Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1.C(O[C:36](=[O:38])[CH3:37])(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([O:26][C:6](=[O:8])[CH3:5])[C@H:24]([O:27][C:13](=[O:14])[CH3:12])[C@@H:23]([CH2:28][O:29][C:36](=[O:38])[CH3:37])[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](OCc2ccccc2)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-α-D-glucopyranoside (400 mg, 0.92 mmol) was dissolved in pyridine (6 ml) and cooled to 0° C., then acetic anhydride (10 ml) was added dropwise. The solution was stirred at room temperature overnight, then evaporated. The residue was purified by chromatography using EtOAc/hexane 3:1 to give Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranoside (11) (465 mg, 90%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]([CH2:34][CH:35]=[CH2:36])([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:18]([CH3:33])[CH:17]=2)[CH2:11][CH:12]=[CH2:13])=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[CH2:11]([C:10]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:33])[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)=[C:20]([CH3:22])[CH:21]=1)[CH2:34][CH:35]=[CH2:36])[CH:12]=[CH2:13]
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)O)s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carboxylic acid methyl ester (0.186 g, 0.361 mmol) in THF (4.0 mL) is treated with LiOH (1N aqueous, 4.0 mL, 4.0 mmol), warmed to 70° C., and stirred overnight. The reaction mixture is cooled to rt., acidified with HCl (1N aqueous, 4.2 mL), and extracted with EtOAc (3×10 mL). The combined extracts are dried over MgSO4, filtered, and conc. to provide 5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carboxylic acid (0.171 g, 94%) as a white foam. MS (ES): 501.4 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].[CH2:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O.[Cu]>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]2[NH:22][C:2]3[CH:3]=[N:4][N:5]([CH3:10])[C:6]=3[C:7](=[O:8])[C:23]=2[CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: Cn1ncc(I)c1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4)cc3c(=O)c21
Temperature: 100 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
A mixture of 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid ((Manaev, Yu. A. et al., J. Gen. Chem. USSR (Engl. Transl.), 1982, 52 (11), 2291), 8.0 g, 31.74 mmol), 4-benzylaniline (21.03 g, 114.76 mmol) and copper powder (3.2 g) in a mixture of 5% aqueous sodium carbonate (160 ml) and dimethylsulfoxide (80 ml) was stirred for 17 h at 100° C. After cooling to room temperature, the mixture was filtered through a pad of Celite, which was washed with water, 2N aqueous sodium hydroxide and diethyl ether. The separated water layer was washed with diethyl ether (100 ml×2). The water layer was acidified with concentrated hydrochloric acid and the formed solid was collected by filtration, dried, to give 4.86 g (50%) of the pure title compound as a pale brown solid.
Reaction SMILES: [NH:1]([C:3](=[O:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[NH2:2].N(C(=O)C(NC1C=CC([C@H]2CC[C@H](CC(OC)=O)CC2)=CC=1)=O)N.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N:51]=[C:52]=S>>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]1[O:19][C:3]([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:11][CH:12]=2)=[O:5])=[N:1][N:2]=1
Reactant: CCCS(=O)(=O)c1ccc(NC(=O)C(=O)NN)cc1
Reactant: Fc1ccccc1N=C=S
Agent: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Product: CCCS(=O)(=O)c1ccc(NC(=O)c2nnc(Nc3ccccc3F)o2)cc1

Procedure:
Following the general procedure of Example 105 but using 2-hydrazino-2-oxo-N-[4-(propylsulfonyl)phenyl]acetamide (Intermediate 97) as starting material in place of methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclohexyl]acetate and using 2-fluorophenylisothiocyanate in place of 2-isothiocyanatopyridine the title compound was obtained as a solid; 1H NMR δ 0.90 (t, 3H), 1.46-1.62 (m, 2H), 3.18-3.27 (m, 2H), 7.12-7.20 (m, 1H), 7.22-7.35 (m, 2H), 7.87 (d, 2H), 7.99-8.10 (m, 3H), 10.90 (s, 1H), 11.50 (s, 1H); MS m/e MH+ 405.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([O:10]COCCOC)[CH:7]=[CH:8][CH:9]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CNCc1cccc(OCOCCOC)c1
Product: CN(Cc1cccc(O)c1)c1ccc2ccccc2n1

