Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[C:26]([OH:31])=[N:27][CH:28]=[CH:29][CH:30]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[C:26]4=[O:31])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccnc1O
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)c1=O
Temperature: 130 °C
Yield: 66 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (150 mg, 0.34 mmol), 3-methoxy-2-hydroxypyridine (85 mg, 0.68 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (25 mg, 0.13 mmol). The mixture in a sealed tube was heated at 130° C. for 4 h. The mixture was then purified by HPLC to give the titled compound (99 mg). MS 441.0 and 443.0 (M+H, Cl pattern)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1N

Procedure:
Prepared from (4-furan-3-yl-2-nitrophenyl)-carbamic acid tert.-butyl ester (Example B6) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a light brown solid. (744 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:5]=[CH:6][CH:7]=1.[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20](=[O:19])[CH:21]=[CH:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(Br)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(Br)c1
Temperature: 85 °C

Procedure:
A mixture of 2-[2-(3-bromophenyl)-2-methylpropyl]-2-trifluoromethyloxirane, 4-hydroxyquinoline (2 equiv.), and sodium ethoxide (21 wt. % solution in ethanol, 1 equiv.) in ethanol was heated at 85° C. for 14 hours, quenched with water, and concentrated in vacuo to remove most of the ethanol. The residue was diluted with half saturated aqueous sodium bicarbonate solution and methylene chloride. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate-hexanes gradient and concentration of the product-rich fractions afforded 1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2[C:30]3[N:29]=[C:28]([O:31]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:25]=[C:24]([C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[CH:23]=2)=[O:21])=[N:18][CH:19]=1.Cl>O1CCCC1.C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:21])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:22]2[C:30]3[NH:29][C:28](=[O:31])[NH:27][C:26]=3[CH:25]=[C:24]([C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[CH:23]=2)=[N:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: CCOc1nc2c(C(=O)c3ccc(Cl)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2ccc(Cl)cn2)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 2-bromopyridine (0.02 ml, 0.2 mmol) in tetrahydrofuran (4 mL) at −78° C. was added n-butyllithium (0.15 mL, 0.24 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 4-(5-chloropicolinoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (33 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added drop-wise to the reaction. After 30 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3 mL) was added hydrochloric acid (0.17 mL, 0.66 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (23-40% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 4-((5-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one as an off-white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>CN(C)C=O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.12 g of pivaloyl chloride was added at 0° C., the mixture was stirred at room temperature for 2 hours, and at 60° C. for 3 hours, and the reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 4-(2,2-dimethylpropionyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (8)).
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.P(=O)(O)(O)O.[NH2:20][C:21]([CH3:54])([CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:51](=[CH:52][CH:53]=1)[C:32]1=[N:33][O:34][C:35]([C:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:38][N:37]=3)=[C:31]1[CH2:30][CH2:29]2)[CH2:22]O.O>CO.ClCCl>[P:2]([OH:13])([OH:9])([O:3][CH2:54][C:21]([NH2:20])([CH3:22])[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:51](=[CH:52][CH:53]=1)[C:32]1=[N:33][O:34][C:35]([C:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[O:38][N:37]=3)=[C:31]1[CH2:30][CH2:29]2)=[O:1]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: CC(N)(CO)CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=P(O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(N)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)COP(=O)(O)O
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of phosphorus pentoxide (150 mg, 0.528 mmol) and 85% phosphoric acid (0.15 mL, 0.017 mmol) was stirred at 100° C. under nitrogen for 1 hr before 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol (Isomer 1 of Example 93, 8 mg, 0.017 mmol) was added. The clear solution was stirred at the same temperature for 3 hr before being cooled. Water (0.4 mL) was added while the mixture was cooled with ice. The mixture was stirred at room temperature for 30 min. The mixture was dissolved in methanol and a little dichloromethane. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butyl dihydrogen phosphate (5 mg, 8.6 μmol, 52% yield) as a white solid. The compound had an HPLC retention time=3.55 min. (condition C); LC/MS M+1=564.6. 1H NMR (400 MHz, MeOD) δ ppm 7.88 (1H, d, J=7.9 Hz), 7.76 (2H, d, J=7.3 Hz), 7.57-7.69 (3H, m), 7.31 (1H, s), 7.28 (1H, d, J=7.9 Hz), 3.82-3.99 (2H, m), 3.04-3.10 (4H, m), 2.67-2.83 (2H, m), 1.89-2.10 (2H, m), 1.40 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@H:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O:30]C)=[O:29].BrBr.P([O-])(O)(O)=O.[K+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C@@H:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([OH:30])=[O:29])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Agent: BrBr
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@H](Cc1ccccc1)Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1

