Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 44.2 %

Procedure:
Using 1-(tert-butoxycarbonyl)-3-hydroxypiperidine (201 mg, 1.00 mmol) and 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (258 mg, 1.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 187 mg (44%) of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12]([OH:17])(=O)[C:13]([CH3:15])=[CH2:14]>>[CH3:14][CH:13]([CH2:15][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)[C:12]([NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)=[O:17]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: C=C(C)C(=O)O
Product: CC(CNC1CC(C)(C)NC(C)(C)C1)C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 145 °C
Yield: 55.4 %

Procedure:
Into a 3 liter flask, 1560 g of 4-amino-2,2,6,6-tetramethylpiperidine was placed. After the temperature was raised to 145° C., 430 g of methacrylic acid was added dropwise thereto. The inner temperature rose gradually and then the reaction mixture was kept at 170°±5° C., while collecting water distilled off, until the water collected had amounted to 90 g. Then the reaction mixture was cooled down to 50° C., and 500 g of acetone was added to the mixture to obtain a light yellowish slurry. The slurry thus obtained was cooled down to 20° C. and filtered. The filter cake was washed with acetone and dried to obtain 1053 g of pure white 2-methyl-3-(2,2,6,6-tetramethyl-4-piperidylamino)-N-(2,2,6,6-tetramethyl-4-piperidyl)propionamide (hereinafter referred to as Compound 1). M.p.: 115.5°-116.5° C. Mass spectrometry (FD-MS): m/z 380 (M+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[O:33][C:32](=[O:34])[N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:30]=2)=[CH:19][CH:18]=1>CN(C)C=O.O.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:33][C:32](=[O:34])[NH:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: O=c1oc(-c2ccccc2-c2ccc(CBr)cc2)nn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
To an ice-cooling solution of 2-butyl-4-chloroimidazole-5-carbaldehyde (0.19 g) in N,N-dimethylformamide (1 ml) was added sodium hydride (60% in oil; 44 mg), and the mixture was stirred for 10 minutes. To the mixture was then added 5-(4'-bromomethylbiphenyl-2-yl)-2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2-one (0.57 g). The reaction mixture was stirred for 1.5 hour at room temperatures, which was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel. The crude product thus obtained was dissolved in trifluoroacetic acid (4 ml), and the solution was stirred for 30 minutes at 60° C. Trifluoroacetic acid was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with an aqueous solution of sodium hydrogencarbonate and dried. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel. Crude crystals thus obtained was recrystallized from ethylacetate-hexane to afford the title compound as colorless prisms (0.12 g, 27%), m.p.178°-179° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH2:8][CH2:9][OH:10])([CH3:7])[CH2:4][O:3]1.CCN(CC)CC.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:10][CH2:9][CH2:8][C@@:5]2([CH3:7])[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: CC1(C)OC[C@](C)(CCO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@@]2(C)COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 4 and Et3N in DCM was added TsCl dropwise. The resulting mixture was stirred at 0° C. for 30 min. The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compound 5.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[I:18].[O:19]1[CH2:24][C:23](=O)[CH2:22][C:21](=[O:26])[CH2:20]1>C(O)C>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:22]3[C:21](=[O:26])[CH2:20][O:19][CH2:24][C:23]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)=[CH:12][C:11]=1[I:18]
Reactant: Cn1oc(=O)cc1N
Reactant: O=C1COCC(=O)C1
Reactant: O=Cc1ccc(F)c(I)c1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(I)c1
Temperature: 25 °C
Yield: 9 %