Procedure:
MS (ESI) 265 (M+H)+. Prepared from 3-[(methylamino)-methyl]-(2-methoxyethoxy-methoxy)benzene (example 28) and 2-chloro-quinoline.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])=[CH:9]2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[N:22]1([C:20]([C:10]2[N:11]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14][CH:13]=3)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Yield: 85 %

Procedure:
A solution of 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid ethyl ester (924 mg, 2.4 mmol) and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in tetrahydrofuran (8 mL), methanol (2 mL) and water (4 mL) was refluxed for 3 h. The volatiles were removed in vacuo and the residue was dissolved in water and acidified with hydrochloric acid (1N). The precipitate was filtered, washed with water and dried in vacuo. The crude product was purified by flash chromatography on silica gel with dichloromethane: methanol (98:2 then 19:1 v/v) as eluant, to give 727 mg (85%) of the desired compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[S:3][C:4]([S:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[CH:5][N:6]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Nc1ncc(Sc2ccncc2)s1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Sc2ccncc2)s1)c1ccc(F)cc1
Yield: 63.2 %

Procedure:
To a mixture of 2-amino-5-(4-pyridylthio)thiazole (2.5 g) and pyridine (3 g) in N,N-dimethylformamide (25 ml) was added dropwise the 4-fluorobenzoyl chloride (2.7 g) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 4 hours under ice cooling. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-(4-fluorobenzoylamino)-5-(4-pyridylthio)thiazole (2.5 g, yield: 63.1%). mp: 220°-225° C. (dec.)
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1[nH]c2ccccc2n1CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1CCN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 4 g of 1-[2-[4-diphenylmethylene-1-piperidinyl]ethyl]-1,3-dihydro-2(2H)-benzimidazolone in 150 cm3 of methanol is hydrogenated with the aid of a Parr apparatus, at ambient temperature, at a hydrogen pressure of 50 psi, in the presence of 5% palladium on charcoal. When the absorption of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated down. The product obtained is recrystallized from ethyl acetate. M.p.=195°-196° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[CH:5]=1.I[CH3:22]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH3:22])[CH2:18][CH2:19]2)[CH:5]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
0.6 g sodium hydride (60%) were added to a cooled solution (−7° C.) of 2.55 g 4-fluoro-2-(trans-4-hydroxy-cyclohexyloxy)-1-nitro-benzene and iodomethane in 30 ml DMF. The mixture was allowed to warm to rt overnight, diluted with EtOAc and washed with water and brine (3×). The organic phase was dried (MgSO4), passed through a hydrophobic frit and evaporated. The residue was purified by flash column chromatography (silica gel, 100% i-hexane→7:1 i-hexane:EtOAc).
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Br)(Br)([Br:24])=O>CC#N>[Br:24][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Yield: 77.7 %

Procedure:
A solution of methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate (2.1 g, 7.50 mmol, 1.00 equiv) and POBr3 (21.5 g, 74.91 mmol, 10.00 equiv) in CH3CN (120 mL) in a 1000-mL round-bottom flask was heated under reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum; the pH value was adjusted to 7-8 with aqueous sodium bicarbonate (saturated), and the solution extracted with 4×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum, giving 2 g (78%) of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate as a white solid. LC-MS (ES, m/z): 343 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) 8.620-8.615 (d, J=1.5 Hz, 1H), 8.38-8.35 (q, J=3.3 Hz, 1H), 8.28-8.25 (d, J=8.7 Hz, 1H), 7.85-7.82 (q, J=6 Hz, 2H), 7.60-7.58 (t, J=2.4 Hz, 3H), 3.99 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])=[CH:10][CH:9]=3)[C:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:6]2[C:24]([OH:26])=[O:25])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate and phenylsulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 5.81 (s, 2H; 7.05-7.10 (m, 1H), 7.16 (d, J=8.3 Hz, 2H, 7.27 (d, J=8.3 Hz, 2H, 7.30-7.40 (m, 2H, 7.40-7.50 (m, 4H, 7.50-7.70 (m, 11H, 9.93 (s, 1H, 13.03 (br s, 1H; MS (ESI) m/z 557 [M-H]−; HRMS calcd for C34H27N2O4S: 559.1689; found (ESI+): 559.1688; Anal. calcd for C34H26N2O4S.0.5H2O: C, 71.94; H, 4.79; N, 4.94. Found: C, 71.81; H, 4.79; N, 5.07.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:29][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1cccs1
Yield: 40.8 %

