Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Zn]CC)C.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Li]CCCC.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C@@:24]([OH:29])([C:10]#[C:9][CH:6]1[CH2:8][CH2:7]1)[C:25]([F:26])([F:27])[F:28]
Reactant: Cc1ccc(N)c(C(=O)C(F)(F)F)c1
Reactant: C#CC1CC1
Agent: CC[Zn]CC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N)c([C@@](O)(C#CC2CC2)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of (1R,2S)—PNE (17.6%-w/w, 21.0 g, 18.0 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature range for 30 min. A solution of cyclopropylacetylene in toluene (69.6%-w/w, 8.55 g, 90.0 mmol) was added at 18° C. and the resulting mixture was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.6 g, 54.4 mmol) and a solution of 1-(2-amino-5-methylphenyl)-2,2,2-trifluoroethanone (CN46217, 36.5%-w/w, 33.4 g, 60.0 mmol) in toluene/THF (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN46217 addition. After completed addition of CN46217 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 72.3% conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid (1 M, 73.9 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g), and water (12.0 g). The organic phase was partially concentrated (60 g residual solution), diluted with toluene (30 g), and partially concentrated again (52 g residue). The residue was diluted with toluene (65 g), cooled to 5° C. and aged over night. The crystals were filtered, washed with cold (approx. 5° C.) toluene (10 g) and dried under vacuum at 40° C. The wet product (10.8 g) obtained as off-white solid with a purity of 99.2 and 100% ep according to method B. The crude product was purified by slurring it in a mixture of toluene (10 mL) and heptane (40 mL) at room temperature for 1 h, filtered and dried at 40° C. in vacuo. The product (compound of formula II, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) was obtained as white solid (10.6 g, 38 mmol, 64% yield) with a purity of 99.4% and 100% ep according to method B. The assay was 97.0%-w/w according to 1H-NMR.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:19]=[N:18][C:17](Cl)=[CH:16][CH:15]=3)[N:9]=2)=[CH:6][CH:7]=1>C(O)C.[Pd]>[N:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:5]3[N:4]=[N:3][CH:2]=[CH:7][CH:6]=3)[N:9]=2)[N:19]=1
Reactant: Clc1ccc(-c2cccc(-c3ccc(Cl)nn3)n2)nn1
Agent: [Pd]
Solvent: CCO
Product: c1cnnc(-c2cccc(-c3cccnn3)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
500 mg (1.65 mmol) of 2,6-bis(3-chloropyridazin-6-yl)-pyridine 32 and 17.5 mg (0.08 mmol) of palladium-on-charcoal are dissolved in 50 ml of ethanol. The mixture is stirred at ambient temperature under a hydrogen pressure for 24 hours. The solution is filtered, evaporated under reduced pressure, and then chromatographed on silica gel (eluent: ethyl acetate/petroleum ether: 8/2). The 2,6-bis(3′-pyridazinyl)pyridine 37 is isolated with a yield of 89%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH:12]1([CH2:15][CH2:16]O)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Li+].Cl>C1COCC1.C(O)C.O>[CH:12]1([CH2:15][CH2:16][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCC2CC2)cc1
Yield: 77.6 %

Procedure:
Methyl 4-hydroxybenzoate (8.83 g, 58.0 mmol), 2-cyclopropylethanol (5.13 g, 59.6 mmol), and triphenylphosphine (15.7 g, 59.9 mmol) were dissolved in THF (250 mL). Then, diethyl azodicarboxylate (29.8 mL, 40% toluene solution, 59.6 mmol) was added thereto under ice-cooling while stirring. The mixture was stirred at room temperature for 2 days, and then water (200 mL) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting residue was dissolved in diethyl ether. The produced precipitate was removed by filtration, and diethyl ether was evaporated. This filtration procedure was repeated twice, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 20:1, v/v) to give an oily substance (13.2 g). All this oily substance was dissolved in ethanol (200 mL), and a 2 M lithium hydroxide aqueous solution (60 mL, 120 mmol) was added thereto. The mixture was stirred at 60° C. for 50 minutes, and then 10% hydrochloric acid (40 mL) was added thereto under ice-cooling. The resulting mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was suspended in diisopropyl ether, and the precipitate was collected by filtration and dried under reduced pressure to give 9.28 g of the title compound (powder, yield: 78%).
Reaction SMILES: C/C=C(/C(N[C@H]([C@@H](O)C(O[C@@H:19]1[C:40]([CH3:41])=[C:39]2[C:42]([CH3:44])([CH3:43])[C@:21](O)([C@@H:22](OC(C3C=CC=CC=3)=O)[C@@H:23]3[C@:28]4(OC(C)=O)[CH2:29]O[C@@H:27]4[CH2:26][C@H:25](O)[C@@:24]3([CH3:49])[C:36]([C@@H:38]2OC(C)=O)=O)[CH2:20]1)=O)C1C=CC=CC=1)=O)\C.CC1[C@@H](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>>[CH3:29][C@H:28]1[C@H:23]2[CH2:22][C@H:21]3[C:42]([CH3:43])([CH3:44])[C@@H:39]([CH2:38][CH2:36][C@:24]2([CH3:49])[CH2:25][CH2:26][CH2:27]1)[C@H:40]([CH3:41])[CH2:19][CH2:20]3
Reactant: C/C=C(\C)C(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C
Yield: 20 %

