=[CH:25][C:22]3=[N:23][CH:24]=[C:19]2[N:18]=1
Reactant: NC(=O)CO
Reactant: N#CCC1CC[C@H](Nc2c(N)cnc3ccsc23)CO1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC[C@H]1CC[C@H](n2c(CO)nc3cnc4ccsc4c32)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A mixture of 2-hydroxyacetamide (93.3 mg, 1.24 mmol) and triethyloxonium tetrafluoroborate (234 mg, 1.23 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.7 mL) and added to a suspension of {(5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}acetonitrile (101 mg, 0.350 mmol) in ethanol (2.6 mL). The reaction mixture was stirred at 80° C. for 1 h, and then cooled to room temperature. The solid was filtered off. The filtrate was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (40 mg, 35%). LCMS calculated for C16H17N4O2S (M+H)+: m/z=329.1. Found: 329.1. 1H NMR (DMSO-d6, 500 MHz) δ 8.98 (s, 1H), 8.04 (d, J=5.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.92 (m, 1H), 4.87 (s, 2H), 4.28 (m, 1H), 4.18-4.11 (m, 1H), 3.98 (m, 1H), 2.95 (dd, J=17.0, 4.3 Hz, 1H), 2.83 (dd, J=17.0, 6.6 Hz, 1H), 2.64 (m, 1H), 2.49 (m, 1H), 2.22 (m, 1H), 2.06 (m, 1H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2=NC=[CH:17][CH:18]=[C:13]2[CH:12]=[CH:11]1>>[CH2:11]([N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:12][CH2:13][CH2:18][CH3:17]
Reactant: c1cnc2cc[nH]c2c1
Reactant: c1cnc2[nH]ccc2c1
Product: CCCCCn1ccc2ncccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations using 1H-pyrrolo[3,2-b]pyridine to replace 1H-pyrrolo[2,3-b]pyridine, the title compound was obtained (75%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.39 (d, 1H), 7.56 (d, 1H), 7.25 (d, 1H), 7.05-7.01 (m, 1H), 6.63 (d, 1H), 4.05-3.99 (m, 2H), 1.79-1.72 (m, 2H), 1.31-1.45 (m, 4H), 0.81 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 146.8, 142.9, 131.0, 128.9, 116.5, 116.1, 102.0, 46.6, 30.0, 29.0, 22.2, 14.0; MS (ES+) m/z 189.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-methylsulfonylmethyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 1): tR=1.26 min; Mass spectrum (ESI+): m/z=471 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CN(C)C=O>[CH:12]1([NH:18][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1NC1CCCCC1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 5.0 g (31 mmol) 2.5-difluoronitrobenzene, 3.8 ml (31 mmol) cyclohexylamine and 4.4 ml (31 mmol) triethylamine in 50 ml dimethylformamide was stirred at 80° C. for 2 h. After cooling to 25° C. 100 ml water was added. The precipitate was filtered off and washed with water to give 6.1 g (82%) N-cyclohexy-4-fluoro-2-nitroaniline. M.p. 93.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([N:30]=[C:31]4[CH2:34][CH2:33][CH2:32]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+]>O1CCCC1.Cl>[CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([NH:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
The product of Example 304G (0.178 g, 0.35 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with methanol (0.025 mL, 0.70 mmol), followed by dropwise addition of a 2.0 M solution of lithium borohydride in tetrahydrofuran (0.260 mL, 0.52 mmol), stirred at 25° C. for one hour, and diluted with 1 N HCl. The resulting precipitate was filtered and dried. The solid was dissolved in tetrahydrofuran and absorbed onto silica gel by evaporating to dryness. The resulting silica was loaded onto a 2 g Alltech sep pack and eluted with dichloromethane to give the title compound (0.059 g, 33%). MS (ESI−) m/z 515 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55 (m, 1 H) 1.71 (m, 1 H) 2.04 (m, 4 H) 3.77 (m, 1 H) 5.26 (s, 2 H) 6.57 (d, J=5.15 Hz, 1 H) 7.45 (m, 8 H) 7.64 (d, J=9.56 Hz, 1 H) 7.88 (m, 1 H) 8.05 (d, J=8.46 Hz, 1 H) 8.17 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][C@H:4]([CH3:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:6].[H][H]>[Pd].CC1CCCO1>[CH3:17][N:2]([CH3:1])[CH2:3][C@H:4]([CH3:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)=[O:6]
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC1CCCO1
Product: C[C@@H](CN(C)C)C(=O)c1cccc(N)c1
Temperature: 2 °C
Yield: 98 %

