Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[Cl-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Zn+])=[CH:22][N:21]=1>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[N:21]=[CH:22][C:23]([CH2:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(Br)c2ccccc2c1OC
Reactant: Clc1ccc(C[Zn+])cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2c1OC
Temperature: 90 °C

Procedure:
To a solution of methyl 4-bromo-1-methoxy-2-naphthoate (see Example 2, 0.500 g, 1.69 mmol) in 5 mL of THF under an atmosphere of nitrogen was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 10.2 mL, 5.08 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.050 g, 0.043 mmol). The reaction was heated at 90° C. for 2 hours, then cooled to room temperature and diluted with water and ethyl acetate. The mixture was filtered through celite and the organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 4-[(6-chloropyridin-3-yl)methyl]-1-methoxy-2-naphthoate that gave a mass ion (ES+) of 342.0 for [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[N+:11]([C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].N1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH3:21][C:20]1([CH2:19][O:18][C:17]2[CH:23]=[CH:24][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:9][C:8](=[O:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2ccccc2O1
Yield: 54.6 %

Procedure:
2 g of o-hydroxyacetophenone, 2.85 g of 4-nitrophenoxyacetone, 2 g of pyrrolidine and 280 mg of p-toluenesufonic acid monohydrate were dissolved in 10 ml of toluene, and the mixture was heated under reflux for 3 hours in apparatus equipped with a water separator. At the end of this time, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 3:1 by volume mixture of benzene and ethyl acetate, to afford 2.5 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]2[CH2:27][CH2:26][C@@H:25]3[C@@H:20]([CH2:21][CH2:22][C:23](=[O:28])[NH:24]3)[CH2:19]2)=[CH:13][CH:12]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[NH4+].[NH4+].[NH4+].[NH4+].S([O-])(O)(=O)=O.S([O-])(O)(=O)=O.S([O-])(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C@H:18]2[CH2:27][CH2:26][C@@H:25]3[C@@H:20]([CH2:21][CH2:22][C:23](=[O:28])[N:24]3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:19]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C[C@H]2CC[C@H]3NC(=O)CC[C@H]3C2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@H]2CC[C@@H]3[C@@H](CCC(=O)N3Cc3ccccc3)C2)cc1
Yield: 21.7 %

Procedure:
A solution of benzylbromide (0.44 ml, 0.0037 mol) in toluene (5 ml) was added dropwise to the refluxing mixture of (-)-(4aS,6S,8aR)-3,4,4a,5,6,7,8,8a-octahydro-6-((4-methoxyphenyl)methyl)quinolin-2(1H)-one (0.512 g, 0.0019 mol, prepared according to Example 32), powdered NaOH (0.175 g), potassium carbonate (0.35 g), tetraammonium hydrogen sulphate (0.02 g) and toluene (20 ml). The reaction was refluxed for 4 days. The reaction mixture was then cooled, diluted with toluene and then washed with water. It was then dried over sodium sulphate, filtered and the solvent evaporated. The solid was then chromatographed on a silica gel column in ethylacetate. The first fraction was collected, the solvent evaporated and the resulting solid recrystallised from acetonitrile to give the title compound (0.15 g), mp=118-9° C.; [α]D25 =-10° (1%, CHCl3).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24](O)=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:25])[N:22]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)N3CCN(C)CC3)cs2)c(C(=O)C2CCCC2)c1

Procedure:
4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazine (337 mg) is prepared from 2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-ylacetic acid (386 mg, 1.0 mmol) and N-methylpiperazine following the general procedure K.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 85 %

Procedure:
5.4 g (21.1 mmol) of 9-bromoanthracene, 2.6 g (21.1 mmol) of phenylboronic acid, 60 mg (0.21 mmol) of Pd(OAc)2 (0), 10 mL (20 mmol) of an K2CO3 aqueous solution of 2M, 263 mg (0.84 mmol) of P(o-tolyl)3, and 20 mL of 1,2-dimethoxyethane (abbreviation: DME) are mixed, and then stirred for 9 hours at 80° C. After reaction, a precipitated solid was collected by suction filtration. Subsequently, the solid was dissolved in toluene and then filtered through Florisil®, celite, and alumina. After a filtrate was washed with water and saturated saline, it was dried with magnesium sulfate. After natural filtration, when the filtrate is condensed, 21.5 g of 9-phenylanthracene which is a target substance was obtained as a light brown solid at a yield of 85% (Synthesis Scheme (f-1)).
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([NH:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[O:18])=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: Nc1nnn[nH]1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Yield: 73.9 %

Procedure:
0.64 g (0.0023 mol) of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 2) and 0.75 g (0.0046 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 70 ml of dimethylformamide are stirred at 70° C. for two and one-half hours. To 0.31 g (0.003 mol) of 5 -aminotetrazole monohydrate (Aldrich Chemical Company) in 40 ml of dimethylformamide cooled to 0°-5° C. is added 1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 2.5 ml (0.018 mol) of triethylamine. The mixture is stirred and allowed to reach room temperature. After two hours the mixture is combined with the previous imidazolide mixture and stirred for fourteen hours at room temperature. The resulting precipitate is collected, slurried in boiling glacial acetic acid, the mixture is cooled and filtered to give 0.58 g of 2-ethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3 -d]pyrimidine-7-carboxamide; mp 310°-312° C. (dec).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:25]4[C:21]([S:22][CH:23]=[CH:24]4)=[CH:20][N:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:25]4[C:21]([S:22][CH:23]=[CH:24]4)=[CH:20][N:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10]
Reactant: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 36 h
Yield: 59.7 %