Procedure:
Batches of crude plant extracts from Taxus yunnanensis or from Taxus wallachiana containing approximately 15-40% cephalomannine, approximately 50-70% paclitaxel and approximately 20-35% other taxane/non-taxane components were obtained from the Peoples Republic of China. Chlorine gas was obtained from Matheson Ltd., and Silica gel used was ICN Silitech, 32-63 um, 60 Å, ICN Biomedicals, Inc., Aurora, Ohio. All solvents used were either HPLC or ACS grade and were obtained from Spectrum Chemical Mfg. Corp. Purified water used was deionized in-house.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[Br-].[CH2:24]([Zn+])[CH:25]([CH3:27])[CH3:26].C1COCC1>Cl>[CH2:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[Zn+]
Reactant: OCc1ccc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)oc2c1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc3ccc(CO)cc3o2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of [2-(4-chloro-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol (1 eq) and Pd(PBut3)2 (0.05 eq) is treated with isobutyl zinc bromide in THF (0.5 M, 3 eq). The resulting mixture is heated at 100° C. in microwave for 30 minutes. The reaction mixture is diluted with aqueous HCl (5%) and extracted with EtOAc. The organic solution is washed with brine and dried over Na2SO4. After concentration, the residue is purified by flash column chromatography (30% EtOAc in hexane) to give the desired intermediate [2-(4-isobutyl-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol. MS: (ES+): 350.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH:19]1[CH2:18][CH2:17][CH:16]([C:14]([N:11]2[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]2)=[O:15])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCNCC2)C1
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A mixture of benzyl 4-({(3S)-3-[(tert-butoxycarbonyl)amino]pyrrolidin-1-yl}carbonyl)piperidine-1-carboxylate (7.5 g, 17 mmol) and palladium on carbon (800 mg, 8 mmol) in methanol (100 mL) was shaken under hydrogen at 50 psi overnight. The mixture was filtered through celite and the filtrate was concentrated to give 5.1 g of product as a white solid. MS (M+H) 298.2.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH3:16])[CH2:11]2)[N:5]=[CH:4][N:3]=1>CO.[Pd]>[CH3:16][N:12]1[CH2:13][CH2:14][CH2:15][C@@H:10]([O:9][C:6]2[C:7]([NH2:8])=[CH:2][N:3]=[CH:4][N:5]=2)[CH2:11]1
Reactant: CN1CCC[C@@H](Oc2ncnc(Cl)c2N)C1
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@@H](Oc2ncncc2N)C1
Reaction time: 2 h
Yield: 99 %

Procedure:
(R)-4-chloro-6-((1-methylpiperidin-3-yl)oxy)pyrimidin-5-amine was dissolved in MeOH (15.0 mL) and Pd/C 10% (324.5 mg, 0.3049 mmol) was added and the reaction mixture stirred under a hydrogen atmosphere for 2 h. The reaction vessel was evacuated and flushed with nitrogen (3×), filtered through a celite pad washing with methanol followed by ethyl acetate. The combined filtrates were concentrated in vacuo to leave the title product 7a as a colourless oil (631 mg, 99%).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1>>[F:7][C:8]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Ic1cccs1
Product: Fc1cccc(-c2cccs2)c1

Procedure:
2-Iodothiophene and 3-fluorophenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-fluorophenyl)thiophene as oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([SH:10])=[S:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20](=[CH2:22])[CH3:21]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([S:10][C:20]([CH3:22])([CH3:21])[CH3:19])=[S:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)SC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 110 °C

Procedure:
A solution of 14.1 g (0.05 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid and 5.6 g (0.1 mol) isobutylene in 20 ml toluene was placed in a glass bomb tube. The tube was sealed and heated at 110° C. for 2 hours. The tube was cooled and opened. The contents were removed and evaporated under reduced pressure to give the product as an orange solid, m.p. 128°-130° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:12].Cl[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1.Cl>CN(C)C=O.O>[Si:26]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:12])=[C:2]([Cl:1])[CH:7]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of methyl 2-({[3-(2-chloro-4-hydroxyphenyl)propanoyl]amino}methyl)benzoate (380 mg) in N,N-dimethylformamide (4.00 mL) were added chloro tert-butyl dimethylsilane (215 mg) and imidazole (114 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 2-({[3-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)propanoyl]amino}methyl)benzoate (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=1[CH2:5][CH:6]([C:12]([CH3:14])=O)[C:7]([O:9]CC)=O.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:29])[N:23]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>O.C(O)C>[NH2:21][C:22]1[N:23]=[C:24]([NH2:29])[C:25]2[C:12]([CH3:14])=[C:6]([CH2:5][C:4]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:3]=3[O:2][CH3:1])[C:7](=[O:9])[NH:28][C:26]=2[N:27]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: CCOC(=O)C(Cc1cc(OC)ccc1OC)C(C)=O
Solvent: CCO
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(OC)c(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)c1
Yield: 65.8 %

