Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])([CH3:19])[CH2:15][CH2:14]2)=[N:8][CH:9]=[CH:10][N:11]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][C:20]([C:16]1([CH3:19])[CH2:15][CH2:14][N:13]([CH2:12][C:7]2[C:6](=[O:5])[NH:11][CH:10]=[CH:9][N:8]=2)[CH2:18][CH2:17]1)=[O:29]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C)(C(=O)Cc2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C(=O)Cc2ccccc2F)CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 1 h
Yield: 81 %

Procedure:
After dissolving 135 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone in 2 ml of ethyl acetate, 2 ml of 4N hydrogen chloride/ethyl acetate was added while stirring on ice. After 1 hour, saturated aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (94 mg, 86% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:45])[C@@H:41]([OH:42])[CH2:40][CH2:39][C@@:38]2([CH3:43])[C:12]1=[CH:13][CH2:14][C@@H:15]1[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:44])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:21]>>[C:1]([O:42][C@H:41]1[CH2:40][CH2:39][C@@:38]2([CH3:43])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:44])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([CH2:22][O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:21])[C:11]1([CH3:10])[CH3:45])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Product: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
34.4 ml of benzoylchloride were added to a solution of 70 g crude (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol (Example 1c) (not purified by chromatography) in 670 mg pyridine at 0-3° C. The reaction mixture was stirred for 2 h at room temperature and poured into ice-water. The precipitate was filtered off, washed with water and recrystallized from acetone to give 42 g of (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol benzoate.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])C.[Li+].[OH-]>C1COCC1.O>[C:17]([O:16][C:14]([N:7]1[CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C@H:6]1[C:4]([OH:5])=[O:3])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)[C@@H]1C2CCCC2CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CCCC2[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2 g of (S)-Hexahydro-cyclopenta[c]pyrrole-1,2-dicarboxylic acid 2-tert-butyl ester 1-ethyl ester and 449 mg of LiOH in 30 ml of THF and 10 ml of H2O is stirred at rt for 16 hours. The reaction is quenched with brine, acidified to pH 2 with aq. 2N HCl solution and extracted with EtOAc. The combined organic phases obtained are washed with brine, dried and solvent is evaporated to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[NH2:47][C@@H:48]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=1)[C:49]([NH:51][C@@H:52]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]([C@@:55]1([CH3:58])[CH2:57][O:56]1)=[O:54])=[O:50].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:15][C@@H:13]([CH3:14])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:47][C@@H:48]([CH2:66][C:67]1[CH:68]=[CH:69][C:70]([O:73][CH3:74])=[CH:71][CH:72]=1)[C:49]([NH:51][C@@H:52]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]([C@@:55]1([CH3:58])[CH2:57][O:56]1)=[O:54])=[O:50])=[O:12]
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
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: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.08 h

Procedure:
To (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-hydroxybutanoic acid (453 mg, 2.07 mmol) in DMF (10 mL) at 0° C. was added HATU (865 mg, 2.28 mmol). The mixture was stirred for 5 min to dissolve the solids at which time (S)-2-amino-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (2.07 mmol assumed) and DIEA (1.71 mL, 10.35 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide crude tert-butyl ((2S,3S)-3-hydroxy-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate as a yellow oil that was carried forward without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[C:24]1([CH2:30][CH2:31][N:32]=[C:33]=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:32]([CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]2=[O:34])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NCCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(CCc3ccccc3)c(=O)n(C3CCCC3)c12
Yield: 48.1 %

Procedure:
1-Cyclopentyl-7-methoxy-3-phenethyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (20 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and (2-phenyl)ethyl isocyanate (0.5 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[C:44]([O:52][C:53](=[O:55])[CH3:54])=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46](O)=[O:47])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[C:44]([O:52][C:53](=[O:55])[CH3:54])=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[O:47])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
4-(Trifluoromethylsulfonyl)aniline (0.361 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.084 g, 0.144 mmol, 27%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1ccc(CO)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1ccc(CCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 59.8 %

Procedure:
To a mixture of [4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]methanol (0.60 g), methyl 2-(2-hydroxyphenyl)acetate (0.35 g), triphenylphosphine (0.79 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 1.39 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. To the reaction mixture was added ethyl acetate, the mixture was washed successively with water, a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]acetate as a colorless oil (0.54 g, 58%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=O)=O.[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19](O)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>C(OCC)(=O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH:16]=1)[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CS(=O)(=O)OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCCN1CCOCC1
Temperature: 90 °C
Yield: 41.7 %

