Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C=C)C=C2)CO)(C)(C)C.C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(OS(C(F)(F)F)(=O)=O)C=C2)(=O)C(C)(C)C.C([O:75][CH2:76][C@@H:77]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])[C:78]1[C:79]([C:92]2[CH:97]=[CH:96][C:95]([Cl:98])=[CH:94][CH:93]=2)=[C:80]2[C:85](=[CH:86][C:87]=1[CH3:88])[N:84]=[C:83]([CH:89]1[CH2:91][CH2:90]1)[CH:82]=[CH:81]2)(=O)C(C)(C)C>>[C:100]([O:99][C@@H:77]([C:78]1[C:79]([C:92]2[CH:93]=[CH:94][C:95]([Cl:98])=[CH:96][CH:97]=2)=[C:80]2[C:85](=[CH:86][C:87]=1[CH3:88])[N:84]=[C:83]([CH:89]1[CH2:91][CH2:90]1)[CH:82]=[CH:81]2)[CH2:76][OH:75])([CH3:103])([CH3:101])[CH3:102]
Reactant: Cc1cc2nc(C3CC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: C=Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Agent: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(C3CC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6-yl)ethanol was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethanol, (compound of Example 26) except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6-yl)ethyl pivalate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): 410.3, 412.2 (M+H)+.
Reaction SMILES: [CH2:1](/[C:3](/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH3:21])[CH:7]=1)=[CH:4]/[CH3:5])[CH3:2].[OH2:22]>>[CH3:21][O:20][C:8]1[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH:4]([OH:22])[CH3:5])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C/C=C(/CC)c1ccc(OCc2ccccc2)c(OC)c1
Reactant: O
Product: CCC(c1ccc(OCc2ccccc2)c(OC)c1)C(C)O

Procedure:
Addition of H2O to 4-((1Z)-1-ethylprop-1-enyl)-1-benzyloxy-2-methoxybenzene to yield 3-(3-methoxy-4-benzyloxyphenyl)pentan-2-ol.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]2[O:29][CH:30]=[C:31]([CH2:33]Cl)[N:32]=2)=[C:22]([F:35])[CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:32]=2)=[C:22]([F:35])[CH:21]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Fc1cc(Cl)ccc1C=Cc1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(CCCCn3ccnn3)cc2)co1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
1H-NMR(400 MHz, D6-DMSO): δ=6.72(d, 1H, 1′-H), 7.35(d, 1H, 5″-H), 7.44(d, 1H, 2′-H), 7.50(d, 1H, 3″-H), 7.95(dd, 1H, 6″-H), 8.21(s, 1H, 5-H-oxazole). 26 mg (1.0 mmol) of 95% sodium hydride were given at 0° C. to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 2.0 ml N,N-dimethyl formamide and stirred for 30 min. 272 mg (1.00 mmol) 2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-4-chloromethyl-oxazole dissolved in 1.0 ml N,N-dimethyl formamide were added at 0° C., stirring continued at 0° C. for 1 h and 12 h at room temperature thereafter. The mixture was quenched by 6 ml water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, three times with cold ether and drying at 40° C. in vacuo, 350 mg (77%) 1-[4-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[F:12].[Br:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:17]([NH2:18])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=1[F:25].BrC1C(F)=CC([NH2:31])=C(C)C=1>>[NH2:31][C:19]([CH3:21])([CH2:20][N:7]1[N:6]=[C:5]2[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[C:3]([F:12])[C:4]2=[N:8]1)[C:17]#[N:18].[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[F:12].[Br:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:17]([NH2:18])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=1[F:25]
Reactant: Cc1cc(Br)c(F)cc1N
Agent: Cc1cc(Br)c(F)c([N+](=O)[O-])c1N
Agent: Cc1cc(Br)c(F)c2nn[nH]c12
Product: Cc1cc(Br)c(F)c2nn(CC(C)(N)C#N)nc12

Procedure:
2-Amino-3-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile [1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similar to that described in Example 1, part a and b, except starting from 5-bromo-4-fluoro-7-methyl-1H-benzotriazole. 5-Bromo-4-fluoro-7-methyl-1H-benzotriazole (4 g, 85%) was prepared using a procedure similar to that described in Example 11, part a, except starting from 4-bromo-3-fluoro-6-methyl-2-nitroaniline. 4-Bromo-3-fluoro-6-methyl-2-nitroaniline (6.1 g) was prepared using a procedure similar to that described in Example 39, part a, b and c, except starting from 4-bromo-5-fluoro-2-methylaniline (10 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:25]4[CH:26]=[CH:27][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:23][CH:24]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)cc1
Temperature: 140 °C
