Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH3:8].[F:10][C:11]([F:21])([F:20])[C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:7]([NH:18][C:15]1[CH:16]=[N:17][C:12]([C:11]([F:10])([F:20])[F:21])=[CH:13][C:14]=1[NH2:19])[CH3:8]
Reactant: CCI
Reactant: Nc1cnc(C(F)(F)F)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1cnc(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
Cesium carbonate (3.1 g, 26.88 mmol) and ethyl iodide (1.76 g, 10.75 mmol) is added to a solution of 6-trifluoromethyl-pyridine-3,4-diamine (1.05 g, 8.96 mmol) in anhydrous DMF (12 mL). The mixture is heated in a sealed tube for 18 h, then cooled to room temperature, and diluted with EtOAc and water. Usual work up and purification by column chromatography, eluting with EtOAc-hexanes provides pure N-Ethyl-6-trifluoromethyl-pyridine-3,4-diamine. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H); 6.95 (s, 1H), 3.21 (q, J=5.4 Hz, 2H), 1.35 (t, J=5.4 Hz, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][CH:35]=[N:36][C:37]=2[NH:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:7][C@@H:6]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH:41][C:42](=[O:49])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@](CO)(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O)c1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of nucleoside 58 (4.18 g, 6.28 mmol) in methanol (50 cm3) was added sodium methoxide (0.75 g, 13.8 mmol) at 0° C. The reaction mixture was stirred for 2 h, and ice was added. The mixture was neutralised using a 20% aqueous solution of HCl. Extraction was performed using dichloromethane (3×75 cm3), the organic phase was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give nucleoside 59 as a white solid material (2.68 g, 73%). δH (CDCl3) 9.42 (1H, br s, NH), 8.58 (1H, s, H-8), 8.16 (1H, s, 2-H), 7.96 (2H, d, J 7.2, Bz), 7.52-7.08 (13H, m, Bn, Bz), 6.18 (1H, d, J 2.5, 1′-H), 4.85-4.38 (4H, m, Bn, 2′-H, 3′-H), 4.33 (2H, s, Bn) 3.90 (1H, d, J 11.9, 1″-Ha), 3.71 (1H, d, J 11.8, 1″-Hb), 3.50-3.39 (2H, m, 5-H). δC (CDCl3) 164.98 (NHCO), 152.19 (C-6), 151.00 (C-2), 149.34 (C-4), 142.28 (C-8), 137.32, 137.25, 133.46, 132.70, 128.69, 128.49, 128.40, 128.11, 128.03, 127.94, 127.83, 127.62, (Bz, Bn), 122.92 (C-5), 90.94, 88.75 (C-1′, C-4′), 77.65, 74.08, 73.44, 73.20, 71.12, 62.39 (C-1″, C-5′, C-2′, C-3′, 2×Bn). FAB-MS m/z 582 [M+H]+. Found: C, 65.6; H, 5.5; N, 11.7. C32H31N5O6 requires C, 66.1; H, 5.4; N, 12.0%.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+].[CH:23](Br)([CH3:25])[CH3:24]>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH:23]([CH3:25])[CH3:24])[CH2:3]1
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)CN(C(C)C)C(=O)O2)cc1OCC1CC1
Reaction time: 17 h
Yield: 29.4 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes and, after adding 0.25 ml (2.7 mmol) of isopropyl bromide, for 17 hours at room temperature. The process was continued analogously to Example 1, thus obtaining 169 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-isopropyl-2-oxazolidinone as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:16]
Reactant: CC(C)c1cc(Cl)nc2ncccc12
Reactant: NN
Product: CC(C)c1cc(NN)nc2ncccc12
Yield: 92 %

Procedure:
A solution of chloro-4-isopropyl-1,8-naphthyridine (690 mg, 3.4 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound (620 mg, 92%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=6.74 Hz, 6 H) 3.45-3.59 (m, 1 H) 6.70 (br. s., 1 H) 7.21 (dd, J=8.06, 4.54 Hz, 1 H) 8.19 (d, J=7.62 Hz, 1H) 8.79 (br. s., 1 H).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:3]([O:5]CC)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:3](=[O:5])[CH:2]([OH:1])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][CH:15]=1)([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(O)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: CC(C)N
Product: CC(C)NC(=O)C(O)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
