Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>ClCCl>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
A solution of 4-hydroxybenzoic acid (6.91 g) and pyridine (12.1 ml) in dichloromethane (100 ml) was cooled to an ice-water temperature, and hereto was added dropwise pivaloyl chloride (13.26 g). The mixture was stirred at same temperature for 1.5 hours, and thereto was added a 10% aqueous hydrochloric acid solution (50 ml). The organic layer was washed with H2O (100 ml) and brine, and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml)-H2O (15 ml), and the mixture was stirred at 50° C. for 17.5 hours. After being cooled to an ice-water temperature, the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution (about 100 ml). After being stirred at room temperature for 4 hours, the mixture was acidified with a 36% aqueous hydrochloric acid solution at an ice-water temperature. The resultant mixture was extracted with ethyl acetate (100 ml), and the organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1-9:1) and triturated with diisopropyl ether to give 4-pivaloyloxybenzoic acid (7.10 g) as a colorless solid. ESI-Mass m/Z 221 (M−H). 1H-NMR (DMSO-d6) δ 1.31 (s, 9H), 7.23 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 10.03 (brs, 1H).
Reaction SMILES: C(O[C:4]([N:6]([CH3:29])[N:7]=[C:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])C.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:49]([O:51][C:52](=[O:54])C)[CH3:50]>C1(C)C=CC=CC=1>[CH2:49]([O:51][C:52](=[O:54])[CH2:29][N:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N:16]([CH2:17][C:18]([CH3:21])([CH3:19])[CH3:20])[C:4]1=[O:5])[CH3:50]
Reactant: CCOC(=O)N(C)N=C(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Reactant: CCOC(C)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-neopentylamino-2',5-dichlorobenzophenone ethoxycarbonyl methyl hydrazone (0.16 g) and triethylamine (90 mg) in toluene (2 ml) was added triphosgene (54 mg). The mixture was stirred for one hour at 70° C., to which was added acetic acid ethyl ester (50 ml). The mixture was washed with water and, then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=3:1 v/v as an eluent) to give 0.16 g of an oily compound.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[C:24]([CH3:31])[C:23]=2[CH:32]=1>CC#N>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([S:27]([NH:7][C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])(=[O:29])=[O:28])=[C:24]([CH3:31])[C:23]=2[CH:32]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
Pyridine (200 μL, 2.48 mmol) was added to a solution of methyl 3-aminobenzoate (188 mg, 1.24 mmol) and 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (349 mg, 1.24 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature over night. After removal of the solvents, the residue was dissolved in EtOAc and water. The phases were separated, and the organic solution was washed with 1M HCl twice, water twice and brine then dried (MgSO4). The crude product, obtained after evaporation of the solvents, was crystallized from MeOH (ca 5 mL). The solid product was triturated using heptane, giving the intermediate methyl 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate as an off-white solid (432 mg, 88%). 1H NMR (500 MHz, CDCl3) δ ppm 2.46 (s, 3 H) 2.45 (s, 3 H) 6.91 (s, 1 H) 7.37 (t, J=7.81 Hz, 1 H) 7.43-7.47 (m, 2 H) 7.72 (d, J=1.96 Hz, 1 H) 7.72 (d, J=8.76 Hz, 1 H) 7.76 (t, J=1.83 Hz, 1 H) 7.85 (dt, J=7.81, 1.34 Hz, 1 H). MS (ESI+) 396 m/z [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:8][C:7]2[CH:9]=[N:10][CH:11]=[CH:12][C:6]=2[NH:5][N:4]=1.[F:13][C:14]([F:25])([F:24])[C:15]([O:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[O:16]>FC(F)(F)C(O)=O>[F:13][C:14]([F:25])([F:24])[C:15]([OH:17])=[O:16].[F:22][C:19]([F:20])([F:21])[C:18]([N:5]1[C:6]2[CH:12]=[CH:11][N:10]=[CH:9][C:7]=2[NH:8][C:3]([CH3:2])=[N:4]1)=[O:23]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1=NNc2ccncc2N1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(C(=O)C(F)(F)F)c2ccncc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
3.7 g (0.02 moles) of 3-methyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are dissolved in 100 ml of trifluoroacetic acid, and the solution is maintained at room temperature for 2 hours. Thereafter 22.4 ml (0.08 moles) of trifluoroacetic acid anhydride are added to the mixture, and the reaction is conducted for additional 3 hours at 20° to 30° C. The reaction mixture is processed to obtain 5.4 g (75.5%) of 1-trifluoroacetyl-3-methyl-1,4-dihydropyrido[3,4-e]-as-triazine trifluoroacetate; m.p.: 208°-209° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[C:33]([F:36])([F:35])[F:34])[C:27](Cl)=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:24]([F:23])[CH:25]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(C(F)(F)F)c(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To the stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 3-fluoro-4-trifluoromethylbenzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with methanol (1 mL) and washed with water (2×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-4-trifluoromethyl-benzamide (0.6 g, 53%) as a white solid: mp 165-167° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=8.20 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.5 Hz, 1H), 7.76-7.84 (m, 3H), 7.95-8.01 (m, 3H), 9.45 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.97, 30.92, 38.54, 48.87, 115.88 (116.17), 118.56 (118.72, 119.00, 119.16), 122.30, 123.94 (123.98), 120.52 (124.13), 127.25, 127.74 (127.80), 131.55, 133.24, 134.83, 138.51, 140.42 (140.52), 157.04 (160.38), 164.19, 166.91, 167.48, 169.81, 172.74; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.00; H, 2.95; N, 8.80; F, 15.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[N:8]([CH2:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