Yield: 42.7 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.15 g, 0.42 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while dichlorobis(triphenylphosphine)palladium(II) (29 mg, 0.042 mmol), 4-acetamidophenylboronic acid (85 mg, 0.48 mmol), cesium carbonate (271 mg, 0.83 mmol) and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 20 minutes. On cooling, the resulting suspension was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8). The residue obtained was treated with diethylether (7 mL) and filtered to give 66 mg of N-{4-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-acetamide as a white solid (43%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:8]([NH2:11])[C:9]=1[NH2:10])=[O:4].CO[C:20](=N)[C:21]([Cl:24])([Cl:23])[Cl:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])=[C:8]2[C:9]=1[NH:10][C:20]([C:21]([Cl:24])([Cl:23])[Cl:22])=[N:11]2)=[O:4]
Reactant: COC(=O)c1sc(OCC(F)(F)F)c(N)c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: COC(=O)c1sc(OCC(F)(F)F)c2nc(C(Cl)(Cl)Cl)[nH]c12

Procedure:
2-Trichloromethyl-6-(2,2,2-trifluoro-ethoxy)-3H-thieno[3,4-d]imidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 100 (i) from 500 mg (1.85 mmol) 3,4-diamino-5-(2,2,2-trifluoro-ethoxy)-thiophene-2-carboxylic acid methyl ester and 328.0 μl (2.59 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].C(N(CC)CC)C>C(O)(=O)C>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:6][CH:7]=1)=[O:23]
Reactant: CC1C(=O)NC(c2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC1C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
9.75 g. (0.0386 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4-methyl-3(2H)-isoquinolinone are reacted, in 80 ml. of glacial acetic acid, with 5.64 g. (0.05 moles) of chloroacetyl chloride, in the presence of 5.06 g. (0.05 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from butanol to yield 4.9 g. of the title compound; m.p. 238°-239°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]=O)=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[CH2:21][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[N:6][CH:7]=1
Reactant: O=Cc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc(NCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carbaldehyde (intermediate B4:1, 0.02 g, 0.06 mmol) in DCE was added methyl 4-aminobenzoate (0.01 g, 0.06 mmol), acetic acid (3.4 ul, 0.06 mmol) and NaBH(OAc)3 (0.015 g, 0.07 mmol). After Stirring at rt overnight, a drop of water was added to the reaction and purified by reverse phase HPLC to give methyl 4-[({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methyl)amino]benzoate. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=2.5 Hz, 1H), 8.05 (m, 2H), 737 (d, J=8.8 Hz, 2H), 7.44 (dd, J=8.4, 2.5 Hz, 1H), 7.14 (m, 2H), 6.90 (d, J=8.4 Hz, 1H), 6.61 (d, 3=8.8 Hz, 2H), 4.43 (s, 2H), 3.84 (s, 3H); HRMS exact mass calc for C23H17ClFN3O3S [M+H]: 470.0736; observed: 470.0734.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[C@@H:20]2[O:25][C:24](=[O:26])[CH2:23][C@@H:22]([OH:27])[CH2:21]2)=[CH:4][CH:3]=1.[OH-:28].[Na+:29]>C(O)C>[Na+:29].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[CH:20]([OH:28])[CH2:21][CH:22]([OH:27])[CH2:23][C:24]([O-:25])=[O:26])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/[C@H]2C[C@H](O)CC(=O)O2)C(C)(C)C1
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/C(O)CC(O)CC(=O)[O-])C(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a solution of 1.17 g (3.14 mmoles) of the lactone prepared in Step 11, and 21 ml of ethanol was added 3.14 ml of 1N NaOH (3.14 mmoles). After stirring for 30 minutes, the ethanol was removed in vacuo. The residue was redissolved in 50 ml of HPLC grade H2O and extracted twice with hexane. The water layer was freeze-dried to yield a white powder. M.P. 160°-190° C. (dec).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:20][C:19]=3[Cl:31])=[CH:14][CH:13]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[Cl:31])=[CH:16][CH:17]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4]
Reactant: CCOC(=O)Cc1cc(Cl)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1cc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)cc1CC(=O)O
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
Powdered potassium hydroxide (88 mg, 1.56 mmol) was added in one portion to ethyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-5-methylbiphenyl-4-yl)acetate (Intermediate 3-1; 228 mg, 0.52 mmol) in tert-butanol (15 mL) at 55° C. The resulting mixture was stirred at 55° C. for 45 minutes, 2M HCl (˜1 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water (20 mL) and air dried to afford crude product as a pale yellow solid, which contained a minor impurity. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-5-methylbiphenyl-4-yl)acetic acid (193 mg, 90%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][Br:13]