Procedure:
Prepared from 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (Example 41) and (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 97). White solid: [a]D25=+17.94° (10.30 mg/mL CHCl3): NMR (CDCl3); δ8.31 (ddd, J=8, 1, 1 Hz, 1 H), 7.76 (ddd., J=8, 1, 1 Hz, 1 H), 7.60 (ddd, J=8, 8, 1 Hz, 1 H), 7.54 (d, J=8 Hz, 1 H), 7.44-7.29 (m, 6 H), 7.24-7.20 (m, 4 H), 7.19-7.04 (m, 3 H), 6.62 (d, J=8 Hz, 1 H), 5.08 (dd, J=7, 5 Hz, 1 H), 3.44 (d, J=5 Hz, 1 H), 3.43 (d, J=7 Hz, 1 H); MS (FAB+): [M+H], bromine isotope pattern, 553 (11%), 569 (12%); Anal. Calc. for C31H21BrO3S: C, 67.27, H, 3.82, N, 0.00. Found: C, 65.17, H, 3.64, N, 0.04. Analytical HPLC determined that this compound was 98.9% pure [column:novapak, 5 micron (4.6 ×250 mm); isocratic, 7:3 accetonitrile: 0.01 M potassium dihydrogen phosphate, pH =3.5; flow rate =1.0 mL/min].
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O.O.[F:26][C:27]([F:35])([F:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[O:29]>C(OCC)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([C:28]([OH:29])([C:30]([F:33])([F:32])[F:31])[C:27]([F:35])([F:34])[F:26])=[CH:10][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCCc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Temperature: 130 °C
Yield: 42.8 %

Procedure:
2-Propylaniline (111 mmol, 15 g), p-toluenesulfonic acid monohydrate (11.09 mmol, 2.110 g) and hexafluoroacetone trihydrate (111 mmol, 24.41 g) were combined and heated to 130° C. for 3 hours. The mixture was allowed to cool and diluted with ethyl acetate (250 mL). The solution was washed with sodium bicarbonate solution (3×100 mL), the organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was allowed to crystallise overnight. The crystals were collected by filtration, washed with heptane (100 mL) and dried under vacuum to afford the title compound (14.3 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]2[CH:16](O)[CH:17]([CH3:21])[CH2:18][CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[Li+].C1CCN2C(=NCCC2)CC1>C(#N)C.O>[C:4]([Si:1]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([CH3:21])[CH2:18][CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC1CCCc2cccc(CO[Si](C)(C)C(C)(C)C)c2C1O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: CC1=Cc2c(cccc2CO[Si](C)(C)C(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (14.43 g, 45.02 mmol), triethylamine (7.53 ml, 54.0 mmol) and 4-N,N-dimethylaminopyridine (0.55 g, 4.50 mmol) in acetonitrile (50 ml) was dropwise added a solution of methanesulfonyl chloride (5.67 g, 49.5 mmol) in acetonitrile (10 ml) under ice-cooling. Lithium chloride (2.86 g, 67.5 mmol) was added thereto and the mixture was stirred at room temperature for 6 hrs. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 ml). 1,8-Diazabicyclo[5.4.0]-7-undecene (13.5 ml, 90.0 mmol) was added and the mixture was stirred overnight at 80° C. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to give the objective substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:28]([O:30][C:31]([CH:33]=[P:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:29].CCO>C(OCC)(=O)C>[CH2:28]([O:30][C:31]([C:33](=[P:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:32])[CH3:29]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N12
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 22 h

Procedure:
A solution of t-butyl 3-bromomethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (5.0 g., ca. 10.56 mmole.) in ethyl acetate (90 ml.) was treated with a solution of ethoxycarbonylmethylenetriphenylphosphorane (9.18 g, 26.4 mmole) in ehtyl acetate (110 ml.) and the mixture stirred at 27° for 22 hours, in the dark. The mixture was cooled to ca 3° and stirred for 2 hours after which time precipitated material was collected by filtration and treated as described in Example 1c to give the ylid (3.85 g, 49%) as photosensitive white prisms (from ethyl acetate), m.p. (darkening at ca 155°) ca 178° (decomp.), [α]D27 + 61.5° (C 1.6, CHCl3), λmax. (EtOH) 266 nm. (ε 10,360) and 272 nm. (ε 10,000); the infrared and p.m.r. spectra resembled those of material described above in Example 1c.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])C)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[OH-:20].[Na+].BrBr>O1CCOCC1.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=[O:20])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CC(=O)c1cc(C)c(Br)cc1OCc1ccccc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)c(OCc2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-{4-bromo-5-methyl-2-[(phenylmethyl)oxy]phenyl}ethanone (may be prepared as described in Description 11; 607 mg, 1.90 mmol) in 1,4-dioxane (10 ml) was added sodium hydroxide (761 mg, 19.02 mmol) in water (10 ml). The solution was cooled to 0° C. and bromine (0.29 ml, 5.71 mmol) was added. The mixture was stirred for 10 minutes at 0° C. and then at room temperature for one hour. The dioxane was removed under reduced pressure and the residue acidified to pH=2 using 2N HCl. The mixture was extracted with ethyl acetate (3×20 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound. 611 mg.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4[CH2:22][CH2:23][S:24][C:25]5[CH:31]=[CH:30][C:29]([C:32]6[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=6)=[CH:28][C:26]=5[CH:27]=4)=[O:20])=[CH:14][CH:13]=3)[CH3:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:30]=[CH:31][C:25]3[S:24][CH2:23][CH2:22][C:21]([C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:9]([CH3:10])[CH:6]5[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]5)=[CH:13][CH:14]=4)=[O:20])=[CH:27][C:26]=3[CH:28]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCS3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC(=O)CC4)cc2)CCS3)cc1
Reaction time: 66 h
Yield: 65.3 %

