Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:37](O)(=[O:46])/[CH:38]=[CH:39]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[C:37](=[O:46])/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(CCN(Cc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3′-[{2-[4-(Aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide (506 mg), trans-cinnamic acid (163 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl; 211 mg) and 1-hydroxybenzotriazole (HOBT; 149 mg) were dissolved in a mixed solvent of dichloromethane (15 ml) and DMF (7 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and water was added to the residues which were then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (dichloromethane/methanol=98/2), whereby the title compound (284 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: OCCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)N1CCCCC1CCO
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Triethylamine (0.79 ml) and myristoyl chloride (1.270 g) were added to a solution of 2-(2-hydroxyethyl)piperidine (0.660 g) in methylene chloride (7 ml) under argon gas atmosphere while being cooled with ice. After being stirred for 2 hours, the reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.664 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[OH:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1ccc(O)cc1C(=O)O
Product: O=c1[nH]cnc2ccc(O)cc12
Temperature: 190 °C

Procedure:
To a solution of 2-amino-5-hydroxybenzoic acid 0201 (30.6 g, 0.2 mol) in formamide was stirred and heated to 190° C. for 0.5 h. The mixture was allowed to cool to room temperature.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[CH:3]\[C:4](OC)=[O:5].C1C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>CO>[CH3:1]/[C:2](/[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[CH:3]\[CH2:4][OH:5]
Reactant: C=C(C)CCC/C(C)=C/C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: c1ccccc1
Product: C=C(C)CCC/C(C)=C/CO
Reaction time: 2 h

Procedure:
To a mixture of the foregoing dienoic ester (0.827 mmol) and 7.5 ml of benzene, under nitrogen, is added 1.5 ml of 1.78 M diisobutyl aluminum hydride (DIBAH). After about 2 hours, 1 ml more of DIBAH is added and the reaction continued to completion as checked by thin layer chromatography. The reaction is worked up by adding about 2 ml of methanol and dilute HCl. The aqueous layer is extracted with ether. Then the combined ether phases are washed with water and brine, dried over sodium sulfate and solvent evaporated to yield (E)-3,7-dimethyl-2,7-octadien-1-ol.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[C:8]([O:22][CH3:23])[CH:7]=2.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1>C(#N)C>[CH2:20]([S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:22][CH3:23])[N:5]=[C:4]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:3]([CH2:2][N:34]1[CH2:39][CH2:38][CH:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH2:36][CH2:35]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:18])=[O:19])[CH3:21]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CBr)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Solvent: CC#N
Product: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A suspension of methyl 3-(bromomethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.983 g, 3.63 mmol) and 4-(4-piperidinyl)morpholine (0.803 g, 4.72 mmol) in acetonitrile (30 mL) was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via reverse phase HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.0 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.98 (s, 1H), 7.90 (t, J=7.91 Hz, 2H), 7.75-7.84 (m, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 3.61 (s, 2H), 3.50-3.58 (m, 6H), 2.63 (d, J=11.04 Hz, 2H), 2.38 (br. s., 4H), 1.93-2.08 (m, 1H), 1.81 (t, J=10.92 Hz, 2H), 1.61 (d, J=11.54 Hz, 2H), 1.22-1.30 (m, 2H), 1.15 (t, J=7.40 Hz, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][Si:15]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+].[C:30](Cl)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.[Pd]>[CH2:33]([O:32][C:30](=[O:31])[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:12]2[CH2:17][CH2:16][Si:15]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[C:4]([F:11])[CH:5]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[Si]1(c2ccccc2)CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si]1(c2ccccc2)CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
To a solution of 9b (1.96 g, 7.59 mmol) in THF, Pd/C is added for hydrogenation under a pressure of 35 psi in a par hydrogenator. The reaction mixture was filtered through celite. To the filtrate, saturated NaHCO3 (1.90 g, 22.77 mmol) and CBzCl (1.3 mL, 9.10 mmol) were added and stirred at 25° C. for 5 h. The solvent is removed, 10 mL water is added and the aqueous layer is extracted with EtOAc. The crude mixture is then subjected to column chromatography on silica gel using hexane-DCM mixtures to afford the product 10b as a viscous liquid (1.80 g) in 71% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1.[H-].[Na+].Cl.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52]Cl.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN(C)C)c3ccccc23)cc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
To a solution of Compound 1 (2.0 g, 3.19 mmol) obtained in Example 1 in 30 ml of N,N-dimethylformamide was portionwise added sodium hydride (60% in oil, 270 mg, 6.71 mmol) with stirring at 0° C., and 2-dimethylaminoethylchloride hydrochloride (460 mg, 3.19 mmol) was added thereto, followed by heating to 80° C. and then stirring for one hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution for neutralization, and water was added thereto followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.9 g of a crude product. The obtained crude product was purified with silica gel column chromatography (ethyl acetate/hexane=1/1-ethyl acetate alone) to give 2.1 g (yield: 94%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]([C:28]1[S:32][C:31]([C:33](O)=[O:34])=[CH:30][CH:29]=1)([CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[C:12]([CH3:27])[CH:11]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:33]([C:31]1[S:32][C:28]([C:4]([CH2:5][CH:6]=[CH2:7])([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH3:27])[C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)=[C:14]([CH3:16])[CH:15]=2)[CH2:1][CH:2]=[CH2:3])=[CH:29][CH:30]=1)=[O:34]
Reactant: COC(=O)CCN
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Yield: 69.7 %