Procedure:
A flask was charged with 2-morpholinoethyl methanesulfonate (1.5 g, 6.9 mmol), 5-fluoro-2-nitrophenol (0.99 g, 6.3 mmol), cesium carbonate (4.0 g, 12 mmol) and DMA (100 mL), and the reaction mixture was heated to 90° C. for 15 hours. Ethyl acetate (200 ml) was added to the cooled reaction mixture and the mixture was extracted with water (2×100 ml), 1N sodium hydroxide (2×50 ml) and aqueous 5% lithium chloride (2×50 ml). The organic solvent was removed on a rotary evaporator under reduced pressure. Purified of the crude product by silica column chromatography using 50:50 ethyl acetate:hexanes as eluant gave 0.71 g of 4-(2-(5-fluoro-2-nitrophenoxy)ethyl)morpholine (39% yield). EI (MS): 271 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:15](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>[Cl-].[Na+].O>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COc1cc(NC(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-hydroxy-4-nitro-phenyl)-acetamide (2 g, 10.15 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added potassium carbonate (2.6 g, 18.88 mmol) followed by methyl iodide (0.71 mL, 11.16 mmol) and the reaction mixture was stirred at room temperature for 1 hour. A second aliquot of methyl iodide (0.15 mL) was then added and the resulting mixture was stirred for 1 hour. Ethyl acetate (100 mL) and brine (100 mL) were added, the organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give N-(3-methoxy-4-nitro-phenyl)-acetamide.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:53]([O:55][C:56](=[O:61])[C@H:57]([CH2:59][NH2:60])N)[CH3:54]>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:60][CH2:59][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:61])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@H](N)CN
Reactant: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of 66.7 mg product from Step A Example 6, 34.5 mg EDC, 24.3 mg HOBt in 0.5 mL DMF was stirred at room temperature for 30 minutes. DIEA (31 μL) and β-amino-alanine ethyl ester hydrochloride (27.6 mg) were added and the mixture stirred for additional 16 hours. The solvent was removed under reduced pressure. The title compound was isolated as a white solid by preparative HPLC using 60˜80% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column followed by lyophilization. 1H NMR (CD3OD, 600 MHz) δ 7.68 (d, J=8.4 Hz, 2H), 7.39˜7.42 (m, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 6.31 (s, 1H), 5.37 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.59 (t, J=6.8 Hz, 2H), 2.66 (tt, J=11.6 & 3.5 Hz, 1H), 2.61 (t, J=6.8 Hz, 2H), 1.96˜2.00 (m, 2H), 1.80˜1.84 (m, 2H), 1.71˜1.75 (m, 1H), 1.45˜1.52 (m, 2H), 1.37˜1.45 (m, 2H), 1.25˜1.33 (m, 1H), 1.21 (t, J=7.1 Hz, 3H). LC-MS: 2.44 min. (M+H=544.4).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:21][NH2:22].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[Cl:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][NH:22][CH3:21])[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.04 g, 2.77 mmol) in CH2Cl2 (10 mL) was added dropwise to a 2M solution of MeNH2 (13.9 mL, 27.73 mmol) in THF. The solution turned light yellow and the flask was stoppered and stirred at RT overnight. Ethyl acetate (200 ml) and saturated NaHCO3 solution (150 ml) were added. The organic layer was separated, washed with brine (150 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.81 g, 90%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.33 (m, 1H), 7.24-7.30 (m, 2H), 7.11-7.14 (m, 1H), 6.98 (dd, 1H), 3.81 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH3:29])[C:16]2[CH:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19][B:18]([OH:27])[C:17]=2[CH:28]=1)(C(C)(C)C)(C)C.C1COCC1.O>C(O)(=O)C>[OH:27][B:18]1[C:17]2[CH:28]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:14]=[C:15]([CH3:29])[C:16]=2[CH:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCCO[Si](C)(C)C(C)(C)C)cc(C)c21
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(OCCCO)cc(C)c21

Procedure:
Ethyl 2-(6-(3-(tert-butyldimethylsilyloxy)propoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate was treated with a mixture of THF:water:acetic acid (ratio 1:1:2) at 55° C. for 1.5 hours. The solvent was then removed under reduced pressure and the resulting residue was dried under vacuum overnight and used directly in next step without further purification.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2.S(Cl)([Cl:16])=O>>[C:1]12([C:11]([Cl:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C12CC3CC(CC(C3)O1)C2
Product: O=C(Cl)C12CC3CC(CC(C3)O1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 56B (0.1 g, 0.55 mmol) in 5 mL of thionyl chloride was warmed to reflux and stirred for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 5 mL of toluene and concentrated under reduced pressure three times to afford title compound, which was used without additional purification or characterization.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([Cu])#[N:22].Cl>CN1C(=O)CCC1>[N+:18]([C:3]1[CH:4]=[C:5]([C:14]([F:17])([F:16])[F:15])[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:7][C:2]=1[C:21]#[N:22])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(OCC(F)(F)F)cc1Br
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 84.6 %

Procedure:
A mixture of 1-bromo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzene from step 2 (30.54 g, 83.0 mmol) and CuCN (7.80 g, 87.1 mmol) in NMP (83 mL) was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 N HCl, extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a dark brown oil (33.9 g). Silica gel column chromatography with heptane/EtOAc 9:1->4:1 gave the title compound as a yellow solid (22.05 g, 85%). MS (EI) 314 [M].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]1[O:21][C@H:20]([CH2:22]O)[C@@H:18]([OH:19])[CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:22][C@H:20]1[O:21][CH2:16][CH2:17][C@@H:18]1[OH:19])(=[O:5])=[O:4]
Reactant: OC[C@H]1OCC[C@@H]1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OC[C@H]1OCC[C@@H]1O)C(F)(F)F

