Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:37]>O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:35][C@:36]([OH:37])([C:38]4[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=4)[O:16][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@](O)(c1ccc([N+](=O)[O-])cc1)CO3
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
(S)-6,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (3.3 g) and potassium carbonate (2 g) were stirred together in a flask containing 25 mL anhydrous acetone at room temperature under nitrogen atmosphere. After 15 minutes, 2-bromo-1-(4-nitro-phenyl)-ethanone (3.2 g) was added and the mixture was stirred at 60-80° C. for 6 hours. The reaction mixture was diluted with 50 mL of water and 100 mL of ethyl acetate and the layers were separated. The organic layer was washed with water three times and brine once, dried over sodium sulfate and concentrated to provide (S)-3-hydroxy-3-(4-nitro-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (3.1 g), and was dissolved in 25 mL of 1:1 ratio of anhydrous triethylamine and dichloromethane under nitrogen atmosphere. The reaction mixture was cooled to −76 to −40° C. and methanesulfonyl chloride (1.9 g) was added dropwise to maintain internal temperature below -30 to −40° C. The reaction mixture was allowed to warm to room temperature gradually (8-10 hours) and was quenched with 1M sodium carbonate solution (10 mL) and extracted with dichloromethane three times (3×25 mL). The organic layers were washed with water, brine and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography and eluted with 7:3 hexanes/EtOAc to give a regioisomeric mixture of (S)-3-(4-Nitro-phenyl)-8,9-dihydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (2.0 g). LCMS: (m/z) 469, 1H NMR (400 MHz, Acetone-d6): 8.12 (d, 1H), 7.61 (d, 1H), 7.15 (m, 1H), 6.78-6.69 (m, 1H), 5.01-511 (m, 1H), 4.94-4.87 (m, 1H), 4.91-4.81 (m, 1H), 4.64-4.49 (m, 1H), 4.43-4.29 (m, 1H), 3.65-3.58 (m, 3H), 3.18-2.99 (m, 2H), 1.53-1.40 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[CH3:14].C(N(CC)CC)C.S(Cl)([Cl:25])=O.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:25])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)CCc1ccc(CO)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCc1ccc(CCl)cc1C
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a 0° C. solution of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (1.02 g, 4.90 mmol) in anhydrous CH2Cl2 (15 mL) is added triethylamine (0.75 mL, 5.38 mmol) followed by thionyl chloride (0.40 mL, 5.48 mmol). The mixture is allowed to warm to RT overnight. Water is added, and the mixture is extracted with CH2Cl2. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield the title compound (1.01 g, 91%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([O:20]C)[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(OC)cnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Temperature: 25 °C
Yield: 113 %

Procedure:
850 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-5-methoxy-1H-pyrrolo[2,3- b]pyridine was dissolved in 50 ml dichloromethane. At −78° C. 1.90 ml of a 1 molar solution of borontribromide in dichloromethane was added. The reaction mixture was allowed to warm up to room temperature. Then the reaction mixture was heated under reflux for additional two hours. 150 ml ethyl acetate were added and the mixture washed with 50 ml of a one molar solution of hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by RP-HPLC to provide 930 mg 1-[4-Butyl-2-(4-trifluoromethylphenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol as a lyophilisate.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35](C=O)[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].S([CH2:52][N+:53]#[C-:54])(C1C=CC(C)=CC=1)(=O)=O.[C:55]([O-:58])([O-])=O.[K+].[K+]>CO.O>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:55]4[O:58][CH:54]=[N:53][CH:52]=4)[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:4])[CH3:5])[N:7]=[CH:8]1
Reactant: CC(C)C(O)(c1ccc2cc(C=O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(O)(c1ccc2cc(-c3cnco3)ccc2c1)c1c[nH]cn1
Yield: 111.9 %

Procedure:
A mixture of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoaldehyde (2.0 g), tosylmethylisocyanide (800 mg) and K2CO3 (1.0 g) in methanol was refluxed for 2 h. The reaction mixture was diluted with water. The precipitate formed was collected and crystallized from THF-hexane to give the titled compound (1.39 g) as colorless powder.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:16][CH3:17])([O:14][CH3:15])[CH:10]([OH:18])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH:10]([O:18][CH3:21])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(Cc2ccccc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b, 5.5g, 22 mmol) from Example 1 in 30ml of dimethylformamide was added slowly to a stirred suspension of sodium hydride (0.81g, 27 mmol, 80% oil suspension) in 100ml of dimethylformamide. The reaction mixture was warmed to 60° C. for 2 hours, then cooled to 0° C. whereupon methyl iodide (3.8g, 27 mmol) was slowly added to the mixture. The reaction mixture was stirred overnight at room temperature then quenched with 10ml of 10% sodium hydroxide solution. The reaction mixture was concentrated under vacuum, the residue slurried in 300ml of water and the aqueous mixture extracted with 3×100ml of ether. The combined organic layers were dried over magnesium sulfate, concentrated under vacuum, then purified by column chromatography (alumina; ethyl acetate/hexane; 2.5:1) to yield the intermediate 1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 3.77g, 64.6%, Rf 0.63).