Procedure:
The product from Example 45A (0.086 g, 0.75 mmol), the product from Example 12C (0.19 g, 0.75 mmol) and 2H-pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and was evaporated under reduced pressure. The residue was chromatographed eluting with 5% methanol/methylene chloride to provide the title compound (0.03 g). 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3H), 4.06 (s, 2H), 4.58 (q, 2H), 4.72 (s, 1H), 7.18 (t, 1H), 7.25 (m, 1H), 7.63 (dd, 1H), 10.9 (s, 1H); MS (ESI) m/z 441 (M−H)−; Anal. Calcd for C16H12N2FIO4: C, 43.46;H, 2.74; N, 6.34. Found: C, 42.96;H, 2.93; N, 5.98.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A mixture of 5-Nitro-isoindole-1,3-dione (177 g, 0.904 mol), 4-fluoro-phenol (128 g, 1.13 mol), K2CO3 (419 g, 3 mol) and DMF (2 l) was refluxed with stirring for 3 h before the mixture was poured into water (12 l) with stirring. The precipitate formed was isolated by vacuum filtration, washed with water (8 l) and dried in vacuo at 70° C. to give the title compound as a tan powder (43.2 g); 1H NMR (CDCl3) δ=7.79 (d, 1 H), 7.57 (br s, 1 H), 7.01 to 7.29 (m, 6 H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][CH2:40]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:44][C:43]2[C@@:10]3([CH2:40][O:41][C:42]=2[CH:47]=1)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 7.1 %

Procedure:
To a solution of 29 (60 mg, 0.77 mmol) in a mixture of MeOH (2.4 mL) and THF (0.8 mL) were added Pd(OH)2/C (25 mg) and 1,2-dichlorobenzene (60 μL). A balloon of hydrogen gas was attached for 0.5 hours with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory TLC (5% MeOH in DCM) to give 30 (23 mg, 71.2%). 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 1H), 7.07 (s, 4H), 6.82 (s, 1H), 4.68 (d, J=10.2 Hz, 1H), 4.59 (d, J=9.9 Hz, 1H), 3.99 (m, 2H), 3.59-3.80 (m, 3H), 3.28-3.37 (m, 3H), 2.58 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][N:10]([CH3:19])[CH2:9][C@H:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1OC1CNCC1O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1O[C@@H]1CN(C)C[C@H]1O
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Dissolve 4-(4-bromo-2-methoxy-phenoxy)-pyrrolidin-3-ol (409 mg, 1.42 mmol) in dichloroethane (15 mL) and add formaldehyde (0.117 mL, 1.56 mmol, 37% aqueous solution), sodium triacetoxyborohydride (451 mg, 2.13 mmol), and acetic acid (0.325 mL, 5.68 mmol). Stir the mixture overnight. Dilute with saturated sodium bicarbonate and extract three times with dichloromethane. Combine all the organics and dry over sodium sulfate, filter, and evaporate the filtrate. Purify by silica gel chromatography, eluting with 0-6% MeOH in dichloromethane with 2 N ammonia to give 410 mg (95%) of the title compound as a clear oil. LC-MS/ES m/z (81Br) 304.0 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][C:20]([NH2:25])=[C:21]([NH2:24])[CH:22]=2)[NH:17][C:16](=[O:26])[CH2:15]1>>[CH3:13][C:14]1([CH3:27])[C:23]2[CH:22]=[C:21]3[NH:24][C:6]([C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[N:25][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:26])[CH2:15]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Product: COc1cc(Cl)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3
Yield: 58 %