Reactant: BrP(Br)Br
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(CCBr)c(Cl)c1
Temperature: 0 °C

Procedure:
2,4-Dichlorophenethyl alcohol (10 g, 52.0 mmol) was dissolved in 100 mL of methylene chloride, cooled to 0° C. under nitrogen atmosphere and 1.5 equiv of phosphorous tribromide (1M in CH2Cl2, 80 mmol, 80 mL) was added dropwise. The resulting reaction mixture was warmed to 23° C. and stirred for 2 h before the very slow addition of 200 mL of saturated aqueous sodium bicarbonate and extraction with methylene chloride (2×150 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by a SiO2 plug (5% EtOAc/hexanes) to yield 2,4-dichlorophenethyl bromide. The product was characterized by 1H NMR and HPLC.
Reaction SMILES: N1CCC1.[Cl-].[CH2:6]([O:13][C:14]([NH:16][S:17]([N:20]1[CH:25]=[CH:24][C:23](=[N+](C)C)C=C1)(=[O:19])=[O:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[N:20]1([S:17]([NH:16][C:14](=[O:15])[O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:18])=[O:19])[CH2:25][CH2:24][CH2:23]1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Agent: C1CNC1
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1102.5 %

Procedure:
Azetidine (0.36 g, 0.5 mmol) was added to N-{1-[N-(benzyloxycarbonyl)-sulfamoyl]pyridin-4(1H)-ylidene}-N-methylmethanaminium chloride (Preparation 21, 2.0 g, 0.5 mmol) in DCM (10 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was discarded and the aqueous layer was acidified with 1M HCl. The aqueous layer was extracted with ethylacetate (2×50 mL), dried over magnesium sulfate and concentrated to afford the title compound (1.49 g, 100%).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23](=[O:41])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[NH:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:20]=2)[CH2:15][CH2:14][C:13]1=[O:42])(C(C)(C)C)(C)C>C(O)C>[CH:35]1([NH:34][C:25]2[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=2[C:23]([NH:22][C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][C:13](=[O:42])[N:12]3[CH2:11][CH2:10][OH:9])=[CH:17][CH:18]=2)=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)N(CCO)C(=O)CC2)c1ccc(C(F)(F)F)cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
1 M Hydrochloric acid (0.37 mL) was added to an ethanol solution (1.5 mL) of N-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]-2-(cyclohexylamino)-4-(trifluoromethyl)benzamide (220 mg), followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under a reduced pressure, and a sodium bicarbonate aqueous solution was added to the residue, followed by extraction with ethyl acetate. After drying the organic layer with sodium sulfate, the solution was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography (hexane:ethyl acetate, 2:1 to 2:3), 2-(cyclohexylamino)-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]-4-(trifluoromethyl)benzamide (148 mg) was obtained as a solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH3:37][C:38](=[O:41])[CH:39]=[CH2:40]>>[O:41]=[C:38]1[CH2:39][CH2:40][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:37]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Benzyl 4-formylpiperidine-1-carboxylate (5.17 g, 20.907 mmol) and p-Toluenesulfonic acid monohydrate (0.398 g, 2.091 mmol) were stirred in Benzene (30.0 ml, 334.136 mmol) at 70° C. But-3-en-2-one (3.76 ml, 41.813 mmol) was added and the reaction mixture was refluxed o/n while removing water with dean-stark trap. After cooling the reaction mixture to rt, sat. NaHCO3 soln. was added and the organic layer was dried over Na2SO4 and evaporated. The resulting oil was purified by Biotage (SiO2, 250 g, EtOAc/Hep 10% to 50%) to afford the title compound (3.58 g, 11.96 mmol, 57.2% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]2[CH:23]=[N:24][C:25]([C:26]([OH:28])=[O:27])=[C:13]2[CH2:12]1.O>O1CCCC1.CN(C)C=O>[N-:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]2[CH:23]=[N:24][C:25]([C:26]([OH:28])=[O:27])=[C:13]2[CH2:12]1
Reactant: c1c[nH]cn1
Agent: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1c[n-]cn1
Reaction time: 1 h

Procedure:
A solution of 1.8 ml thionyl chloride in 25 ml of dry tetrahydrofuran (THF) was added dropwise to a solution of 6.8 g imidazole in 75 ml dry THF. After stirring for 1 hour, the reaction mixture was filtered and the filtrate was added dropwise to 0.0125 mole of dry 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 100 ml dry dimethyl formamide. The reaction mixture was left overnight at room temperature with exclusion of water.