Ethyl α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyrate 0.1 mole is stirred with 20 ml. of isopropylamine at about 35°C with stirring overnight and the temperature is then raised to reflux for 28 hours. The reaction mixture is evaporated in vacuo and the residue distilled to obtain N-isopropyl α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyramide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B].[C:22]([O-])(=[O:24])C.[Na+]>CN(C)C=O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:22]=[O:24])=[C:16]([CH3:20])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(OCc2ccccc2)c1
Agent: [B]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Dry N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (18.3 ml, 200 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min stirring at 0° C., a solution of 1-benzyloxy-3-methyl-benzene (22 g, 111 mmol) in N,N-dimethylformamide (22 ml) was added dropwise within 30 min (for the preparation of 1-benzyloxy-3-methyl-benzene see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 110° C. After 10 min at 110° C., the mixture was kept at 90° C. for 3.5 h, cooled to 10° C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 4.3 g (19 mmol, 17%) of the title compound as yellow solid.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:29]1[N:33]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[O:31][N:30]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:39][CH2:38][C:37]2[CH:36]=[CH:35][C:34]([C:32]3[O:31][N:30]=[C:29]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:33]=3)=[CH:41][CH:40]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CN)cc2)n1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNC(c3ccc(C(F)(F)F)cc3)C3CCCC3)cc2)n1
Yield: 55 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using cyclopentyl[4-(trifluoromethyl)phenyl]methanone and 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzylamine gave the title compound as a colorless oil (55%). 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 2H), 7.64 (m, 2H), 7.50 (m, 4H), 3.62-3.34 (m, 2H), 2.74 (m, 2H), 2.12-1.85 (m, 2H), 1.70 (m, 2H), 1.60-0.92 (m, 25H), 0.83 (m, 3H). HPLC (Condition A), Rt: 5.42 min (HPLC purity: 98.3%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:19]3[C:25]([O:32][CH3:33])=[CH:26][C:27]([CH:29]([OH:31])[CH3:30])=[CH:28][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:19]3[C:25]([O:32][CH3:33])=[CH:26][C:27]([C:29](=[O:31])[CH3:30])=[CH:28][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)O)cc(OC)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)=O)cc(OC)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 0.17 ml oxalylchloride in 4 ml dichloromethane, 0.285 ml DMSO (in 0.8 ml dichloromethane is slowly added at −60° C. This mixture is stirred under argon at −60° C. for 0.5 h. Then 180 mg (0.488 mmol) 1-[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-ethanol (in 2 ml dichloromethane) are added and stirring is continued at −60° C. for 1 h. 1 ml triethylamine is added and the reaction mixture is allowed to warm to room temperature, poured on water and extracted (3×) with dichloromethane. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 163 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[N:15]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([F:26])[CH:17]=3)[C:13]([NH2:27])=[N:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[N:15]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:26])[CH:17]=3)[C:13]([NH2:27])=[N:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2nc(C3CCCN(C(C)=O)C3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N1CCCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 4-(6-(1-acetylpiperidin-3-yl)-3-aminopyrazin-2-yl)-2-fluorobenzoate (50 mg, 0.134 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (0.500 mL, 0.500 mmol). The reaction mixture was stirred at room temperature for 4 h. The pH of reaction mixture was adjusted to ˜3 with 2 N HCl, and the product was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded for next step without purification (34 mg, 70.7%). LCMS (m/z): 359.1 (MH+), 0.534 min.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:35])[CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[NH:27][C:26]3=[O:34])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1.CC1C=CC=CC=1.[OH-].[NH4+]>O>[C:1]([N:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]([CH2:24][CH2:23][N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)=[O:35])[CH2:22][CH2:21]2)[C:26]1=[O:34])(=[O:3])[CH3:2]