Procedure:
In a manner analogous to that described in EXAMPLE 2, from 4-chloro-2-methoxybenzoyl chloride and 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)), after column chromatography, there was obtained a yield of 58% of theory of the title compound; m.p. 300°-303° C.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[Br:34][C:35]1[S:39][C:38]([CH:40]=O)=[CH:37][CH:36]=1.O>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:40]\[C:38]2[S:39][C:35]([Br:34])=[CH:36][CH:37]=2)=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(/C=C\c2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a 0° C. suspension of 4-fluorobenzyl triphenylphosphonium chloride (1.82 g, 4.47 mmol) in THF (20 mL) was added a solution of n-BuLi (2.5M in hexane, 1.8 mL, 4.47 mmol) and the reaction mixture was stirred for 1 h. 5-Bromothiophene-2-carbaldehyde was added, the reaction was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was treated with water and extracted with Et2O. The crude product was purified by preparative TLC (30% EtOAc/hex) to give 5-[(1Z)-2-(4-fluorophenyl)vinyl]-2-bromothiophene (170 mg, 13%) as a colorless oil: 1H NMR (CDCl3) δ 6.51 (d, J=11.9 Hz, 1H), 6.59 (d, J=11.9 Hz, 1H), 6.72 (d, J=4.3 Hz, 1H), 6.85 (d, J=3.8 Hz, 1H), 7.04-7.11 (m, 2H), 7.27-7.33 (m, 2H) and 5-[(1E)-2-(4-fluorophenyl)vinyl]-2-bromothiophene (200 mg, 16%) as a white solid: 1H NMR (CDCl3) δ 6.74-6.80 (m, 2H), 6.95-7.07 (m, 4H), 7.39-7.44 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][NH:8][C:9](=[O:11])[CH:10]=[C:5]2[S:4][CH:3]=1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[CH:7][N:8]([CH3:14])[C:9](=[O:11])[CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: O=c1cc2scc(Br)c2c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2c(Br)csc2cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 3-bromothieno[3,2-c]pyridin-6(5H)-one (235 mg, 1.02 mmol) in DMF (3.9 mL) was added sodium hydride (25.7 mg, 1.07 mmol). The mixture stirred 1 h at room temperature, and then methyl iodide (69.9 μL, 1.12 mmol) was added. The reaction stirred a further 1 h at room temperature and then was poured into water (100 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic fractions were washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated. Trituration with diethyl ether (˜5 mL) and filtration to collect the resultant solid afforded 120 mg (48%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1 H), 6.91 (s, 1 H), 6.89 (d, J=0.8 Hz, 1 H), 3.75 (s, 3 H); MS (ESI): 244.03, 245.98 [M+H]+; HPLC tR=2.76 min (ZQ3, polar—4 min).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:20]2[CH:19]([C:21](Cl)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:21]([CH:19]1[C:20]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[S:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22]
Reactant: Nc1ncco1
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1ncco1)C1c2ccccc2Sc2ccccc21
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a stirred solution of (0.048 g, 0.575 mmol) 2-amino-oxazole [Cockerill & al., Synthesis 591(1976)], and DMAP (0.003 g, 0.03 mmol) in pyridine (2 ml) was added at 0° C. (0.100 g, 0.384 mmol) 9H-thioxanthene-9-carbonyl chloride. Stirring was continued at RT for 16 h, the reaction mixture was evaporated and water (5 ml)/sat. NaHCO3 solution (2 ml) was added. The solid was filtered off, dissolved in dichloromethane, dried (MgSO4), and concentrated in vaccuo. The crude material was purified by column chromatobraphy on silica gel (methylene chloride/ methanol 40:1) to give the product (0.022 g, 18%) as a white solid, m.p. 188-191° C. and MS: m/e=309.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].O>CC(C)=O>[CH:17]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH2:10])=[CH:18][CH3:19]
Reactant: C=CCc1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1ccccc1OC=CC
Yield: 98.7 %

Procedure:
200 g of 3-(2-hydroxyphenyl)propene, 226 g of potassium carbonate and 180 g of allyl bromide were stirred in 490 ml of acetone at reflux temperature for 23 hours and then cooled. One liter of water was added and the resultant layers were separated. The aqueous layer extracted with two volumes of diethyl ether, dried and stripped of solvent to give 256 g of 3-(2-propenyloxyphenyl)propene which was subsequently rearranged as described in Example 56 to the 2,6-di-propenylphenol intermediate. 52.2 g of said intermediate was dissolved in 500 ml of THF and chilled to -5° C. 300 ml of one molar borane was added over 15 minutes (maximum temperature not exceeding 18° C.), after which the mixture was stirred for 36 hours and chilled to 0° C. 80 ml of water was added over a 5 minute period, after which 120 ml of 5N sodium hydroxide was added all at once. When the temperature of the reaction mixture reached 1° C., 81 ml of 30% hydrogen peroxide was added over a 25 minute period and the mixture stirred for one hour and then concentrated. An additional 500 ml of water and 250 ml of ethyl acetate were added which, following workup, gave about 54 g of the desired 2,6-di(3-hydroxypropyl)phenol intermediate, m.p. 176°-187° C.
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1O[C:21]2([CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)OC1>C(O)C>[C:2]([N:10]1[C:21]2[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][C:22]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C(c1ccccc1)n1c2c(c3ccccc31)CC(CO)CC2