Procedure:
Compound 46-2 (1.29 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.62 g) and N-bromosuccinimide (1.76 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (760 mg) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.CCOC(C)=O>[CH3:20][S:21]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of tert-butyl 3-hydroxypropylcarbamate (431 mg) at 0° C. in dichloromethane, triethylamine (686 μL) was added, followed by methanesulfonyl chloride (209 μL). The reaction was stirred for 15 minutes, then allowed to warm to room temperature and stir for 1 hour more. Additional triethylamine (686 μL) and methanesulfonyl chloride (209 μL) were added. One hour later the reaction was diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 259 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([CH2:19][NH:20]C(OC(C)(C)C)=O)[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>CO>[ClH:28].[ClH:28].[ClH:28].[NH2:20][CH2:19][C@H:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CN)N1CCN(Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
8.9 g (23.5 mmol) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate are placed in solution in 60 ml of methanol and in 20 ml of isopropanolic hydrochloric acid having a concentration of 5-6N. The reaction medium is stirred at 40° C. for 18 h and then concentrated under vacuum. 9.0 g (100%) of methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=[N:21]2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:4]=[C:3]([CH2:2][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=[CH:7][N:6]=1
Reactant: FC(F)(F)c1cc(CCl)ccn1
Reactant: CCOC(=O)Cc1cnc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cnc2cc(OCc3ccnc(C(F)(F)F)c3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(chloromethyl)-2-(trifluoromethyl)pyridine (162.06 mg, 0.83 mmol) in DMF (5 mL) was added ethyl 2-(7-hydroxyquinolin-3-yl)acetate (Intermediate 2, 150 mg, 0.55 mmol) and Cs2CO3 (356 mg, 1.10 mmol). The reaction was stirred at ambient temperature for 16 h. A mixture of mono benzylated and bisbenzylated products were observed. Cesium carbonate was filtered off and DMF was removed under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded a mixture of methyl and ethyl esters along with 25% of bis-benzylated product. The mixture was advanced into the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl (3-fluoro-4-hydroxyphenyl)carbamate (17.2 g, 75.7 mmol) in dimethyl sulfoxide (100 mL) were added 2-chloro-5-nitropyridine (10 g, 63.1 mmol) and cesium carbonate (30.8 g, 94.6 mmol), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=5/1) and collected by filtration to give the title compound (17.0 g, 77%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=2)[CH2:10][CH:9]1[C:24](=[O:36])[NH:25][C:26]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH:27]1[CH:29]=[CH2:30])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:16]1[N:15]=[C:14]([O:13][CH:11]2[CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH:9]([C:24](=[O:36])[NH:25][C:26]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH:27]3[CH:29]=[CH2:30])[CH2:10]2)[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Yield: 100.9 %

Procedure:
Compound 18c (0.92 g, 1.83 mmol) was treated with triethylsilane (0.58 g, 5.0 mmol) and TFA (25 ml) in DCM (25 ml) according to the procedure described in Example 13 step b which gave the title compound, (0.83 g), (M+H)+450.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=[CH:5]2.C([Li])CCC.[Cl:28][CH2:29][C:30](N(OC)C)=[O:31]>O1CCCC1>[Cl:28][CH2:29][C:30]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:3]=1)=[O:31]
Reactant: CON(C)C(=O)CCl
Reactant: CC(C)[Si](Oc1cccc2cc(Br)ccc12)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc2cc(C(=O)CCl)ccc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (6-bromonaphthalen-1-yloxy)triisopropylsilane (10.4 g, 27.5 mmol) in tetrahydrofuran (180 mL) under argon at −78° C. was added n-butyllithium (2.5M in hexanes, 11.5 mL, 28.7 mmol). After stirring at this temperature for one hour, a solution of 2-chloro-N-methoxy-N-methyl acetamide (7.6 g, 55.2 mmol) in tetrahydrofuran (10 mL) was added to the reaction via cannula. The dry ice bath was removed and the reaction was allowed to warm to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4Cl solution, water and brine. The organic layer was dried (MgSO4) and concentrated, and the resulting residue was purified by flash chromatography to yield 2-chloro-1-(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone (7.8 g, 75%) as a pale yellow oil.