Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[O:11]=[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]1[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]1
Reactant: O=c1ccc2cccnc2[nH]1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 57.5 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of 0.15 g of 1,8-naphthyridin-2(1H)-one in 2 mL of N,N-dimethylformamide, 45 mg of 60% sodium hydride was added, and the mixture was stirred at 50 to 65° C. for 1 hour. Thereto was added a solution of 0.44 g of 1-tert-butyl 4-ethyl 4-(3-((methylsulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate in 1.2 mL of N,N-dimethylformamide, and the reaction mixture was stirred at 80 to 90° C. for 1 hour 30 minutes and cooled to room temperature, and water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=3:2 to obtain 0.29 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][C:13]([CH3:15])=[CH2:14])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[NH:7]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CCCCCC>[Br:20][CH2:14][C:13]1([CH3:15])[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:16])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:17])[C:5]([CH3:19])([CH3:18])[CH2:4]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)Cc1cc(C)c2c(c1O)CC(C)(C)C(=O)N2
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CBr)C2
Yield: 74.2 %

Procedure:
Using 5-hydroxy-6-(2-methyl-2-propenyl)-3,3,8-trimethyl-3,4-dihydrocarbostyril (1.35 g, 5.18 mmol) and N-bromosuccinimide (968 mg, 5.44 mmol), the procedure of Example 299 was followed (reaction, post-treatment, and recrystallization from chloroform-hexane) to obtain 1.30 g of the title compound as colorless needles (74%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:8]2[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2ccc(Cl)cc2)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccc(Cl)cc2)c1NC(=O)CBr
Reaction time: 1 h

Procedure:
Bromoacetyl bromide (39 g, 194 mmoles) was added slowly to a mixture of (4-amino-5-methylisoxazol-3-yl)-4-chlorophenylmethanone of Example Vb (22.9 g, 97 mmoles) in dichloromethane (200 ml) with 2N sodium carbonate (200 ml) and saturated sodium bicarbonate (300 ml) at 5° C. After stirring for 1 hour, the mixture was diluted with dichloromethane (400 ml) and water (400 ml). The organics were washed with water, saturated sodium chloride, dried (sodium sulfate) and evaporated to give 34 g of a solid. The residue (3.0 g) was flash chromatographed (25% ethyl acetate:hexane) to yield 2.4 g (80%) of a solid, melting point 107°-110° C.
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH:12]([CH3:16])[C:13](O)=[O:14])[S:8][CH:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].OC(C(F)(F)F)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:46])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH:12]([CH3:16])[C:13]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][C:37]3=[O:46])[CH2:34][CH2:35]2)=[O:14])[S:8][CH:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CC(C)CCN1C(=O)C(C(C)C(=O)O)SC1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(C(C)C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)SC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoic acid (11 mg, 0.034 mmol), 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one TFA (17 mg, 0.051 mmol) and DiPEA (24 ul, 0.14 mmol) in DMF (0.2 ml) was added HATU (17 mg, 0.044 mmol) and the reaction mixture was stirred at RT for 16 hours. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:6]([CH2:8][C:9]#[N:10])=O.COC(OC)[N:21]([CH3:23])C.C(=O)(O)O.[NH2:30][C:31](N)=[NH:32].C[O-].[Na+]>CO>[NH2:32][C:31]1[N:30]=[C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=2)[C:8]([C:23]#[N:21])=[CH:9][N:10]=1
Reactant: COC(OC)N(C)C
Reactant: N=C(N)N
Reactant: COc1cc(C(=O)CC#N)cc(OC)c1OC
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2nc(N)ncc2C#N)cc(OC)c1OC

Procedure:
From 3,4,5-trimethoxybenzoylacetonitrile and N,N-dimethylformamide dimethyl acetal. Then treatment with guanidine carbonate and sodium methylate in methanol. EI-MS m/e (%): 286 (M+, 100), 271 ([M—CH3]+, 44), 243 (27), 228 (15), 213 (30), 157 (16).
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>O.O1CCCC1.CO>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:22])=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)C1CCCC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)NS(=O)(=O)C1CCCC1
Yield: 20.3 %

Procedure:
The general method of procedure B was followed with cyclopentanesulfonamide (7.45 g), sodium methoxide (2.7 g), methanol (200 ml), tetrahydrofuran (200 ml), and 4-fluorophenyl isocyanate (6.85 g). The residue was dissolved in water and the solution acidified with 1N HCl. The resulting solid was separated and recrystallized from benzene to give 2.9 g of white solid with a melting point of 155-157° C.
Reaction SMILES: I[C@@H:2]1[CH2:7][CH2:6][C@H:5]2[C:8]([O:10][C@@H:3]1[CH2:4]2)=[O:9].[CH:11]1(C(O)=O)CCC=C[CH2:12]1.N12CCCN=C1CCCCC2.I.[C@H]12C(=O)[O:38][C@@H](C1)C=CC2.[OH-].[K+]>C(O)C>[OH:10][C@@H:3]1[CH2:4][C@H:5]([C:8]([O:9][CH2:11][CH3:12])=[O:38])[CH2:6][CH:7]=[CH:2]1
Reactant: O=C1O[C@@H]2C=CC[C@@H]1C2
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Reactant: O=C(O)C1CC=CCC1
Agent: I
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC=C[C@H](O)C1