Reaction SMILES: II.C(=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]=O)=[CH:13][N:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:40])([C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)([NH2:32])[CH3:31])[CH3:29])=[CH:24][CH:23]=1>C(O)(C)(C)C.C(OCC)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@@:28]2([CH3:29])[C@:30]([C:33]3[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=3)([CH3:31])[NH:32][C:19]([C:14]3[C:15]([O:17][CH3:18])=[N:16][C:11]([O:10][CH3:9])=[N:12][CH:13]=3)=[N:40]2)=[CH:24][CH:23]=1
Reactant: COc1ncc(C=O)c(OC)n1
Reactant: CC(N)(c1ccc(Cl)cc1)C(C)(N)c1ccc(Cl)cc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COc1ncc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2)c(OC)n1
Temperature: 65 °C

Procedure:
The title compound was prepared using the procedure described by Ishihara, M. and Togo, H. Synlett 2006, 2, 227-230 and ibid Tetrahedron 2007, 63,1474-1480. Iodine (172 mg, 0.68 mg) was dissolved in tert-butanol (20 mL) and potassium carbonate (300 mg, 2.2 mmol) was added. 2,4-Dimethoxy-5-formylpyrimidine (100 mg, 0.6 mmol, Frontier) and (rac)-2,3-Bis(4-chloro-phenyl)-butane-2,3-diamine (200 mg, 0.65 mmol) was added to the mixture. This was warmed to 65° C. for 2 h. This was cooled, diluted with ethyl ether (50 mL) and filtered through Celite. After evaporating to dryness, the residue was purified by flash column chromatography (silica gel, eluting with 2-5% methanol/methylene chloride) to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-dimethoxy-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]([CH3:14])[CH2:12][O:11][CH2:10][CH:9]2[CH3:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1>>[NH2:39][C:38]1[CH:40]=[CH:41][C:35]([C:2]2[N:7]=[C:6]([N:8]3[CH:13]([CH3:14])[CH2:12][O:11][CH2:10][CH:9]3[CH3:15])[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[N:3]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3C(C)COCC3C)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 86 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 86% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:64][C:58]1[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:57]=1[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 49.6 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (55 mg, 0.29 mmol) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (140 mg, 0.7 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (98.5 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by washing with ether to afford 63.5 mg (49.6% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 441.17. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 2H), 7.44 (t, 1H), 7.3 (m, 1H), 6.84 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.7 (bs, 2H), 3.5 (bs, 1H), 2.1 (t, 2H), 1.8 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]([O:18]C)=[O:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[Li+].[OH-].Cl>C1COCC1.CO.C(OCC)C>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COC(=O)c1ccc(-c2cccc3c2CNC3=O)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc(-c2cccc3c2CNC3=O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
A suspension of Example 127A (0.34 g, 1.24 mmol) in THF (30 mL) and methanol (30 mL) was treated with 1N LiOH (10 mL), stirred at room temperature for 5 hours, then acidified with 1N HCl and diluted with diethyl ether. The resulting suspension was filtered and the filter cake was washed with water and dried to give 288 mg of the desired product. MS (ESI(−)) m/e 258 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(O)c1C(=O)O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
Step 1 A solution of ethyl 2-hydroxy-6-methylbenzoate (2.04 g, 11.32 mmol) in methanol (25 mL) was treated at rt with 1 M aqueous sodium hydroxide (45.3 mL, 45.3 mmol) and the mixture was heated at reflux for 6 h. The mixture was cooled to rt and the methanol was removed under vacuum. The aqueous residue was treated with 1 M hydrochloric acid to pH ca. 1. The precipitate was collected by filtration, washed with water and dried under vacuum to give 2-hydroxy-6-methylbenzoic acid as a white solid (1.62 g, 94%). 1H NMR (400 MHz, methanol-d4) δ 7.26 (1H, t, J=7.92 Hz), 6.75 (2H, t, J=7.92 Hz), 2.55 (3H, s). Mass spectrum m/z 153.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([OH:15])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41](Cl)=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C(C1C=C(CCC(O)=O)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCl>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([O:15][CH:10]2[C:9]3[CH:8]=[C:7]([CH3:16])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=3[O:12][C:11]2=[O:14])=[O:42])[CH:29]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]=1[OH:34])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2OC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 5.5 g (25.