Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:38])[CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[CH2:21]2)[CH:15]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>[Pd].CO>[CH:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][CH:20]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[O:13][C:10]([CH3:11])([CH3:12])[C:9]([OH:39])=[O:8])[CH2:21]2)=[O:38])=[CH:34][CH:33]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1ccc(C=CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(CCC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
10% Palladium on carbon (10 mg, 10 wt %) was added to a solution of 2-(3-{1-[3-(4-Isopropyl-phenyl)-acryloyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester (89 mg, 0.17 mmol) in methanol (2 mL) and the resulting mixture hydrogenated at atmospheric pressure for 3 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 73 mg (99%) of 2-(3-{1-[3-(4-Isopropyl-phenyl)-propionyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid as a clear oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:30](=[O:32])[CH3:31])[N:23]=3)[C:18](Br)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].CCN(CC)CC.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:30](=[O:32])[CH3:31])[N:23]=3)[C:18]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(C#C[Si](C)(C)C)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Step 5 A mixture of N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)thiophene-2-carboxamide (294.0 mg, 0.5 mmol, 1.0 eq), Pd(PPh3)2Cl2 (40.8 mg, 0.5 mmol, 0.1 eq) and CuI (9.5 mg, 0.05 mmol, 0.1 eq) was flushed with nitrogen. Anhydrous THF (10 mL) and Et3N (154.5 mg, 1.5 mmol, 3.0 eq) were added and the reaction mixture was flushed with nitrogen. Ethynyltrimethylsilane (149.9 mg, 1.5 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was concentrated to 5 mL. The conc. liquid was extracted with EtOAc and washed with water, brine. The organic layers were concentrated to afford the residue, which was purified by silica gel chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to afford N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-((trimethylsilyl)ethynyl) pyrimidin-2-yl)thiophene-2-carboxamide (96.1 mg, 35.2%) as pale yellow solid. LC-MS (m/z)=549.9 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Cl:33])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Cl
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1Cl)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[ 2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.3 ml (11.5 mmol) of 2-chlorophenol and 20 ml of dry dimethylformamide is stirred at room temperature for 5 days, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel, the elution being carried out successively with ethyl acetate/n-hexane (1:1), ethyl acetate/n-hexane (3:2) and ethyl acetate/n-hexane (7:3). After recrystallization from ethyl acetate, there is obtained o-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 214°-215°.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[CH:20][C:19]=2[NH2:26])[C:14](F)=[N:15][CH:16]=1>C1COCC1.O>[CH3:25][O:24][C:22]1[N:21]=[CH:20][C:19]2[NH:26][C:14]3[N:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=3[C:18]=2[CH:23]=1
Reactant: COc1cc(-c2cc(Br)cnc2F)c(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A 1N solution of bis(trimethylsilyl)amide in THF (6.81 mL, 6.81 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-6′-methoxy-[3,4′]bipyridinyl-3′-ylamine (203 mg, 0.681 mmol) in THF (12.0 mL). The reaction mixture was stirred for 30 minutes at ambient temperature, diluted with water, and extracted into ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and methanol, absorbed onto silica gel, and purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in hexanes) to provide the title compound as an orange-tan solid (89.0 mg, 47%). 1H NMR (DMSO-D6, 400 MHz): 12.44-12.12 (m, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.66 (d, J=3.5 Hz, 2H), 6.56 (s, 1H), 3.75 (s, 3H). LCMS (Method B): RT=1.83 min, M+H+=278/280.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-:15].[Na+].CS(C)=O>C(OCC)(=O)C>[F:13][C:4]1[C:3]([CH:2]=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C=O)c1F
Temperature: 115 °C
Yield: 68.2 %

Procedure:
Dimethylsulfoxide was degassed with argon for 1 h. Methyl 3-(bromomethyl)-2-fluorobenzoate (3.6 g, 14.5 mmol) from Step B above and solid sodium bicarbonate (10.5 g, 124.6 mmol) were added to the DMSO and the mixture was heated at 115° C. for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 2% ethyl acetate in hexanes) to give methyl 2-fluoro-3-formylbenzoate (1.8 g, 67%): 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 8.22-8.19 (m, 1H), 8.09-8.06 (m, 1H), 7.37-7.34 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([NH2:18])=O)=[CH:14][N:15]=2)[CH2:7]1.C(N(CC)CC)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]#[N:18])=[CH:14][N:15]=2)[CH2:7]1
Reactant: NC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Reaction time: 0.08 h

Procedure:
A suspension of 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboxamide (670 mg, 1.9 mmol) and triethylamine (0.92 mL, 6.6 mmol) in CH2Cl2 (25 mL) was cooled with an ice-acetone bath. Triflic anhydride (412 μL, 2.4 mmol) was added dropwise over 10 min. The mixture was stirred for 5 min and then the cooling bath was removed. After further stirring at rt for 15 min, the mixture was quenched with water and extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed twice with diluted brine, dried (Na2SO4) and concentrated. Combi-Flash chromatography (40 g, 40-80% EtOAc in hexanes in 20 min, 35 mL/min, 18 mL/fraction) gave a gum that was triturated with hexanes-Et2O (1:1) to give the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 7.88 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.18 (t, 1 H), 5.53 (s, 1 H), 3.99 (m, 1 H), 3.85-3.67 (m, 3 H), 2.63-2.45 (m, 2 H). MS (+ESI) m/z 340 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[N:21]=[C:20](N2CCCCC2)[C:19]([N+:28]([O-])=O)=[CH:18][N:17]=1>>[NH2:28][C:19]1[C:18]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[N:17][CH:16]=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ncncc2N)C1