Procedure:
A mixture of ethyl α-(2,5-dimethoxybenzyl)acetoacetate (21.2 g), 2,4,6-triaminopyrimidine (10 g) and diphenyl ether (100 ml) was heated at 190°-230° C. for 1.5 hours in an apparatus fitted with a Dean-Stark trap and water-ethanol (4 ml) was collected. Methanol (200 ml) and ethanol (50 ml) was added to the cooled reaction mixture. The resulting solid was collected by filtration and treated with boiling water (1 l) to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (17 g), m.p. 325°-326° C.
Reaction SMILES: [O:1]=[C:2]1[CH:14](C(OC(C)(C)C)=O)[N:6]2[C:7]3[C:12]([CH:13]=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3>C1(C)C=CC=CC=1>[CH:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:14][N:6]12
Reactant: CC(C)(C)OC(=O)C1C(=O)CCc2cc3ccccc3n21
Solvent: Cc1ccccc1
Product: O=C1CCc2cc3ccccc3n2C1
Yield: 82 %

Procedure:
A solution of the crude tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-α]indole-6-carboxylate from Step 5 in toluene (0.06 M) was treated with silica gel (5 g per g of substrate) and the mixture was heated to reflux for 6 h. After cooling, the mixture was filtered, the cake washed with EtOAc and the combined organics were concentrated under vacuum to give the crude title compound (82%) as a brown solid. This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:33]3[CH:34]=[N:35][C:30]([C:29]([F:38])([F:28])[F:37])=[CH:31][CH:32]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)nc3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 48.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.150 g, 0.301 mmol), 6-(trifluoromethyl)pyridine-3-amine (0.067 g, 0.451 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.23 (s, 3H), 3.09 (s, 2H), 7.23-7.31 (m, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.98 (s, 1H), 9.10 (bs, 1H), 10.08 (s, 1H), 10.90 (bs, 1H); MS [M]+: 516.16.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46]>>[CH3:39][O:38][N:33]1[C:32]([CH3:41])([CH3:40])[CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]3[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]3)[N:7]=[C:2]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[N:3]=2)[CH2:35][C:34]1([CH3:37])[CH3:36]
Reactant: NCCC(=O)O
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(NCCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and β-alanine according to the procedure of Example 15.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1.[BH4-].[Li+].O>C1COCC1>[C:21]([O:20][C:18](=[O:19])[N:5]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:10]=1)[CH2:4][CH2:3][OH:2])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1nc(-c2ccc(F)cc2)cs1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)c1nc(-c2ccc(F)cc2)cs1

Procedure:
Under argon, 435 mg (1.18 mmol) of (tert-butoxycarbonyl-(4-(4-fluorophenyl)thiazol-2-yl)-amino)acetic acid methyl ester and 51.7 mg (2.37 mmol) of lithium borohydride were stirred in 20 ml of THF at 60° C. for 1 h. After cooling, the mixture was cautiously hydrolyzed with water, the precipitate was filtered off with suction, and water and ethyl acetate were added to the filtrate. The organic phase was separated, washed with water and concentrated. Yield: 273 mg (68%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])[C:6]=1[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30]>CN(C=O)C.CC(OC)(C)C>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([NH:15][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])[C:6]=1[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30]
Reactant: C[O-]
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COc1nc(Cl)c(-c2c(F)cc(F)cc2F)c(N[C@@H](C)C(F)(F)F)n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
294 mg (1.30 mmol) of sodium methoxide (90% in methanol) were added to a solution of 282 mg (0.65 mmol) of sulfone 1 in 4 ml of anhydrous DMF. The mixture was stirred at 20-25° C. for 16 hours and then diluted with MTBE, washed with water and dried. Distillative removal of the solvent and chromatography on silica gel gave 0.14 g of the title compound of m.p. 121-129° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
345 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 16(g)] were N-alkylated with 450 mg of butyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was then subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:9][C:5]1[CH:4]=[C:3]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[N:14]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(OB([O-])[O-])c1
Reactant: COc1ccc2nc(Cl)ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(-c3cccc(C)c3)ccc2c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3-Methylphenyl borate (1.3 mmol), 2-chloro-6-methoxyquinoline (1 mmol), tetrakis(triphenylphosphine) palladium(O) (0.05 mmol) and potassium carbonate (3 mmol) were dissolved in THF (30 mL) and H2O (10 mL). The resulting solution was stirred in a bath at 100° C. for 24 hours. After completion of the reaction, the solvents were removed. The reaction mixture was extracted with dichloromethane and water and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether, and filtered to yield 2-(3-methylphenyl)-6-methoxyquinoline as a solid.