Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[C:5]2[CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].[C:19]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].N(C([O-])=O)=NC([O-])=O>O1CCCC1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[C:5]3[CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:16])[F:17])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2cncc(CCCC(F)(F)F)c2c1
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cncc(CCCC(F)(F)F)c3c2)CC1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
100 mg of compound 88, 118 mg of Boc-(4-hydroxy)piperidine and 416 mg of Diphenyl-[4-[1H,1H,2H,2H-perfluorodecyl]phenyl]phosphine were dissolved in 5 mL of dry tetrahydrofuran. 208 mg of Bis (1H, 2H, 2H, 3H, 3H-perfluorononyl)-azodicarboxylate were added and the reaction was allowed to stir overnight. The mixture was evaporated to dryness and filtered over a 5 g Fluoro-Flash cartridge. The obtained crude product was purified by preparative HPLC to yield 46 mg of the desired product.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[N:12][CH:13]=2)=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(Sc2ccc(Nc3nccs3)nc2)cc1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(c1ccccc1)c1ccc(Nc2nccs2)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 44 %

Procedure:
(5-Phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine (0.13 mmol) is dissolved in dichloromethane, cooled to 0° C. and m-chloro-perbenzoic acid (1 eq.) is added. The reaction is stirred 30 min at 0° C. and 2.5 hours at RT. Sodium disulfite (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with saturated NaHCO3, dried over MgSO4 and the solvent is removed in vacuo. “A13” is obtained after reversed phase column chromatography (water/acetonitrile) as a yellow powder in a yield of 44% HPLC (method C): 1.41 min; LC-MS (method A): 1.223 min, 301.95 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.657 (s, 1H), 8.634-8.628 (m, 1H), 7.853 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 7.722-7.703 (m, 2H), 7.583-7.507 (m, 3H), 7.425 (d, 1H, J=3.6 Hz), 7.152 (d, 1H, J=8.9 Hz), 7.100 (d, 1H, J=3.6 Hz).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][C:15]([C:22]([F:25])([F:24])[F:23])([C:19](F)=[O:20])[C:16](F)=[O:17]>C(COC)OC>[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][C:15]1([C:22]([F:23])([F:24])[F:25])[C:16](=[O:17])[NH:4][C:2](=[O:3])[NH:1][C:19]1=[O:20]
Reactant: CC(C)=CCC(C(=O)F)(C(=O)F)C(F)(F)F
Reactant: NC(N)=O
Solvent: COCCOC
Solvent: c1ccncc1
Product: CC(C)=CCC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 0.96 g (0.016 mol) of urea, 2.45 g (0.031 mol) of pyridine and 20 ml of glyme was stirred at 25°C while 3.8 g (0.0155 mol) of (3-methyl-2-butenyl)trifluoromethylmalonyl fluoride in 10 ml of glyme was added rapidly. The mixture was stirred overnight, heated for 10 minutes at 70°C, and evaporated to a viscous residue. Trituration of the residue with 20 ml of water gave 2.7 g (66%) of 5-(3-methyl-2-butenyl)-5-trifluoromethylbarbituric acid, mp 150°-153°C. A sample for analysis was recrystallized from water, mp 154°-155°C; ir (KBr): 3.04 and 3.18 (NH), 3.32, 3.39 and 3.44 (CH), 5.63 and 5.81 (C=O), and 8-8.5 μ (CF). Raman ir spectrum showed C=C at 5.95 μ; nmr ((CD3)2CO): 1H at ca. 9.0 (very broad (partly exchanged into acetone-d6), 2, NH), 5.03 (triplet, JHH = 7.7 Hz, 1, =CH), 3.07 (doublet, JHH = 7.7 Hz, 2, =CCH2), 1.69 and 1.67 ppm (singlets, 6, =CCH3); 19F at -69.0 ppm (singlet, CF3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[N:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([O-:3])=[O:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[OH:50][CH:46]1[C:16]2[C:9](=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[CH:15]=2)[NH:8][CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:47]1([CH3:49])[CH3:48]