Procedure:
To a solution of 0.35 g of allyl (1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazole-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 12 ml of THF was added under ice-cooling 0.66 ml of acetic acid and 2.9 ml of a 1 M solution of tetra-n-butyl-ammonium fluoride in THF, and the mixture was stirred at room temperature for 36 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous saline in this sequence, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate) to give 0.16 g of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine (18.4 mg, 0.042 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.063 mmol, 1.5 eq.) and triethylamine (0.02 mL, 0.126 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 20 mg (91%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(1-methanesulfonylpiperidin-4-yl)-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.58-1.76 (m, 2 H) 2.21 (d, J=10.64 Hz, 2 H) 2.76 (s, 3 H) 2.90 (t, J=10.93 Hz, 2 H) 3.77 (d, J=12.15 Hz, 2 H) 4.33 (br. s., 1 H) 5.84 (br. s., 1 H) 7.04-7.51 (m, 8 H) 8.36 (s, 1 H), [M−H]− 515.7.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[N:3][CH:2]=1.F[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.CS([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:1]1[CH:6]=[C:5]([O:7][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cncnc1
Agent: CS(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cncnc2)cc1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a solution of pyrimidin-5-ol (500 mg, 5.20 mmol) in DMF (5.20 mL) under argon was added 4-fluorobenzaldehyde (0.558 mL, 5.20 mmol), sodium methanesulfinate (133 mg, 1.30 mmol), and potassium carbonate (1.079 g, 7.81 mmol). The reaction mixture was heated at 120° C. for 3 hour. The mixture was allowed to cool to room temperature and was diluted with water (25 mL). The mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate], providing 4-(pyrimidin-5-yloxy)benzaldehyde (666 mg) as a yellow solid. LCMS m/z 201.0 (M+H)+, Rt 0.52 min.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8](C(OC)=O)[C:7](=[O:16])[C:6]=2[CH:5]=[N:4][CH:3]=1.Cl>>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:16])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)C1CCc2c(Br)cncc2C1=O
Agent: Cl
Product: O=C1CCCc2c(Br)cncc21
Yield: 69.4 %

Procedure:
The crude methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (7.79 g, 27.4 mmol) was dissolved (small amount of not dissolved material) in aq. 6M HCl (84.1 ml, 505 mmol) and heated at reflux for 2.5 h. The acidic solution was concentrated in vacuo, suspended in water (ca. 25 mL), cooled in ice and basified with 6.0 M KOH. The aqueous solution was extracted with ether (2×) and CH2Cl2 (3×), the combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (4.30 g, 69%) as a brown solid. MS: 226.0 (M+H+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].BrN1C(=[O:20])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1N2CN3CN(C2)CN1C3>C1C=CC=CC=1.C(O)(=O)C.O>[CH:13]([C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(OC)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2.50 g of methyl 3-methoxy-4-methylbenzoate was dissolved in 25 mL of benzene, to which 2.72 g of N-bromosuccinimide and 0.23 g of 2,2′-azobisisobutyronitrile were successively added at room temperature, and this solution was stirred for one hour while heating it under reflux. After 3.90 g of hexamethylenetetramine dissolved in 7.8 mL of acetic acid and 7.8 mL of water was added dropwise to the reaction mixture, benzene was distilled out therefrom, and then the mixture was stirred for one hour while heating it under reflux. The reaction mixture, which was cooled to room temperature, was added to a mixture of chloroform and water and then adjusted to pH 7 with a 20% aqueous solution of sodium hydroxide, and the organic phase was separated therefrom. After the resultant organic phase was successively washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 1.74 g of methyl 4-formyl-3-methoxybenzoate as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[C:17](OC)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:21])[C:18]([CH3:20])=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: C=C(C)C(=O)OC
Reactant: COc1ccc2[nH]c3cc(Br)ccc3c2c1
Solvent: C1CCOC1
Product: COc1cc2c(=O)c(C)cn3c4cc(Br)ccc4c(c1)c23
Yield: 95 %