30 g (0.106 mol) of 6-chloro-1-(2-ethylbutyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 350 ml of concentrated sulfuric acid and cooled to 0°C. Then, at 0° C., 10.8 g of potassium nitrate were added a little at a time, and the solution was stirred for 1.5 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction, washed with water and dried to yield 31 g (91%) of the product. Melting point 232°-233° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[F:17][C:18]([F:28])([F:27])[C:19]1[N:20]=[C:21]([C:24](O)=[O:25])[NH:22][CH:23]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[F:28][C:18]([F:17])([F:27])[C:19]1[N:20]=[C:21]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:22][CH:23]=1
Reactant: O=C(O)c1nc(C(F)(F)F)c[nH]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.90 g, 3.91 mmol), 4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained in Example (33c) (0.40 g, 2.22 mmol), WSC hydrochloride (1.25 g, 6.52 mmol) and HOBT (0.30 g, 2.22 mmol), to obtain 0.67 g of the title compound as a white foamy substance (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N1C(C)=CC=CC=1C.CN1CCCC1.Cl[C:27]1[C:28]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:33][C:29]=2[N:30]=[CH:31][N:32]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:27]1[C:28]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:33][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Agent: CN1CCCC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
After adding 328 mg of 3-fluoro-4-nitrophenol, 0.22 ml of 2,6-lutidine and 0.9 ml of N-methylpyrrolidine to 360 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728 and stirring the mixture overnight at 130° C., it was returned to room temperature, water was added, the precipitated solid was filtered out and washed with water and diethyl ether, and the collected solid was dried to obtain 112 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:11]=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(=O)O)cc1Br
Reaction time: 1.5 h

Procedure:
To a solution of dimethyl 2-bromoterephthalate (1.04 g) in methanol (10 mL) was added 1 N sodium hydroxide (5.71 mL) at room temperature. After stirring for 1.5 hour, the reaction was quenched by adding 1 N hydrochloric acid (7 mL). White crystals were formed. Water (10 mL) was added to aid crystalyzation. The crystals were collected by filtration, washed with water, and dried in the air. 3-Bromo-4-(methoxycarbonyl)benzoic acid was obtained as white crystals (532 mg).
Reaction SMILES: [NH2:1][C:2]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]([CH2:6][C@H:7]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[Cl:33].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:46][CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[NH:42][C:41]2=[O:51])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][C:5]([CH2:6][C@@H:7]([CH2:8][C:9]([N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:46][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[NH:42][C:41]3=[O:51])[CH2:38][CH2:39]2)=[O:11])[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)=[O:13])=[CH:4][C:3]=1[Cl:33]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)O)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 6.3 g (12.8 mmol) of (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo-butanoic acid, 3.16 g (12.9 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 4.66 g (14.5 mmol) of TBTU, 1.96 g (14.5 mmol) of HOBt, 9.45 mL (68 mmol) of triethylamine and 300 mL DMF was stirred for 12 h at RT. The reaction mixture was evaporated down i. vac., the residue was distributed between EtOAc and saturated NaHCO3 solution. The org. phase was separated off, dried and evaporated down i. vac. The residue was purified by chromatography on silica gel. The yellow oil obtained was triturated with ether and suction filtered. The desired product was obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:28]=[C:29]([N:32]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:33]([NH:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:34])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:28]=[C:29]([N:32]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:33]([NH:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:34])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OCC)cc3)c2c1
Solvent: CCO
Product: CCCCCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 72 from ethyl 4'-[(2-n-butyl-6-(N-(cyclohexylamino-carbonyl)-n-octylamino)-benzimidazol-1-yl)-methyl]bi-phenyl-2-carboxylate in ethanol/2N sodium hydroxide solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:28]3[CH2:27][CH2:26][N:25]([C:30]4[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=4)[CH:24]([CH3:23])[CH2:29]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