Procedure:
Method 1 was followed using (S)-tert-butyl piperidin-3-ylcarbamate and 2-chloro-5-nitro-4-(piperidin-1-yl)pyrimidine. LCMS (m/z): 294.2 (MH+), Rt=0.56 min.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>O>[Br-:1].[C:24]([O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N+:14]([CH3:15])([CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:26])[CH3:25]
Reactant: CCCCCCCCCCCC[N+](C)(C)C1CCCCC1O
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC[N+](C)(C)C1CCCCC1OC(C)=O
Reaction time: 16 h

Procedure:
A mixture of 1.0 g of dodecyl(2-hydroxycyclohexyl)-dimethylammonium bromide prepared in Example 3, 5 ml of acetic anhydride and 5 ml of dry pyridine was allowed to stand at room temperature for about 16 hours. Twenty-five milliliters of water was added and the mixture allowed to stand for one hour. The solution was concentrated under reduced pressure at 50° using a rotary film evaporator. Two 20 ml portions of water were added successively to aid removal of pyridine, followed by absolute ethanol for final drying. The residue was 1.11 g of (2-acetoxycyclohexyl)(dimethyl)dodecylammonium bromide. The ir spectrum was consistent with the assigned structure and clearly showed esterification of the hydroxy group to have occurred.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])CO)[CH3:19]>C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCC(CC)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Temperature: 140 °C
Reaction time: 10 h
Yield: 94.6 %

Procedure:
A mixture of 45 g of methyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate, 24.7 g of 2-ethylhexylalcohol, 0.5 g of dibutyltin oxide and 50 ml of toluene was heated to 140° C., whereto toluene was further added while the solvent was being distilled off. After the mixture was stirred for 10 hours, toluene was distilled off. The obtained residue was purified by silica gel column chromatography to give 60 g of 2-ethylhexyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate as a pale yellow oily substance.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH:20]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:32]>CO>[ClH:32].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1ccc2c(OC3CCNC3)cccc21

Procedure:
A solution of thus-obtained t-butyl 3-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}-1-pyrrolidinecarboxylate (0.41 g, 0.93 mmol) in methanol and HCl (5.0 ml, 1M in ether) is heated at 60° C. under nitrogen for 2 h and concentrated in vacuo. The residue is treated with ethyl acetate and filtered. The filtercake is dried under vacuum to give the title product as an off white solid, 0.301 g, mp 200-201° C., identified by NMR and mass spectral analyses.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH3:12][S:13]([NH:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Br:40])=[CH:24][C:25]2[CH:30]=[N:29][C:28](SC)=[N:27][C:26]=2[N:33]=1)=[O:21])(=[O:15])=[O:14].[OH:41][CH2:42][CH2:43][S:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>ClCCl>[CH3:12][S:13]([NH:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Br:40])=[CH:24][C:25]2[CH:30]=[N:29][C:28]([NH:48][C:47]3[CH:49]=[CH:50][CH:51]=[C:45]([S:44][CH2:43][CH2:42][OH:41])[CH:46]=3)=[N:27][C:26]=2[N:33]=1)=[O:21])(=[O:14])=[O:15]
Reactant: CSc1ncc2cc(-c3ccccc3Br)c(C(=O)NCCNS(C)(=O)=O)nc2n1
Reactant: Nc1cccc(SCCO)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)NCCNC(=O)c1nc2nc(Nc3cccc(SCCO)c3)ncc2cc1-c1ccccc1Br
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
2.6 g m-chloroperbenzoic acid (MCPBA, purchased from Aldrich, 57–86%) were dissolved in 20 ml dichloromethane and dried by filtration over sodium sulfate. 2 ml of this solution were added at 0–5° C. to a solution of 480 mg (0,97 mmol) of the product from example g in 3 ml dichloromethane. The mixture was allowed to reach RT and monitored by TLC. After 20 min another 0.1 ml of the above MCPBA solution were added at RT and stirring was continued for 10 min. Excess peracid was quenched by addition of 30 μl dimethylsulfide and stirring for another 20 min. The resulting mixture was used immediately without further purification for the next step: 0.625 ml of the above solution (containing 0.12 mmol) were added at RT to a solution of 22 mg meta-(2-hydroxyethylthio)aniline (0.13 mmol) in 0.5 ml dichloromethane. After 15 hrs the mixture was diluted with 10 ml dichloromethane and washed with aqueous acetic acid and with saturated potassium bicarbonate solution. Purification by chromatography on silica yielded 52 mg of the title product.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:20]3[CH:34]=[CH:33][C:23]([C:24]([O:26]CC[Si](C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:33][CH:34]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)O)cc3)ccc21
Reaction time: 8 h