Procedure:
To a mixture of 5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carboxylic acid (0.1695 g, 0.338 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.0533 g, 0.382 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.0561 g, 0.415 mmol) in DMF (3.5 mL) is added N, N-diisopropylethylamine (0.175 mL, 1.00 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.0836 g, 0.436 mmol) and stirred overnight. The reaction mixture is poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide 3-({5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.138 g, 70%) as a white foam. MS (ES): 584.3 [M−H]−.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1>ClCCl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([CH:21]1[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:20])=[O:15])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 3 °C

Procedure:
A 5 L four-necked flask (equipped with mechanical stirrer, nitrogen inlet, thermocouple, and glass stopper) was charged with Boc-D-Valine (143.6 g, 0.661 mol) and dichloromethane (2.8 L). The reaction was chilled to ˜3° C. in an ice bath, and then 4-N,N-dimethylaminopyridine (124.6 g, 1.02 mol) and Meldrum's acid (104.8 g, 0.727 mol) were added to the reaction. To the reaction mixture was then added 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (EDCl, 139.4 g, 0.727 mol) over a five-minute period, and then the reaction mixture was allowed to warm to room temperature over 18 h (overnight). The reaction mixture washed with 5% (w/w) aqueous potassium bisulfate (4×600 mL), dried (MgSO4), and the solution was used directly in the next step without concentration or purification. A small portion was concentrated and displayed the following analytical data.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:32]=[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(4-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 11, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24](Cl)[S:25][C:21]=2[CH:20]=1>C1COCC1.O>[Br:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[S:25][C:21]=2[CH:20]=1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (590 mg, 2.79 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 142 mg, 3.55 mmol) followed by 6-bromo-2-chlorobenzo[d]thiazole (631 mg, 2.54 mmol). The reaction mixture was stirred at 60° C. for 4 h. The mixture was cooled to rt, diluted with water (40 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol, 65% yield) as a white solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:15]([F:23])=[CH:14][C:11]=1[C:12]#[N:13].ClC1N=C(Cl)C(F)=CC=1C#N.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]1[C:15]([F:23])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:9])[N:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1cc(F)c(NCCCO)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of t-butyidimethylsilyl chloride (0.73 9, 4.79 mmol) in CH2Cl2 (21 mL) was added 2-chloro-5fluoro-6-[(3-hydroxypropyl)amino]nicotinonitrile [prepared as in Example 302] and starting from 2,6dichloro-5fluoronicotinonitrile] (1.0 g, 4.35 mmol), followed by Et3N (0.48 9, 4.79 mmol) and DMAP (0.01 g, 0.09 mmol). The resulting cloudy mixture was stirred at rt for 18 h, and then diluted with CH2Cl2. The organic layer was washed with water, dried (MgSO4), filtered, and then concentrated under reduced pressure. The product (1.47 g, 98%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.46 (d, 1H), 3.67 (t, 2H), 3.49 (t, 2H), 1.77 (qt, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.CO.C(OCC)C.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Nc1ccnc(Cl)c1
Solvent: CO
Solvent: CCOCC
Product: CN1CCN(c2cc(N)ccn2)CC1
Temperature: 135 °C
Yield: 18.6 %