Reactant: N#Cc1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(O)c2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a mixture of 4-[(3-nitro-benzylidene)-amino]-benzonitrile (21 g, 84 mmol) and ytterbium(III) triflate hydrate (5.21 g, 8.4 mmol) in dry tetrahydrofuran (150 mL) at 25° C. was added isobutyraldehyde (8.4 mL, 92 mmol) and water (1.5 mL, 84 mmol) dropwise. The reaction mixture was stirred at 25° C. for 15 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (25 g, 92%) as a light yellow oil: LC/MS m/e calcd for C18H17N3O3 (M+H)+: 324.35, observed: 324.1.
Reaction SMILES: C([O:4][CH:5]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH3:12])([CH3:11])[C:7](=[O:10])[CH2:8][CH3:9])(C)C.C([N-][CH:21]([CH3:23])[CH3:22])(C)C.[Li+].[CH3:25][C@@H:26]([CH2:29][CH:30]=[CH2:31])[CH:27]=[O:28].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[CH:14]([O:13][CH:5]([O:4][CH:21]([CH3:22])[CH3:23])[C:6]([CH3:11])([CH3:12])[C:7](=[O:10])[C@H:8]([CH3:9])[C@@H:27]([OH:28])[C@@H:26]([CH3:25])[CH2:29][CH:30]=[CH2:31])([CH3:15])[CH3:16]
Reactant: CC(C)[N-]C(C)C
Reactant: CCC(=O)C(C)(C)C(OC(C)C)OC(C)C
Reactant: C=CC[C@H](C)C=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1-diisopropoxy-2,2,-dimethyl-3-pentanone (3.29 g) in 15 mL of THF is added slowly to a solution of lithium diisopropylamide (15.7 mmol) in 20 mL of THF cooled to −78° C., the mixture is stirred for 30 minutes, warmed to −40° C. and stirred for 30 minutes, then recooled to −78° C. A solution of (2S)-2-methyl-4-pentenal (16.36 mmol) in 2 mL of CH2Cl2 is added and the mixture is stirred for 1 hour at −78° C. Saturated aq. NH4Cl is added and the mixture is warmed to ambient temperature and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered, and evaporated. The residue is purified by silica gel chromatography (2% ethyl acetate/hexanes) to separate the two diastereomeric products.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:33])[CH:12]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:9][O:10][C:11](=[O:33])[CH:12]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:27][CH:26]=1)=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(COc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
p-Fluorophenol (75 mg, 0.7 mmol) was dissolved in DMSO along with 181 mg (0.5 mmol) 2-(4-chloromethylbenzyloxycarbonyl)amino-3-phenyl-propionic acid methyl ester 37. Cesium carbonate (300 mg) was added, and the suspension was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ether and dilute aqueous HCl. The organic phase was dried, evaporated and chromatographed to give about 121 mg of 2-[4-(4-fluorophenoxy methyl) benzyloxycarbonylamino]-3-phenyl-propionic acid methyl ester 38.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6]C(C=C)=[CH:4][C:3]=1[F:10].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:32]C)C=C4)N(CC2)C1.[CH3:69][C:70]([OH:73])(C)[CH3:71].O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:69]([C@@H:70]([OH:73])[CH2:71][OH:32])=[CH:4][C:3]=1[F:10]
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(Cl)c(F)c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Product: OC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Chloro-2-fluoro-4-vinylbenzene (12.1 g, 77.3 mmol) was added to a cold (0° C.) solution of AD-mix-β (108 g, 139 mmol) in t-BuOH/H2O (600 mL; 1:1), and the mixture was allowed to warm up to room temperature overnight. The next day, the reaction was placed in an ice bath and quenched with solid Na2SO3 (114 g). The mixture was stirred for 1 hour and then extracted with ethyl acetate (3×500 mL). The combined organics were dried, filtered and concentrated to give (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol as an oil. The crude product was used in Step C without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2Cl)=[O:9])[CH2:4][CH2:3]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].Cl>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:36]2[CH2:37][CH2:38][N:33]([C:31](=[O:32])[C:30]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:34][CH2:35]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCN(c3c(C(=O)N4CCN(C)CC4)c4ccccc4n3-c3ccccc3)CC2)cc(OC)c1OC