54 mg (65%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (53 mg, 0.179 mmol), 2-methyl-1-m-tolylpiperazine (32 mg, 0.179 mmol), DIPEA (0.033 mL, 0.187 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.O[C@@H:22]([CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH:9]([C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([C@H:22]([CH2:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:11]1)=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Product: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenyl pyrrolidine (from EXAMPLE 1, Step E) and 2-(S)-hydroxy-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 25, Step A) using procedures analogous to those described in EXAMPLE 1, Steps G-I. For the title compound: 1H NMR (300 MHz) δ 1.542.08 (m, 8H), 2.31 (m, 1H), 2.75 (t, J=8.6 Hz, 1H), 2.96 (m, 1H), 3.11-3.35 (m, 4H), 3.56 (q, J=7.9 Hz, H3), 5.16 (s, 2H), 7.19-7.39 (m, 10H), 9.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([O:5][CH:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.Cl.[CH2:30]([NH2:33])[CH:31]=[CH2:32]>O1CCCC1>[CH2:30]([N:33]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:2]1[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[CH:31]=[CH2:32]
Reactant: CC(OC(=O)C(Br)CCCCBr)C(=O)N1CCCC1
Reactant: C=CCN
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCCCC1C(=O)O[C@@H](C)C(=O)N1CCCC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
TO 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2,6-dibromohexanoate (295 mg, 0.75 mmol), NaI (225 mg, 1.5 mmol), triethylamine (303 mg, 3.0 mmol) and tetrahydrofuran (4 mL) were added. Subsequently, allylamine hydrochloride (84.2 mg, 0.9 mmol) and tetrahydrofuran (4 mL) were added thereto. The mixture was stirred at 20° C. for 4 hours and then at 40° C. for 15 hours. It was confirmed with NMR analysis of the reaction solution that the conversion ratio was 100% and the diastereo ratio was 75:25.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]1=2.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([O:12][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[N:17]=[CH:16][N:15]=3)=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1cccc2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sccc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (0.104 g, 2.6 mmol, 60% suspension in mineral oil, Aldrich) was added in small portions to a solution of benzo[b]thiophen-4-ol (0.3 g, 2 mmol, prepared according WO 01/68653) in DMF (4 mL) and the mixture was stirred at room temperature for 0.5 h. (4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.776 g, 3 mmol) was then added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under vacuum, the residue was dissolved in EtOAc (50 mL), washed with 1 N NaOH and water, dried over MgSO4, and filtered. The filtrate was evaporated under vacuum and the residue purified by silica gel chromatography (10% EtOAc in hexanes) to give the title compound. Mp: 122.3-122.4° C. MS (ESI, pos. ion) m/z: 373.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH2:24][CH2:23][CH2:22][C:21](=O)[CH2:20]1>>[F:15][C@H:14]1[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:21]2[CH2:22][CH2:23][CH2:24][O:19][CH2:20]2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reactant: O=C1CCCOC1
Product: C[C@]1(c2cc(NC3CCCOC3)ccc2F)N=C(N)COC[C@@H]1F
Yield: 49.6 %

Procedure:
In an analogous manner as described for example 1 the reductive amination of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) and dihydro-2H-pyran-3(4H)-one (CAS [23462-75-1]) (8.63 mg, 86.2 μmol) yielded the title compound (13.2 mg, 49.6%) as a colorless solid. MS (ISP): m/z=340.2 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH:1]=[O:3])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOC(=O)Cc1ccc(NC=O)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of acetic anhydride (0.33 mL, 3.57 mmol) and formic acid (0.17 mL, 4.46 mmol) was heated at 60° C. for 2 hours. The reaction mixture was cooled to 0° C., a solution of (4-amino-phenyl)-acetic acid ethyl ester (Preparation 267, 500 mg, 2.79 mmol) in THF (10 mL) was added slowly to the reaction mixture and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was neutralized with sat. aq. Na2CO3 solution and extracted with diethyl ether (2×25 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:MeOH 100:0 to 98:2) to afford the title compound as an oil in 93% yield, 500 mg.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:31]([NH:35][NH2:36])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([NH:35][NH:36][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NNc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Yield: 20.1 %

Procedure:
A mixture of Example 1A (300 mg, 0.7 mmol), tert-butylhydrazine hydrochloride (261 mg, 2.1 mmol) and potassium carbonate (385 mg, 2.8 mmol) in DMF (15 mL) was stirred at 40° C. for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried with MgSO4, and concentrated under reduced pressure. Purification by chromatography (SiO2) afforded 70 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (s, 9 H), 1.30-1.35 (m, 9H), 1.63-2.04 (m, 4 H), 3.68 (t, J=6.7 Hz, 1 H), 3.76-3.88 (m, 1 H), 4.18-4.39 (m, 3 H), 4.62 (s, 1 H), 7.28-7.32 (m, 1 H), 7.46-7.60 (m, 2 H), 8.51 (d, J=1.6 Hz, 1 H), 9.90 (s, 1 H). MS (DCI/NH3) m/z 499 (M+H)+. Anal. calculated for C24H33F3N4O2S: C, 57.81H, 6.67 N, 11.24. Found: C, 58.22H, 6.72 N, 10.98.