Procedure:
4-Amino-2-chloropyridine (180 mg, 1.4 mmol) was dissolved in 1-methylpiperazine (1 ml), followed by heating at 135° C. for 16 hours in a pressure vessel. After cooling to room temperature, methanol (2 ml) and diethyl ether (2 ml) were added, and the deposited precipitate was filtered off. The resulting solid was washed with cooled diethyl ether followed by drying, to obtain a colorless crystal powder (50 mg, 18.6% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=2)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([NH:31][CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[O:20])=[CH:22][CH:23]=2)=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCC1CCOCC1
Reactant: Cc1c(-c2ccc(OCC(=O)O)cc2)noc1-c1ccccc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCC(=O)NCC3CCOCC3)cc2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
To a solution of product of step 2 (309 mg, 1.00 mmoles) in DMF (3 mL), (tetrahydro-2H-pyran-4-yl)methanamine (126 mg, 1.10 mmoles), HOBT (202 mg, 1.50 mmoles), EDC.HCl (230 mg, 1.20 mmoles) and N-ethyl morpholine (345 mg, 3.00 mmoles) were added and reaction mixture was stirred at room temperature for 20 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water, solid separated was filtered, washed with water and dried over P2O5 under vacuum to yield 260 mg of title product as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1)=[O:16].S([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.C1(C)C=CC=CC=1.O>[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)=[CH:19][CH:18]=1)=[O:16]
Reactant: Nc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: Nc1cccc(O)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(Oc2ccc(C(=O)c3cccc(N)c3)cc2)c1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of m-aminophenol 25 g (0.23 mol.) in 160 ml of dimethylsulfoxide and 190 ml of toluene was degassed for 30 minutes by bubbling nitrogen. The temperature was raised to 50° C. and 9.16 g (0.23 mol) of sodium hydroxide as 50% aqueous solution was added. The reaction temperature was slowly raised to 110° C. (oil bath 140° C.) and water was distilled off via toluene-water azeotrope. After all the water was distilled off, the toluene was distilled off till the reaction temperature reached 160° C. Reaction mixture was cooled to 80° C. and 3-amino-4'-chlorobenzophenone 53 g (0.23 mol) was added in small portions. After the addition was complete the reaction temperature was raised to 150° C. and maintained for 4 hours. After cooling to room temperature, the reaction mixture was poured into 800 ml of 2% sodium hydroxide and 1% sodium sulfite solution with rapid stirring. The precipitate semi-solid obtained was washed with water and then taken up in 200 ml of chloroform. The chloroform solution was washed twice with water. After drying with magnesium sulfate, chloroform was removed to provide a dark yellow resin like solid 52.3 g (72%), m.p. 48°-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:22])=[O:21])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:22])=[O:21])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2[C@](CCCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1

Procedure:
N-{3-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]propyl}pyridine-2-sulfonamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:2), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2].O1CCCC1.[H][H]>[C].[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1ccc(N)cc1
Yield: 73.8 %

Procedure:
Ethyl(4-nitrophenoxy)acetate (10.0 g, 44.4 mmol) and 10% palladium-carbon (50% water-containing product, 3.0 g) were added to a mixed solution of tetrahydrofuran (50 mL) and ethanol (50 mL), and the mixture was stirred at room temperature for 18 hr in a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2-2:3-1:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (6.4 g, yield 74%) as pale-pink prism crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>O>[NH:17]([C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1)[NH2:18]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(O)c2c1
Reactant: NN
Solvent: O
Product: NNc1nc(O)c2cc([N+](=O)[O-])ccc2n1

Procedure:
The wet product from Step A was dissolved in a mixture of 90 ml hydrazine hydrate and 900 ml of water and the mixture was stirred at 90°-100° C. until crystallization took place. The mixture was allowed to cool and was filtered. The product was washed with water and methanol and dried to obtain 97.2 g of 2-hydrazino-4-hydroxy-6-nitro-quinazoline in the form of a high melting, orange crystalline solid.