Procedure:
This compound was prepared from 2-chloro-1-phenyl-indole 3-carboxylic acid 4-methyl-piperazide and 3,4,5-trimethoxy benzoic acid piperazide in boiling diglym according to Examples 7, 40, 42 and 45. The yield of amorphous product amounted to 77% of the theoretical yield. The hydrochloride melted at 253°-255° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([N:12]=[N+]=[N-])[CH3:11])[CH:5]=1.[H][H]>C(O)C.[C].[Pd]>[NH2:12][CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:15])[CH3:11]
Reactant: COC(=O)c1cccc(C(C)N=[N+]=[N-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(C(C)N)c1
Yield: 57.3 %

Procedure:
600 mg of the methyl 3-(1-azidoethyl)benzoate [100-1] was dissolved in 15 mL of ethanol, 200 mg of 10% palladiumcarbon catalyst was added thereto, and stirred overnight in a hydrogen atmosphere. The insolubles were filtered through celite, washed with ethanol, and then the filtrate was concentrated under reduced pressure to obtain 300 mg of methyl 3-(1-aminoethyl)benzoate [100-2] as a colorless oily product.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[S:23][CH:24]=[C:25]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[N:26]=3)[CH:15]=2)=[O:12])[CH:5]=1.O1CCCC1.CO.O.[OH-].[Li+]>O>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:31])=[O:2])[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1cccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Cc1cccc(C(=O)O)c1)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A solution composed of 0.5 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 20 ml of tetrahydrofuran, 3 ml of methanol, 3 ml of water and 353 mg of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of excess acetic acid caused the precipitation of 0.49 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 208°-209° C. after recrystallization from 2-propanol.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[CH2:15]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2ncnn2c2c1CCN2Cc1ccccc1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.94g of benzylamine, 3 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was washed with water. The crystals thus obtained were recrystallized from ethanol to give 1.4g of colorless prisms of m.p. 170.5° - 172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(O)[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1.C(=O)(O)[O-:24].[K+].[C:28](#[N:30])[CH3:29]>CS(O)(=O)=O>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([NH:30][C:28](=[O:24])[CH3:29])([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC#N
Reactant: OC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Agent: CS(=O)(=O)O
Agent: [K+]
Product: CC(=O)NC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Reaction time: 18 h

Procedure:
A mixture of 3.0 g of 8-chloro-5-(4-chlorophenyl)-5H-indeno[1,2-d]pyrimidin-5-ol in 15 ml of acetonitrile and 50 ml of methanesulfonic acid were stirred for approximately 18 hours. The reaction mixture was added to a large excess of a potassium bicarbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Crystallization from acetonitrile/water provided 2.53 g of the desired title product, m.p. 238°-241° C. Two further recrystallizations provided material with a melting point of 245°-248° C.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[C:16]=1[CH3:36])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[C:16]=1[CH3:36])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(C(=O)N(C)C)oc3c2F)cs1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C(=O)N(C)C)oc3c2N2CC[C@H](N(C)C)C2)cs1
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (442 μl, 3.48 mmol) was added at 140 to 150° C. to a dimethyl sulfoxide (56 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-2-carboxamide (I-129) (1.00 g, 2.90 mmol) and triethylamine (525 μl, 3.77 mmol), followed by stirring at the same temperature for 10 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diethyl ether to obtain the entitled compound (670 mg, 53%) as a yellow solid. The fraction containing impurities and the filtrate in suspension washing were recovered and purified in the same manner to obtain 145 mg of the entitled compound, 815 mg (64%) of the entitled compound was obtained in total.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH2:7]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I)[CH3:8]>N1C=CC=CC=1.[OH-].[NH4+]>[CH2:7]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:4][C:2]([CH3:5])([CH3:3])[CH3:1])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCNC(=O)c1ccccc1I
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCNC(=O)c1ccccc1OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide (12.25 g, 0.109 mol) was dissolved in pyridine (50 mL) and cuprous chloride (10.81 g, 0.109 mol) was added. The black suspension was stirred at RT for 30 min and N-ethyl-2-iodobenzamide (10.00 g, 36.4 mmol) dissolved in pyridine (20 mL) was added dropwise. The mixture was stirred at room temperature for 1 h and was poured in aq ammonium hydroxide and extracted with ether. The organic extracts were washed with 1 N NaOH, brine, dried (MgSO4) and concentrated to afford a brown semi-solid. The crude product as purified by flash chromatography (ethyl acetate/exanes) to afford the title compound as a light yellow olid (2.36 g, 29%). m.p. 34.5-36° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([OH:53])(=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:53][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 60 °C