Procedure:
The title compound was prepared, in racemic form, by generating (1R*,3R*,4R*)-4-iodocyclohexane-1,3-carbolactone from cyclohex-3-ene carboxylic acid, which was then treated with the base DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to eliminate HI. The resultant (1R*,5S*)-cyclohex-3-ene-1,5-carbolactone was then treated with potassium hydroxide dissolved in ethanol to yield the title compound (Marshall, J. A., and Shiping, X., 1995)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[I:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][CH:42]=[C:34]([I:33])[CH:35]=2)=[C:3]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=2)[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)=[O:17])[CH:4]=1)[CH3:10]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(I)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (440 mg, 1.0 mmol), 3-iodobenzoic acid (248 mg, 1.0 mmol) and DIPEA (387 mg, 3.0 mmol) in DMF (5 mL) was added HATU (418 mg, 1.1 mmol). After one hour, the reaction mixture was added to EtOAc (150 mL) washed with water (5×50 mL) and saturated aqueous NaCl (25 mL), dried (Na2SO4) and concentrated. The residue was triturated with DCM (3 mL) to give a solid (718 mg) which was dried under vacuum.
Reaction SMILES: [CH2:1]([O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Br:31])C1C=CC=CC=1>>[BrH:31].[CH2:1]([O:13][CH:14]1[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:20])([CH3:21])[CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCc1ccccc1
Agent: CCCCCCCCCCCCOC1CC(C)(C)NC(C)(C)C1
Product: Br

Procedure:
A misture of 13.0 parts of 4-dodecyloxy-2,2,6,6-tetramethylpiperidine and 3.42 parts of benzyl bromide was heated at 100° C. for 48 hours. Petroleum ether (b.p. 40°-60° C.) was added to the cooled reaction mixture and the 4-dodecyloxy-2,2,6,6-tetramethylpiperidine hydrobromide formed during the reaction was filtered off. The petroleum ether solvent was removed by distillation under reduced pressure and the residue fractionally distilled to give 4-dodecyloxy-1-benzyl-2,2,6,6-tetramethylpiperidine having a boiling point of 200° C. at 0.5 m.m. of Hg. and the following elemental analysis by weight:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:26][C@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:28][C:29](O)=[O:30])(=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CCC.C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:29](=[O:30])[CH2:28][C@H:27]([O:26][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: CI
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCC
Yield: 90.2 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (250 mg, 1.08 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (478 mg, 1.2 mmol) in the presence of EDC·MeI (357 mg, 1.2 mmol) in CH2Cl2 to afford 0.52 g (84%) of N-[(R)-3-heptanoyloxytetradecanoyl]-L-serine benzyl ester: mp 52-53° C.; 1H NMR (CDCl3) δ 0.87 (t, 6H, J=6.9 Hz), 1.1-1.7 (m, 34H), 2.29 (t, 2H, J=7.5 Hz), 2.49 (d, 2H, J=5.8 Hz), 3.67 (s, 1H),3.97 (m, 2H), 4.63 (m, 1H), 5.19 (m, 3H), 6.61 (d, 1H, J=7.1 Hz), 7.35 (br s, 5H).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][CH:6]=1>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCF
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
1g (15.6 mmol) of 2-fluoroethanol was dissolved in pyridine (15 mL), and 6.5 g (34.1 mmol) of p-toluenesulfonic acid was added thereto over a period of 30 minutes while stirring on ice. The mixture was stirred at 0° C. under nitrogen atmosphere for 3 hours, and after adding 35 mL of ice water to the reaction mixture, extraction was performed with 30 mL of ethyl acetate. The obtained organic layer was washed three times with 30 mL of 1N hydrochloric acid, and then further washed with sodium carbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to yield the title compound (3.19 g, 94%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:13]([C@@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)[C:5]2=[C:6]3[S:12][CH:11]=[CH:10][C:7]3=[N:8][CH:9]=[C:4]2[N:3]=1.N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:21][CH2:20][C@H:17]2[CH2:16][CH2:15][C@H:14]([N:13]3[C:5]4=[C:6]5[S:12][CH:11]=[CH:10][C:7]5=[N:8][CH:9]=[C:4]4[N:3]=[C:2]3[CH3:1])[CH2:19][O:18]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c(C)nc4cnc5ccsc5c43)CO2)cc1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a solution of [(2R,5S)-5-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]methanol (60.1 mg, 0.198 mmol) in methylene chloride (2.3 mL) and pyridine (51 μL, 0.62 mmol) was added p-toluenesulfonyl chloride (38.7 mg, 0.203 mmol) and 4-dimethylaminopyridine (1.2 mg, 0.010 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (50 mg, 55%). LCMS calculated for C22H24N3O4S2 (M+H)+: m/z=458.1. Found: 458.1.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[N:21]1[CH2:26][CH2:25]O[CH2:23][CH2:22]1.ClC(OCC(C)C)=O.N1CCCC1>C1COCC1>[O:19]=[C:17]([N:21]1[CH2:26][CH2:25][CH2:23][CH2:22]1)[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
To a solution of N-Boc-(2S)-3-(pyridin-4-yl)alanine (500 mg, 1.9 mmol) in THF (12 mL) was added N-methylmorpholine (200 μL, 1.9 mmol) and the solution was stirred for 5 min, cooled at −15° C. and treated dropwise with isobutyl chloroformate (249 μL, 1.9 mmol). The mixture was stirred for 10 min and pyrrolidine (1.08 g, 15.2 mmol) was added and allowed to warm to 25° C. with stirring for 3 h. The solvent were removed under reduced pressure and the residue was partitioned between EtOAc and NaH2PO4 pH=7.2. The aqueous layer was discarded and the organic layer was washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered and evaporated. The resulting solid was purified by column chromatography (SiO2) with a gradient of 0% to 10% [v/v] MeOH in EtOAc to give tert-butyl (S)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06190 (167 mg, 28% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[CH:38]1([OH:42])[CH2:41][CH2:40][CH2:39]1>N1C=CC=CC=1>[CH:38]1([O:42][C:26]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:3]([C:5]4[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]([CH3:14])[CH:6]=4)([OH:4])[C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[O:27])[CH2:41][CH2:40][CH2:39]1
Reactant: OC1CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Solvent: c1ccncc1
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)OC3CCC3)c2)C(F)(F)F)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.142 mmol) and carbonyldiimidazole (0.185 mmol) in 1 mL of pyridine was heated at 80° C. for 10 hours, cooled to room temperature, and cyclobutanol (1.4 mmol) was added. The mixture was stirred overnight. The volatiles were removed and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to provide 0.076 mmol of the desired compound, m.p. 82° C.-84° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1.[Cl-].[CH3:19][O:20]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:19]([C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1)=[O:20]
Reactant: O=C1CCC(COc2cccc(F)c2F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Yield: 78.7 %