Procedure:
(S)-3-(dimethylamino)-2-methyl-1-(3-nitro-phenyl)-propan-1-one (100 g, 0.423 mol), methyl-tetrahydrofuran (400 ml) and Pd/C 5%, anhydrous (4.0 g) are added into a 1 liter autoclave, at room temperature. The suspension is cooled to 0-4° C., then it is hydrogenated at 2 bars of hydrogen gas without exceeding 8° C. The conversion is monitored using HPLC and it is deemed complete when the HPLC area % of the initial product and the reaction intermediates is <0.3. Then catalyst is filtered and the solution can be used as it is in the subsequent step or concentrated under vacuum at 45-50° C. to oily residue. About 86 g of yellow to dark red oil are obtained (about 98% yield, ee≧97%, purity ≧92%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][O:36][CH2:37][CH3:38])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:34])[CH2:21][CH2:22][C:23]([NH:25][NH:26]C(OC(C)(C)C)=O)=[O:24])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][O:36][CH2:37][CH3:38])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:34])[CH2:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NN
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of tert-butyl 2-[4-({2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoyl]hydrazinecarboxylate (792 mg, 1.50 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL). After stirring for 2 hours, additional trifluoroacetic acid (3 mL) was added to the reaction mixture and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting syrup was dissolved in water. The solution was made basic by the addition of concentrated ammonium hydroxide and then was extracted repeatedly with 10% methanol/chloroform. The combined organic portions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude white solid was purified by chromatography on silica gel (gradient elution, 25%-75% CMA in chloroform) gave 340 mg of N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-4-hydrazino-4-oxobutanamide.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[O:27][CH3:28])=[CH:15][CH:14]=2)[CH:5]=1.[OH-].[Li+].CO>C1COCC1>[F:26][C:22]1[C:23]([F:25])=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[F:10])[C:3]([OH:29])=[O:2])=[CH:18][CH:17]=2)=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COC(=O)c1ccc(F)c(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cc(C(=O)O)ccc2F)cc1
Yield: 94.9 %

Procedure:
3-(4′,5′-Difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid methyl ester (0.76 g, 1.9 mmol) was dissolved in THF (10 mL) and lithium hydroxide solution (0.5N, 8 mL) was added followed by addition of methanol (2 mL). The mixture was refluxed for 2 hrs and solvents were evaporated. The mixture was extracted with ether and water. The aqueous layer was treated with hydrochloric acid (1N, 5 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Solvents were evaporated to give a white solid as 3-(4′,5′-difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid (0.7 g, 96%). HRMS-ES calculated for C21, H15, F3, O4, 411.0814; found m/z 411.0815 [M+Na]+; 1H-NMR (DMSO-d6) δ ppm 13.15 (br, s, 1H), 8.16 (dd, J=7.2, 1.8 Hz, 1H), 7.96-8.04 (m, 1H), 7.32-7.45 (m, 4H), 7.24 (dd, J=13.0, 6.9 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 5.24 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18.0 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure to give a residue which was dried in vacuum to obtain a yellow solid of 4-nitrobenzoyl chloride. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. 4-nitrobenzoyl chloride (3.34 g, 18.0 mmol) was then added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. Evaporated the solvents under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, and washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(4-nitrobenzamido)benzoic acid (1.8 g, yield 100%) as a yellow solid. MS (ESI) m/z 303 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCCCCC.C([Li])CCC.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C(OCC)C>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(C)c([Si](C)(C)C)c1
Reaction time: 5 h