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (102), Example 2), and 3.9 ml (28.0 mmol) of triethylamine in 30 ml of dichloromethane is added dropwise to a solution of 8.32 g (28.0 mmol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl chloride (prepared from 7.8 g (28.0 mmol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid and thionyl chloride) in 10 ml of dichloromethane. The reaction mixture is then refluxed for 1 hour, then cooled and washed with water and 5% aqueous sodium hydrogencarbonate solution. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Three crystallisations of the residue from acetonitrile yield 4.6 g (38%) of 3-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxy]-7-tert-butyl-5-methyl-3H-benzofuran-2-one, m.p. 151°-154° C. (compound (113), Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:35].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:28][CH2:29][S:30](=[O:35])[CH2:31][CH2:32]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCSCC2)cc1Cl
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCS(=O)CC2)cc1Cl
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.1 g, 0.2 mmol) in methanol (20 mL) at 0° C. was added a solution of potassium peroxymonosulfate (0.13 g, 0.2 mmol) in water (5 mL). After 5 minutes, the reaction was quenched by addition of aqueous 5% sodium bisulfite solution. The mixture was extracted with methylene chloride/methanol, and the organic phase dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.064 g (62% yield) of N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow powder; NMR (DMSO-d6/TFA) 11.2 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 2), 7.6 (m, 1), 7.4 (m, 3), 4.7 (s, 2), 3.7 (m, 2), 3.5 (m. 2), 2.9 (br s, 4) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:11][CH2:10][N:9](C)[CH2:8][C@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].ClC([O-])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:11][CH2:10][N:9]([C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[CH2:8][C@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 2.48 g of the free base cis-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine, of Example 36, 1.14 g of anhydrous potassium carbonate and 30 ml of dry benzene is treated with 1.42 ml of 2,2,2-trichloroethyl chloroformate. After 30 minutes at room temperature the mixture is refluxed 18 hours. Another 0.36 ml of chloroformate is added, and the mixture is refluxed another 4 hours. The mixture is then cooled and partitioned between 100 ml of ether and 50 ml of water. The aqueous phase is extracted with 50 ml of ether, and the combined organic extracts are washed with 2 N HCl solution, saturated aqueous NaCl solution, and dried over Na2SO4. Concentration in vacuo affords a mixture of a solid and an oil which is triturated with 25 ml of ether and then diluted with hexane to a volume of about 125 ml. After refrigeration for 18 hours the mixture is filtered, the solid is washed with hexane, and the filtrate is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution. After drying over Na2SO4 the solution is concentrated in vacuo to a gum. Chromatography of this material on silica gel affords a colorless gum of cis-4-(3-chlorophenoxy)-3-phenyl-1-(2,2,2-trichloroethoxycarbonyl) piperidine.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)[N:8]=1)#[N:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CC#N>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:5]2[C:4](=[O:20])[C:3]([C:1]#[N:2])=[N:8][N:7]([C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)[C:6]2=[O:19])=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1cccc(-n2nc(C#N)c(=O)[nH]c2=O)c1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(-n2nc(C#N)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
According to Scheme 7 Step 3: A suspension of 11(B) (500 mg, 1.8 mmol), 4-chlorobenzyl bromide (455 mg, 2.2 mmol) and potassium carbonate (510 mg, 3.7 mmol) in CH3CN (10 mL) was stirred 12 h under reflux. The mixture was cooled at room temperature and 100 mL of water were added. The aqueous layer was extracted thrice with DCM (100 mL). The organic layers were mixed, dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (AIT Flashmart prepacked column 50 g SiO2) using CH2Cl2/MeOH (98/2) as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 11(C) (460 mg, 63%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccccn2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccccn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.09 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4].Cl.[Cl:43]CCl>O1CCOCC1>[ClH:43].[CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCSc1ccccc1)CCCC3
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.50 g, 0.86 mmol), a 4 M solution of hydrochloric acid in dioxane (5 mL), and dichloromethane (5 mL). The reaction was judged to be complete after stirring at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford an off white solid. The material was recrystallized from acetonitrile to provide 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1-H-imidazo[4,5-c]quinolin-4-amine hydrochloride (0.17 g, 1.30 mmol) as fluffy white needles, m.p. 237–238° C. Analysis. Calculated for C22H28N4S.((H2O)1/4.(HCl)2: % C 57.70; % H, 6.71; % N, 12.23. Found % C 57.62; % H, 6.57; % N, 12.41.