Procedure:
To a solution of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (130 mg) in THF (15 ml) was added at room temperature 6N hydrochloric acid (1 ml), and the mixture was stirred for 66 hours. To the mixture was added sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting solid was recrystallized from ethyl acetate/hexane to give pale yellow crystals of 7-(4-methoxyphenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 284) (78.3 mg).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]([CH3:25])[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(#N)C.F[B-](F)(F)F.[Li+].[OH-].[NH4+]>O>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]([CH3:25])[CH2:22][C:23]#[N:24])[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[C@@H](CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: C[C@@H](CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Yield: 79 %

Procedure:
Into a 5 liter four neck round bottom flask equipped with overhead stirring, condenser, thermocouple and nitrogen inlet was charged (3S)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile ((S)-38, 82.3 g, 0.215 mol), acetonitrile (1510 mL), water (135 mL) and solid lithium tetrafluoroborate (LiBF4, 206 g, 2.15 mol, 10.0 equiv). The resulting reaction mixture was warmed to reflux and stirred at reflux for 24-36 h. When HPLC and TLC showed that the reaction was deemed complete, the reaction mixture was cooled to room temperature. An aqueous ammonium hydroxide (NH4OH) solution (20% v/v) was added to the reaction mixture to adjust pH to 9-10. The resulting reaction mixture was stirred at room temperature for 15-24 h. When HPLC and TLC showed the de-protection reaction was deemed complete, the reaction mixture was filtered through a Celite pad to remove the insoluble materials. The Celite pad was washed with ethyl acetate (500 mL). The filtrate was further diluted with ethyl acetate (1 L) before being washed with a 20% sodium chloride (NaCl) aqueous solution (1 L). The aqueous fraction was back extracted with ethyl acetate (2×500 mL). The combined organic fractions were then concentrated under reduced pressure to remove the solvents to generate a thick white slurry. The slurry was treated with water (2 L) and the resulting mixture was stirred at room temperature for 18 hours. The solids were collected by filtration, and the wet cake was washed with methyl tert-butyl lether (MTBE, 500 mL) and heptane (500 mL) before being dried at 50° C. in a vacuum oven to constant weight. The dried, crude product (45 g) was then re-crystallized in ethanol (500 mL) and heptane (350 mL) to afford (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile ((S)-39, 42.8 g, 54.2 g theoretical, 79% yield) as white solids. For (S)-39: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.1 (bs, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.59 (d, 1H, J=3.5 Hz), 6.98 (d, 1H, J=3.5 Hz), 4.98 (m, 1H), 3.19 (d, 2H, J=6.6 Hz), 1.57 (d, 3H, J=6.6 Hz); C13H12N6 (MW, 252.27), LCMS (EI) m/e 253 (M++H).
Reaction SMILES: [I-:1].[Na+].[C:3]1([C:9]2([CH2:14]CS([O-])(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(C(C)=O)C(C)C>[C:3]1([C:9]2([CH2:14][I:1])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])CCC1(c2ccccc2)CCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: ICC1(c2ccccc2)CCCC1
Yield: 44.8 %

Procedure:
5.00 g (33.3 mmol) of sodium iodide were added to a solution of 1.00 g (3.93 mmol) of (1-phenylcyclopentyl)methylmethanesulfonate [prepared as described in step (ii) above] in 10 ml of methyl isobutyl ketone, and the resulting mixture was heated under reflux for 18 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between diethyl ether and water. The organic phase was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 1:1 by volume mixture of methylene chloride and hexane as the eluent, to give 504 mg (yield 45%) of the title compound as an oil.
Reaction SMILES: CC(C)([O-])C.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]#[N:15].[CH2:16]([O:19][CH2:20][CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:17]=[CH2:18].C1OCCOCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:19][CH2:20][CH2:21][CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])[C:14]#[N:15])[CH:17]=[CH2:18]
Reactant: C=CCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N#CCc1ccccc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOCCC(C#N)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
Piotassium tert-butoxide (9.93 g) was added to a solution of 2-fluorophenylacetonitrile (10 g), toluene-4-sulfonic acid 2-allyloxyethyl ester (19 g) and 18-crown-6 (3.91 g) in tetrahydrofuran (400 mL) under ice-cooling. The reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was warmed to room temperature and further stirred for four hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.9 g).