Reactant: O=C(CC1CCN(CCn2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1c(=O)n(CCN2CCC(CC(=O)c3ccc(F)cc3)CC2)c2ccccc21
Yield: 40 %

Procedure:
A mixture of 3.1 parts of acetic acid anhydride, 5 parts of 1-[2-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazol-2-one and 56 parts of methylbenzene is stirred and refluxed for 4 hours. The reaction mixture is cooled and water and ammonium hydroxide are added. Upon stirring, the product is crystallized. It is filtered off, washed with water and dried in vacuo, yielding 2.2 parts (40%) of 1-acetyl-3-[2-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 149.2° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:52]3[N:51]=[C:45]([NH:46][C:47](=[S:50])[NH:48][CH3:49])[N:44]=[C:27]([O:28][C:29](=[O:43])[N:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)(C(C)(C)C)(C)C.COC1C=CC(C(OC[C@H]2O[C@@H](N3C4N=C(NC(=O)NC)N=C(OC(=O)N(C5C=CC=CC=5)C5C=CC=CC=5)C=4N=C3)C[C@@H]2O)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[C:37]1([N:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:29]([O:28][C:27]2[C:26]3[N:25]=[CH:24][N:23]([C:52]=3[N:51]=[C:45]([NH:46][C:47](=[S:50])[NH:48][CH3:49])[N:44]=2)[C@@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:8])[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Agent: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (900 mg, 1.17 mmol) was azeotroped with anhydrous tetrahydrofuran three times and dissolved in anhydrous tetrahydrofuran (6.0 mL), and triethylamine 3 hydrogen fluoride (574 μL, 3.51 mmol) was added thereto. The mixture was stirred at room temperature overnight, and then toluene (5 mL) was added thereto. The solvent was evaporated under reduced pressure. To the residue, methanol (5 mL) and hexane (25 mL) were added for precipitation. The resulting precipitate was purified by filtration to give 6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (504 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][NH:18][C@H:19]1[CH2:38][N:23]2[C:24]3[C:29]([C:30]([CH2:31][C:32]([O:34]CCC)=[O:33])=[C:22]2[CH2:21][CH2:20]1)=[CH:28][CH:27]=[CH:26][CH:25]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([N:18]([CH3:17])[C@H:19]3[CH2:38][N:23]4[C:24]5[C:29]([C:30]([CH2:31][C:32]([OH:34])=[O:33])=[C:22]4[CH2:21][CH2:20]3)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCOCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1(c2ccc(F)cc2)CCOCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 465.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][C:40]=4[Cl:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O.O1CCOCC1>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][C:40]=4[Cl:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:52])([F:51])[F:1])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc(F)c(-c2ccc(C(=O)O)cc2Cl)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 2 h

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-chloro-6′-fluoro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (84.5 mg, 0.11 mmol), lithium hydroxide monohydrate (46.2 mg, 1.1 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature. LCMS of aliquot at reaction time was 2 hrs indicated completion of reaction. Volatiles were removed under reduced pressure. Crude mixture was dissolved in MeCN and acidified by HCl (1N, aq.) to afford a clear solution. This solution was purified by a reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford a colorless glass. This glass was dissolved in DCM and washed with water. Organic extracts were combined, dried/Na2SO4, filtered and evaporated to afford the title compound. LCMS (ESI) calc.=749.10; found-750.06 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 8.21 (dd, J=10, 2 Hz, 1H), 8.03 (dd, J=8, 2 Hz, 1H), 7.86 (s, 1H), 7.73-7.68 (m, 1.5H), 7.68-7.62 (m, 2.5H), 7.48 (t, J=7.5 Hz, 1H), 7.41 (dd, J=11, 8 Hz, 1H), 7.17 (dd, J=8.5, 2 Hz, 1H), 6.86 (dd, J=11, 3.5 Hz, 1H), 6.60 (d, J=8 Hz, 0.5H), 5.40 (d, J=8 Hz, 0.5H), 4.94 (t, J=15 Hz, 1H), 4.18 (d, J=16 Hz, 0.5H), 3.95 (d, J=16 Hz, 0.5H), 3.87 (s, 3H), 3.85-3.74 (m, 1H), 0.56 (d, J=6.5 Hz, 1.5H), 0.46 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1.[H][H].[NH3:20]>[Ni]>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:20])=[C:7]([F:13])[CH:6]=1