Reaction SMILES: O[Li].O.O.[OH:5][C:6]1([C:18]([O:20]C)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1>C1COCC1>[OH:5][C:6]1([C:18]([OH:20])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C1(O)CCCc2ccc(OC)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH.H2O (0.41 g; 9.8 mmol) and water (4 mL) were added to a solution of 1-hydroxy-7-methoxytetralin-1-yl-carboxylic acid, methyl ester (1.16 g; 4.9 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at room temperature for 3 h, the THF was evaporated, and the water phase was washed with methylene chloride. The reaction mixture was acidified with HCl (2M) and some NaCl was added. After extraction with methylene chloride, the organic phase was dried and concentrated. Yield: 765 mg (70%).
Reaction SMILES: [C:1]([O:5][P:6](=[O:13])([O-:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:32][CH2:33][CH2:34][OH:35]>COCCOC>[OH:35][CH2:34][CH2:33][CH2:32][O:13][P:6](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Product: CC(C)(C)OP(=O)(OCCCO)OC(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a 100 mL flask was added tetra-n-butyl ammonium phosphoric acid di-tert-butyl ester salt (3.08 g, 6.8 mmol), ethylene glycol dimethyl ether (10 mL), and 3-bromo-1-propanol (freshly distilled from potassium carbonate). The reaction mixture was heated to reflux for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl ether (60 mL) and cooled in a refrigerator until a white solid precipitated. The solid was filtered through Celite and the filtrate was evaporated in vacuo, affording the title compound as a clear oil (1.85 g, ˜100%). 1H NMR (CDCl3, 500 MHz) δ 4.10 (m, 2H), 3.73 (m, 2H), 1.84 (m, 2H), 1.46 (s, 18H).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[C@@H:18]2[CH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@:14]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15](=[O:28])[CH2:16][CH2:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:35]1C[CH2:38][CH2:37][CH2:36]1>>[CH2:6]([N:13]1[C@@H:18]2[CH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@:14]1([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@:15]([C:38]#[C:37][CH2:36][OH:35])([OH:28])[CH2:16][CH2:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)C#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6M, 34 ml, 55.4 mmol) was added dropwise to a stirred solution of O-trimethylsilyl propargyl alcohol (8 ml, 52 mmol) in tetrahydrofuran (40 ml) at −78° C. This solution was added via syringe to a stirred solution of (1R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 24; a 3:1 mixture of C6 epimers, 5 g, 12.7 mmol) in tetrahydrofuran (30 ml) at −78° C. over 30 minutes. The reaction mixture was stirred for 1 hour and quenched with acetic acid (3.1 ml), warm up to room temperature and concentrated in vacuo. The residue was treated with tetrahydrofuran (50 ml) followed by 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (75 ml). The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was treated with ethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (4.05 g, 71%) as a 3:1 mixture of C6 epimers.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:6])[CH2:2][CH3:3].CC(O[Na])=O.[Br:27]Br>C(O)(=O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([Br:27])=[N:9][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCn1c(=O)c2[nH]cnc2n(Cc2ccccc2)c1=O
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(Br)nc2n(Cc2ccccc2)c1=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 1-propyl-3-benzyl xanthine (2.82 mmol), CH3CO2Na (2.82 mmol) and acetic acid (15 mL) was heated at 40-50° C. To the solution was added Br2 (2.82 mmol) and the reaction was stirred for further 30 minutes at 45° C. After cooling at room temperature the precipitate was collected by filtration and finally crystallized from EtOH. (White solid. Yield 85%).