Procedure:
To a stirred solution of 1.0M of 2-bromo-p-xylene in diethyl ether at 0° C. was added n-butyllithium hexane solution solwly, and the mixture was stirrd for 5 hr. To the above reaction mixture was added 1.0M of chlorotrimethylsilane as dropwise and it was stirred for 24 hr. The solvent was removed under reduced pressure, and the residne was redistilled in vacuo to afford titled compound(TSTX) in colorloss state. The structure of product was identified by infrared and nuclear magnetic resonance spectrum, and the result is summarized in Table 1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:27]=1.[C:29](OCC)(=[O:32])[NH:30][NH2:31]>>[CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8]3[N:7]([C:29](=[O:32])[NH:30][N:31]=3)[C:6]=2[CH:27]=1
Reactant: CCOC(=O)NN
Reactant: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2NC(=S)c2cccnc21
Product: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 8,9-dimethyl-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-thione is heated to about 200° C. wth ethyl carbazate to give 6,7-dimethyl-2,9-dihydro-9-[(dipropylamino)-acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:27][CH:28]=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3)n2)cc1
Yield: 84.1 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (391 mg), 65% oily sodium hydride (60 mg) and 4-(chloromethyl)-2-((E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (375 mg), the same reaction as Example 2 was carried out to yield the titled compound (583 mg).
Reaction SMILES: [CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][NH:10][CH2:9]1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)C[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 4 h
Yield: 85 %

Procedure:
A sample of (3R,4S)-tert-butyl 3-(isopropylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)piperidine-1-carboxylate (0.688 g) was dissolved in CH2Cl2 (10 mL) prior to the addition of trifluoroacetic acid (0.92 mL, 11.9 mMol). After 4 h, the reaction was made basic with saturated NaHCO3. Extracted with CH2Cl2. The organic layer was washed with brine and dried (MgSO4). Concentrated and dried in vacuo to yield the desired product, N—((S)-1-((3R,4S)-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide) (0.482 g, yield=85%). MS found: (M+H)+=476.31.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])=[CH:15][C:14]=1[Cl:20]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3ccccc3-c3nc4ccccc4s3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 4-methoxybenzene-1-sulfonyl chloride.
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[OH-].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)O.C(O)C>[CH3:2][C:3]1[N:8]=[C:7]([OH:1])[CH:6]=[C:5]([Cl:10])[N:4]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(O)cc(Cl)n1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of water (8.5 mL) in sulfuric acid (32 mL) was added 2-methyl-4,6-dichloropyrimidine (13.4 g, 82 mmol). The mixture was stirred for 1 hour at 23° C. and then poured onto an ice/water slurry containing sodium hydroxide (24 g, 600 mmol). When the ice had melted, sodium chloride (90 g) was added and allowed to dissolve. The product precipitated and was isolated by filtration (9.5 g) 80%. An analytical sample was prepared by recrystallization from ethanol m.p. 230°-234° C. as a fluffy yellow solid.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1C=CC=CC=1.CO>[Br:1][CH:2]([CH3:6])[C:3]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: C1COCCN1
Solvent: c1ccccc1
Solvent: CO
Product: CC(Br)C(=O)N1CCOCC1

Procedure:
This compound is prepared by reaction of 2-bromopropionylchloride with morpholine under the experimental conditions of Example 10: b.p. 115°-120° C. (0.1-0.2 mm); Rf=0.52 (C6H6 -MeOH 80:20); IR (neat) νmax: 2860, 1660, 1470, 1440, 1280, 1260, 1125, 1040 cm-1. The product is very irritating to the skin and mucosae.