Reactant: N
Reactant: [H][H]
Reactant: O=Cc1ccc(Oc2ccccc2Cl)cc1F
Agent: [Ni]
Product: NCc1ccc(Oc2ccccc2Cl)cc1F
Temperature: 35 °C
Reaction time: 4 h

Procedure:
148 mg (0.59 mmol) of 4-(2-chlorophenoxy)-2-fluorobenzaldehyde were dissolved in 10 ml of 7M methanolic ammonia and 50 mg Raney nickel were added. The mixture was shaken for 4 h at 35° C. and 3 bar hydrogen pressure. The catalyst was removed by suction filtering, the residue was evaporated down and purified by reversed-phase chromatography.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1(C)[C@]23C4(ON4S(=O)(=[O:54])C2)C[C@H]1CC3.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[C:17]([CH:22]([OH:54])[C:23]([O:25][CH3:26])=[O:24])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:34][CH:35]=1
Reactant: CC1(C)[C@@H]2CC[C@@]13CS(=O)(=O)N1OC13C2
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
A −78° C. solution of methyl 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetate (45 mg, 0.096 mmol) in Tetrahydrofuran (THF) (1 mL) was treated with LiHMDS (0.207 mL, 0.207 mmol) and then stirred at −78° C. for 20 minutes. A solution of (1R)-(−)-(10-Camphorsulfonyl)oxaziridine (71.1 mg, 0.310 mmol) in Tetrahydrofuran (THF) (1 mL) was added and the mixture was then warmed to 0° C. for 20 minutes. The mixture was treated with HCl (1M) until pH<2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to afford methyl 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)-2-hydroxyacetate (42 mg, 0.087 mmol, 90% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.30-7.45 (m, 5H) 7.16-7.26 (m, 2H) 6.89-7.02 (m, 3H) 6.54-6.63 (m, 1H) 6.29-6.37 (m, 1H) 6.13-6.24 (m, 1H) 6.01-6.11 (m, 1H) 5.34-5.42 (m, 1H) 3.81 (s, 3H) 3.70 (s, 3H) 2.51 (s, 3H); LCMS (m/z) ES+=485 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[C:4](=[O:16])[C:3]=1[C:17](OCC)=[O:18].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.O>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[C:5]([CH3:14])([CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:18]
Reactant: CCOC(=O)C1=C(O)c2cc(SC)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Temperature: 120 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of ethyl 4-hydroxy-1,1-dimethyl-6-(methylthio)-2-oxo-naphthalen-3-carboxylate (0.800 g, 2.61 mmol), glycine tert-butyl ester hydrochloride (0.525 g, 3.13 mmol) and DIPEA (0.910 mL, 5.22 mmol in 1,4-dioxane (25 mL) in a 75 mL sealed vessel, was stirred at 120° C. for 3 hours. Deionized water (75 mL) was added, and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were then washed with brine (50 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 1.44 g crude product which was purified by flash column chromatography (silica, 0-50% DCM in hexane) to give the title compound (0.886 g). MS m/e=336 (M+H-tBu)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)n1c(N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 28.7 %

Procedure:
2-amino-benzimidazole (1.0 g, 7.5 mmol) was dissolved in 15 mL of anhydrous CH2Cl2 and 3 mL anhydrous DMF and cooled to ˜0° C. Trethylamine (1.6 mL, 1.5 eq.) was added followed by an addition of methanesulfonylchloride (580 μL, 7.5 mmol) over ˜1 minute. After 1 minute at ˜0° C., the reaction was warmed to RT. After 1 hour the reaction was quenched with water, and partitioned between a saturated sodium bicarbonate solution and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with water (2 times), brine then dried over NaSO4, filtered and the solvent was removed in vacuo to give 455 mg of N-methanesulfonyl-2-aminobenzimidazole. HPLC shows the material to be 91% pure, (ret. time=3.70). LCMS: obs. M+H@ 212.1 amu. The material was carried on without purification.