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.16 g, 2.14 mmol) in dimethyl formamide (20 mL) was added palmitic acid (825 mg, 3.22 mmol) and cesium carbonate (524 mg, 1.61 mmol). The reaction was heated to 60° C. for 5 hours then allowed to cool to room temperature. The reaction was diluted with ethyl acetate (20 mL) and washed with 1:1 water/brine (3×40 mL). The organics were filtered to remove a white precipitate then dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give palmitoyloxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-89 (548 mg, 32% over 2 steps). The material was determined to be 83% pure by LCMS.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[OH-:24].[Na+].OO>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C@@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:15]([OH:24])[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccccc2)CC1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-benzyloxycarbonyl-4-phenyl-1,2,3,6-tetrahydropyridine (1.0 g) in tetrahydrofuran (20 mL) was cooled to 0° C. and treated with borane:tetrahydrofuran (3.75 mL of 1M solution in tetrahydrofuran). The reaction mixture was stirred for 16 hours at ambient temperature, diluted with methanol (50 mL), and treated with 3N sodium hydroxide (1.25 mL). The resulting reaction mixture was cooled to 0° C. and treated with 30% hydrogen peroxide solution (0.58 mL). After refluxing for 2 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and the aqueous layer was extracted with ethyl acetate. Combined organic layers were dried and evaporated to afford the crude product (0.88 g). Chromatography, eluting with hexane:ethyl acetate (3:1) afforded the trans-1-benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine (0.31 g); MS: m/z=312(M+1); NMR: 1.54-1.72 (m, 2), 3.51 (m, 1), 4.02 (m, 1), 4.17 (m, 1), 4.86 (d, 1, J=5), 5.1 (s, 2), 7.17-7.37 (m, 10).
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].O.[NH2:13][NH2:14]>CO>[CH:2](=[N:13][NH2:14])[C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: NN
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: O
Solvent: CO
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=NN

Procedure:
A solution of 4.0 g of 6-deoxy-L-galactose in 10 ml of methanol and 10 ml of hydrazine hydrate was stirred overnight, then evaporated to dryness, giving 4.4 g of 6-deoxy-L-galactose hydrazone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[C:27]([C:28](Cl)=[O:29])=[C:26]([Cl:31])[N:25]=[CH:24][N:23]=1>O1CCCC1.ClCCl>[Cl:21][C:22]1[C:27]([C:28]([O:8][C:6]2[CH:5]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=[C:2]([OH:1])[CH:7]=2)=[O:29])=[C:26]([Cl:31])[N:25]=[CH:24][N:23]=1
Reactant: CS(=O)(=O)Nc1cc(O)cc(O)c1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(Cl)ncnc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.8 %

Procedure:
N-(3,5-Dihydroxyphenyl)methanesulfonamide (260 mg, 1.28 mmol) was dissolved in tetrahydrofuran (5 ml) and triethylamine (214 μl, 1.52 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (298 mg, 1.40 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dropwise added. The reaction mixture was stirred at room temperature over 48 hours. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The product was purified by reverse phase using SP1® Purification System to give 280 mg (18% yield) of the title compound. Purity 100%.