Procedure:
1-Benzoyl-1-phenylhydrazine hydrochloride (23.8 g.) and 18 g. of 4-hydroxymethylcyclohexanone ethylene ketal in 450 ml. of absolute ethyl alcohol was heated under reflux for four hours. The chilled mixture was filtered, the filtrate was evaporated to dryness under reduced pressure and the resulting residue was dissolved in ether. The ether solution was washed with water, dilute hydrochloric acid, water, dilute sodium bicarbonate, and water, dried and evaporated to dryness to give, after recrystallization from ethyl acetate-hexane, 9.6 g. of 9-benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole; m.p. 105°-107° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].I[C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=1>C1(C)C=CC=CC=1.CCO>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[C:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[CH:15][C:16]=1[C:25]([F:26])([F:27])[F:28]
Reactant: FC(F)(F)c1cc(I)ccc1C1OCCO1
Reactant: NC(=O)c1cccc(B(O)O)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-(aminocarbonyl)phenyl boronic acid and 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (I-IX-7) according to the procedure described for IX-10, using PhMe/EtOH (4:1) as organic cosolvents. Colorless solid. LC/MS (method A) 2.38 min; m/z 338 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: Clc1ccc(OC2CCNCC2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 2-chloro-5-(piperidin-4-yloxy)-pyridine (4.55 g, 21.39 mmol) and Et3N (5.92 mL, 42.8 mmol) in DCM (50 mL) was treated with methanesulfonyl chloride (2.48 mL, 32.09 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-70% EtOAc in cyclohexane) gave 2-chloro-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (3.19 g, 51%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=2.9 Hz, 1H), 7.28-7.16 (m, 2H), 4.58-4.49 (m, 1H), 3.44-3.28 (m, 4H), 2.83 (s, 3H), 2.13-1.92 (m, 4H). LCMS (m/z, Method A) ES+ 290.9 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.C[O:30][C:31](=[O:36])[CH:32]([CH3:35])[CH:33]=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O.C1COCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:33][CH:32]([CH3:35])[C:31]([OH:36])=[O:30])[CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: COC(=O)C(C)C=O
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(CN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21)C(=O)O
Temperature: 150 °C
Yield: 7.3 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (25.1 mg, 0.06 mmol, 1.0 equiv; Example 147) in a 1:1 mixture of THF and water (1 mL) was added 2-methyl-3-oxo-propionic acid methyl ester (27.9 mg, 0.24 mmol, 4.0 equiv; [CAS RN 51673-64-4]), dibutyltin dichloride (1.8 mg, 0.006 mmol, 0.1 equiv; [CAS RN 683-18-1]) and phenylsilane (13.0 mg, 15 μL, 0.12 mmol, 2.0 equiv; [CAS RN 694-53-1]). The reaction mixture was heated by microwave irradiation to 150° C. for 1.5 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 2.2 mg (7%) of the title compound as a light yellow solid. MS (ISP): 504.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71](O)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]>CN(C=O)C.ClCCl>[C:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71]([NH:14][CH2:13][CH2:12][C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=4)[NH:8][CH:7]=3)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]
Reactant: CC(=O)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 1-(4-acetylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.213 g; 0.865 mmol) in DMF (3 mL). Dichloromethane was added to the crude mixture to precipitate 1-(4-acetylphenyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxopyrrolidine-3-carboxamide 0.105 g (29%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1.[F:18][B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.F[B-](F)(F)F>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[F:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(C)=O
Product: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A mixture of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (244 mg, 1 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate (425 mg, 1.2 mmol) in Acetone (2 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated and purified using prep-TLC (petroleum ether:EtOAc=2:1) to provide desired product of 6-chloro-2-(3-fluoro-1H-indol-2-yl)pyridin-3-ol (120 mg, yield: 46.2%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.55 (d, J=8.0 Hz, 1H), 7.39˜7.44 (m, 1H), 7.25˜7.34 (m, 1H), 6.97˜7.20 (m, 3H). MS (M+H)+: 263/265.