Procedure:
2-bromo-6-methoxycarbazole (4 g) produced in Example 101, step 4 was dissolved in anhydrous tetrahydrofuran (32 ml), and to the solution were added methyl methacrylate (12.4 ml) and then Triton B (1.12 ml). The mixture was heated under reflux in an argon atmosphere for 1 hour, and the solvent was evaporated under reduced pressure. The resulting residue was suspended in methanol (40 ml), and sodium hydroxide (1 g) dissolved in water (13 ml) was added dropwise to the solution at room temperature, and the mixture was heated under reflux for 4 hours. The solvent was evaporated under reduced pressure, and water and ether were added for phase separation. The aqueous layer was rendered acidic by addition of 1N hydrochloric acid, and ethyl acetate was added for extraction. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and recovered by filtration to obtain the title compound (4.0 g, 95%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C@@H:6]1[CH2:8][C@@H:7]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:3][CH2:4][CH2:5][C@@H:6]2[CH2:8][C@@H:7]2[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)=[N:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (424 mg, 60% dispersion in mineral oil, 10.6 mmol) was added to a solution of benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (1.07 g, 3.53 mmol) in N,N-dimethylformamide (10 mL) under nitrogen at RT. The mixture was stirred for 30 min at RT and 2-bromo-5-(methylsulfonyl)pyridine (1.25 g, 5.30 mmol) was added. The mixture was stirred overnight, diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The organic layer was washed with brine (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g RediSep, eluted with a gradient of hexanes to ethyl acetate, 9:1, 200 mL; 4:1, 500 mL; 1:1, 1 L) to provide the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.71 (dd, J=0.5, 2.5 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 7.40-7.28 (m, 5H), 6.84 (dd, J=0.6, 8.7 Hz, 1H), 5.13 (s, 2H), 4.48 (t, J=7.2 Hz, 2H), 4.30-4.10 (m, 2H), 3.07 (s, 3H), 2.90-2.60 (m, 2H), 2.20-2.00 (m, 1H), 1.85-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.45-1.20 (m, 2H), 1.10-0.85 (m, 2H), 0.75-0.50 (m, 2H), −0.12 (q, J=5.1 Hz, 1H). MS (Multimode) m/z 459 [M+H]+.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]2([C:24]([OH:26])=O)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1CCCC1.B.[C:33](=O)([O:39]C(C)(C)C)[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:26][CH2:24][C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:19][CH2:20][N:21]([C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH2:22][CH2:23]1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: B
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Temperature: 0 °C
Yield: 62.8 %

Procedure:
4-Phenyl-4-piperidinecarboxylic acid p-methylbenzenesulfonate (19.0 g, 50.3 mmol) was suspended in dry tetrahydrofuran (100 mL) and cooled to 0° C. To this was added borane tetrahydrofuran complex (1 M in THF, 100 mL, 100 mmol) cautiously over 15 min and the reaction mixture allowed to warm to room temperature overnight. The reaction mixture was cooled to 0° C., treated with di-tert-butyl carbonate (15.0 g, 218 mmol) and 10 N sodium hydroxide (12 mL), stirred at 0° C., and at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate and concentrated. The crude product was triturated with 10% ethyl acetate/hexanes solution to afford 9.2 g (63%) of the title compound. 1H-NMR (CD3OD, 300 MHz) δ 7.35-7.43 (m, 4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m, 2H), 3.49 (s, 2H), 2.97 (m, 2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H), 1.46 (s, 9H). Mass spec.: 292.17 (MH)+.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:17][C:18]([NH:20][C@:21]1([C:34]([O:36][CH3:37])=[O:35])[CH2:25][CH2:24][C@@H:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=2)[CH2:22]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B([O-])[O-:39].[OH-].[Na+].OO>C1COCC1>[CH2:10]([O:17][C:18]([NH:20][C@:21]1([C:34]([O:36][CH3:37])=[O:35])[CH2:25][CH2:24][C@@H:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][OH:39])=[CH:30][CH:31]=2)[CH2:22]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=Cc1ccc([C@@H]2CC[C@](NC(=O)OCc3ccccc3)(C(=O)OC)C2)cc1
Reactant: [O-]B[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC[C@@H](c2ccc(CCO)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
9-BBN (25 ml, 12.50 mmol) was added dropwise to a stirred and cooled solution of (1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-vinylphenyl)cyclopentanecarboxylate (0.682 g, 1.797 mmol) in THF (15 mL). The reaction mixture was checked by TLC to ensure complete conversion to boronate. Once complete the ice bath was removed and stirring was continued overnight. The reaction mixture was cooled to 0° C. and methanol (20 ml) was added. Aqueous NaOH (7.30 ml, 14.59 mmol) and H2O2 (1.522 ml, 14.90 mmol) were poured into the reaction mixture. Stirring was continued for 2 hours. The solvent was removed under reduced pressure and the product purified by FCC to afford (1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-(2-hydroxyethyl)phenyl)cyclopentanecarboxylate (0.507 g, 1.276 mmol, 71.0% yield) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=2[N+:17]([O-:19])=[O:18])[CH:4]=[C:5]([CH3:7])[N:6]=1
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Reactant: Cc1c[nH]c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-n2cc(C)nc2Br)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2-bromo-4-methyl imidazole (3.7 g, 23.4 mmol) and 2-fluoro-6-methoxy-nitrobenzene were dissolved in DMF (80 mL). To this was then added potassium carbonate (6.3 g, 46.8 mmol). The reaction was heated to 90° C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 20:1 ethyl acetate/methylene chloride. A tan solid (2.6 g) was recovered. MS (ES) m/z 311.9 [M+1]+