Procedure:
13.8 g of 1-((4-oxocyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 23.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 7.7 g of potassium-t-butoxide was added dropwise at an internal temperature of 10 to 25° C., and the solution was stirred for 30 nm. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 mL of THF, and 100 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 3 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline, saturated sodium hydrogencarbonate, and saturated saline in this order, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. To the residue, 30 mL of methanol and 20% sodium hydroxide aqueous solution were added, and the solution was stirred with ice-cooling for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 11.5 g of 1-((trans-4-formylcyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[N+](=[CH2:14])=[N-]>CCOC(C)=O.CO.CCOCC>[CH3:14][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[NH2:11]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1N

Procedure:
To a suspension of 5-chloroanthranilic acid (6.1 g) in AcOEt-MeOH (20 ml+10 ml), a solution of an excess amount of diazomethane in ether (50 ml) was added at 0° C. After termination of reaction, reaction solvent was evaporated to dryness to give the title compound (6.6 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].S(Cl)(Cl)(=O)=O.[N+:33]([C:36]1[CH:37]=[C:38]([S:42]([CH2:45][CH2:46][O:47][C:48](=[O:59])[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([S:55](Cl)(=[O:57])=[O:56])[CH:50]=2)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1)([O-:35])=[O:34]>C(Cl)Cl.O>[N+:33]([C:36]1[CH:37]=[C:38]([S:42]([CH2:45][CH2:46][O:47][C:48](=[O:59])[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([S:55]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:57])=[O:56])[CH:50]=2)(=[O:43])=[O:44])[CH:39]=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccc(C(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 80 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (600 mg, 1.62 mmol) in CH2Cl (10 mL) was added NaH (45 mg, 1.95 mmol) at room temperature, resulting in a clear solution. To this clear mixture was added the sulfonyl chloride (Intermediate 1, 845 mg, 1.95 mmol, 1.2 eq), in CH2Cl2 at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added and the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated. The residual oil was purified by column chromatography (3% MeOH in CH2Cl2) to yield 1.0 g (80%) of yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[C:8](=[O:12])[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc[nH]c(=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c(=O)c1
Temperature: 25 °C

Procedure:
The title compound of example 18.1 (32 g, 191 mmol) and potassium carbonate (132 g, 957 mmol) were stirred in dimethylformamide (350 mL) at room temperature. Diisopropylethylamine (10 mL, 57 mmol) was added via a syringe, followed by 2-(trimethylsilyl)ethoxymethyl chloride (44.0 mL, 249 mmol). The reaction was stirred at room temperature and diisopropylethylamine (56.6 mL, 325 mmol) was added over 5 hours via a pressure equalized addition funnel. The reaction was then stirred overnight at room temperature. When TLC analysis showed that the reaction was complete the reaction mixture was diluted with ethyl acetate and washed four times with water and once with brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel in 5-40% ethyl acetate in hexanes to purify the desired product (80%, trace amount of o-alkylated product observed).