Procedure:
To a solution of 2-trimethylsilylethyl 4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate (Compound E10, 100.0 mg, 0.198 mmol) in 2.0 mL THF at room temperature was added 155.3 mg of tetrabutylammonium fluoride (0.594 mmol 0.6 mL of a 1M solution in THF). After stirring overnight the reaction was diluted with EtOAc and washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The solvents were removed under reduced pressure and the residue washed with hot acetonitrile leaving the product as a colorless solid.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[H-].[Na+].[F:11][C:12]([F:16])([F:15])[CH2:13]I>CN(C)C=O>[F:11][C:12]([F:16])([F:15])[CH2:13][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)CI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccnc(SCC(F)(F)F)[nH]1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 113.5 %

Procedure:
To solution of 2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (14 g, 0.109 mol) in dimethylformamide (300 mL) was added NaH (13.1 g, 0.327 mol). When the addition was complete, the solution was stirred at 40° C. for 1.5 hours, and 2,2,2-trifluoroethyliodide (27.4 g, 0.131 mol) was added to the solution. The reaction was stirred at 40° C. for 3 hours. The solvent was removed and the residue was poured into water, the mixture was adjusted to pH 3-4 with dilute HCl and extracted with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 2-(2,2,2-trifluoroethylsulfanyl)-3H-pyrimidin-4-one (26 g, crude) as solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][S:39]([C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ncccn4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ncccn4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.23 g) was dissolved in methylene chloride (7.5 ml), m-chloroperbenzoic acid (68 mg) was added to the mixture at 0° C., and the mixture was stirred for 15 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 189) (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[NH:12]C(=O)O[C:8](=[O:9])[C:7]=12.[NH3:15]>CN(C=O)C.O>[NH2:12][C:6]1[C:5]([CH3:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([NH2:15])=[O:9]
Reactant: N
Reactant: Cc1ccc(Cl)c2c(=O)oc(=O)[nH]c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C(N)=O)c1N

Procedure:
Using the procedure of Example A3, the reaction of 98.8 g (0.467 mol) of 6-chloro-3-methylisatoic anhydride in 330 ml of DMF with 42 ml (0.560 mol) of 25% strength aqueous ammonia solution in 140 ml of water and a further 110 ml of water gave 24 g (37% of theory) of the title compound as a yellowish powder of m.p. 149-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzoic acid (976 mg, 4.46 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (1.950 mL, 22.28 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-4-fluorobenzoyl chloride as a white solid (1.00 g, 94%). A portion of this material (200 mg, 0.842 mmol) was added to an ice-cold solution of 4-fluoroaniline (0.081 mL, 0.842 mmol) in pyridine (4 mL), and the solution was stirred at rt for 65 h The solution was concentrated and the residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, washed with water and dried to provide 3-bromo-4-fluoro-N-(4-fluorophenyl)benzamide as an off-white solid (227.5 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H) 8.29 (dd, J=6.7, 2.1 Hz, 1H) 8.01 (ddd, J=8.6, 4.8, 2.2 Hz, 1H) 7.75 (dd, J=9.0, 5.1 Hz, 2H) 7.55 (t, J=8.6 Hz, 1H) 7.20 (t, J=8.9 Hz, 2H). Mass spectrum m/z 312, 314 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C@@H:9]1[C@@H:15]([OH:39])[C@@H:16]([N:24](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C@@H:9]1[C@@H:15]([OH:39])[C@@H:16]([NH2:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)CCC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2ccccc2)CCC1(C)C
Yield: 86.9 %

Procedure:
Dissolve 2-(R)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-5,5-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (182 mg, 0.34 mmol) in methanol (4 mL) and add 10% palladium hydroxide on carbon (43 mg). Stir under 1 atmosphere of hydrogen gas overnight and filter through a filtering agent, wash with methanol and concentrate to give the title compound as a colorless oil (103 mg, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](OC(C)(C)C)=[O:27])[CH2:21]3)=[O:19])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:35](O)(C(F)(F)F)=O>O1CCOCC1.CO>[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([C:18]([NH:17][C@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:33])(=[O:9])=[O:10])[CH2:12]2)=[O:19])[CH2:21]1)(=[O:27])[CH3:35]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCC[C@H](C(=O)N[C@H]2CCCN(S(=O)(=O)c3cccc(Cl)c3C)C2)C1

Procedure:
tert-Butyl (3S)-3-[((3S)-1-[(3-chloro-2-methylphenyl)sulfonyl]piperidin-3-ylamino)-carbonyl]piperidine-1-carboxylate (10.0 mg, 200 μmol) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (0.5 mL) at rt for 1 h. The volatiles were removed in-vacuo and the residue was dissolved in acetonitrile (0.8 mL) and was treated with diisopropylethylamine (20.0 μL) and acetyl chloride (5.0 μL). The crude reaction mixture was diluted with MeOH (1.3 mL) and was adjusted to a pH of 2 using TFA and was purified by prep-HPLC to give the desired product. LCMS: (M+H)+=442.1/444.1.