Procedure:
To a -20° C. solution, under argon, of 8.4 ml of trifluoromethanesulfonic anhydride in 75 ml of methylene chloride is added, dropwise, a solution of 5.9 g of product from Example 268 and 4.05 ml of pyridine in 25 ml of methylene chloride. The temperature is maintained below -10° C. during the addition. The progress of the reaction is monitored by tlc. The reaction is filtered and the filtrate concentrated in vacuo to an oily residue. The residue is purified by chromatography (silica gel: 50% ethyl acetate/hexane) to give 7.03 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7]C(=O)OC(C)(C)C)[CH2:2]1.Br[C:16]1[N:21]=[C:20](F)[C:19]([CH3:23])=[CH:18][CH:17]=1.[CH3:24][C:25]1[N:30]=[C:29]([C:31]2[N:36]=[CH:35][C:34]3[CH:37]=[N:38][NH:39][C:33]=3[CH:32]=2)[CH:28]=[N:27][CH:26]=1>>[CH3:23][C:19]1[C:20]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH2:7])[CH2:2]2)=[N:21][C:16]([N:39]2[C:33]3[CH:32]=[C:31]([C:29]4[CH:28]=[N:27][CH:26]=[C:25]([CH3:24])[N:30]=4)[N:36]=[CH:35][C:34]=3[CH:37]=[N:38]2)=[CH:17][CH:18]=1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Cc1ccc(Br)nc1F
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C)c(N3CCC[C@H](N)C3)n2)n1
Yield: 4.5 %

Procedure:
Following the procedures as described in EXAMPLE 86 and starting with tert-butyl N-[(3S)-3-piperidyl]carbamate, 6-bromo-2-fluoro-3-methyl-pyridine, and 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine, 205 was obtained as an off-white solid (4.4 mg, 4.5%) over 3 steps. 1H NMR (400 MHz, DMSO) δ 9.75-9.70 (s, 1H), 9.48-9.44 (s, 1H), 9.33-9.29 (s, 1H), 8.68-8.61 (d, J=12.1 Hz, 2H), 8.38-8.15 (s, 1H), 7.78-7.74 (d, J=8.1 Hz, 1H), 7.59-7.55 (d, J=8.0 Hz, 1H), 2.90-2.84 (m, 1H), 2.67-2.63 (s, 3H), 2.37-2.32 (s, 3H), 2.04-1.95 (d, J=9.2 Hz, 2H), 1.80-1.68 (d, J=9.4 Hz, 1H), 1.57-1.47 (d, J=8.6 Hz, 1H); MS (ESI) m/z: 433.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(N)CN.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:24])([F:25])[F:26])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(F)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(F)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 1 h

Procedure:
2-(5-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 1-2a (78 mg, 0.145 mmol) was dissolved in DCM (2 ml). TFA (1.114 ml, 14.45 mmol) was added and mixture allowed to stir for 1 hr. Reaction concentrated then resuspended in MeOH (4 ml) and ethylenediamine (0.020 ml, 0.289 mmol) and sodium hydroxide (10 M aqueous) (0.101 ml, 1.012 mmol) added. After 30 min the reaction was treated with HCL (1.012 ml, 1.012 mmol) concentrated in vacuo and the residue was purified by preparative HPLC Reverse phase (C-18). (5-95% Acetonitrile/0.1% TFA/water). Product fractions were treated with aq. NaHCO3, concentrated and product extracted into DCM and ethyl acetate. Extracts dried over sodium sulfate, filtered and concentrated to give white solid 1-2. (40 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([Cl:28])=[N:13][C:14]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]2[CH3:27])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:28].[CH3:10][C:11]1[C:12]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:13][C:14]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]2[CH3:27])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(N2CCc3ccsc3C2C)nc(Cl)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccsc3C2C)nc(C)c1C
Product: Cl
Yield: 23.9 %

Procedure:
After 2-methyl-4-fluoroaniline(0.3 ml, 3 mmol) was added to a mixture solution of 5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-4-chloropyrimidine (0.4 g, 1.4 mmol) and dimethylformamide(10 ml), 0.14 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [OH:1][C:2]1[C@@:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[OH:1][C:2]1[C@@:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4](=[O:14])[C:3]=1[CH:15]([C:25]1[NH:26][C:27]2[C:32]([C:24]=1[CH3:23])=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: C[C@]1(c2ccccc2)NC(=O)C=C1O
Reactant: O=Cc1ccccc1
Product: Cc1c(C(C2=C(O)[C@@](C)(c3ccccc3)NC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure D, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (prepared according to Lit. 11, see also Lit. 19) was reacted with benzaldehyde and 3-methyl-1H-indole to give the title compound as a yellow foam. MS: 409.2 ([M+H]+).