Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[C:12]([O:16][C:17](=[O:20])[CH2:18]Br)([CH3:15])([CH3:14])[CH3:13].Cl>C(O)C>[C:12]([O:16][C:17]([CH2:18][S:8][C:5]([CH3:7])([CH3:6])[C@H:4]([NH:3][C:17]([O:16][CH2:12][CH3:13])=[O:20])[C:9]([OH:11])=[O:10])=[O:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (0.81 g; 35.2 mmol) was added in portions to 40 mL ethanol while cooling. Subsequently D-penicillamine (2.50 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which bromoacetic acid tert.-butyl ester (2.55 mL) was added. The mixture was allowed to stir 16 h at ambient temperature and subsequently hydrolyzed with 2 N HCl. The solvents were distilled off, the residue was redissolved in 50 mL of water and 50 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (2.1 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 10) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a colorless oil, which was purified by HPLC (RP-18; pH 2.3, H2O/CH3OH 3/7) to give 0.86 g (15%) of the title compound as a colorless oil. (+)-APCI-MS: 358 (MNa+).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:13]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.ClC1C=C(Cl)C2C(=CC=C(Cl)C=2)N=1>>[Cl:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH:22]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: c1ccc2c(c1)CCCNC2
Agent: Clc1ccc2nc(Cl)cc(Cl)c2c1
Product: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, CDCl3) δ ppm 7.92-7.88 (dd, J=1.2, 8.0 Hz, 1 H), 7.65 (d, J=8 Hz, 1 H), 7.53-7.45 (m, 2 H), 7.24-7.10 (m, 5 H), 4.81 (s, 2 H), 4.09 (brs, 2 H), 3.02-2.97 (m, 2 H), 1.94-1.88 (m, 2 H).
Reaction SMILES: C(OC([O:11][C:12]1[C:21]2[C:16](=[C:17]([CH2:33][N:34]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:18]([O:22]C(OCC3C=CC=CC=3)=O)=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:51][N:52]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[OH:11][C:12]1[C:21]2[C:16](=[C:17]([CH2:33][N:34]([C:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:42])[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:18]([OH:22])=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:51][N:52]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=C(OCc1ccccc1)Oc1ccc2c(OC(=O)OCc3ccccc3)c(CN(C(=O)OCc3ccccc3)C3CCCCC3)ccc2c1CN(C(=O)OCc1ccccc1)C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N(Cc1ccc2c(CN(C(=O)OCc3ccccc3)C3CCCCC3)c(O)ccc2c1O)C1CCCCC1

Procedure:
A solution of the crude product from Step B (2.0 g, 2.3 mmol) in methanol (50 ml) was treated with sodium methoxide (120 mg, 2.2 mmol) for 18 hours at room temperature. The mixture was evaporated, the residue taken up in diethyl ether, acetic acid (1 ml) added, the solution washed three times with water, saturated aqueous sodium chloride solution, dried (sodium sulfate) and evaporated. The crude product was vacuum filtered through a column of silica gel (Merck #7734) eluted with 2:1 hexane-ether; yield 1.5 g.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH2:20]3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 25.8 mg, 0.22 mmol, 1.5 equiv), DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) and HATU (87 mg, 0.22 mmol, 1.5 equiv) were added to anhydrous acetonitrile (2 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 11-2 as a white solid. MS m/z (M+H): calculated=424.2345; observed=424.2353.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c(F)cc1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
4-Fluoro-2-hydroxybenzoic acid (29.01 g, 0.186 mol) was dissolved in acetic acid (290 ml), then a solution of bromine (31.18 g, 0.195 mol) dissolved in acetic acid (15 ml) was gradually dropwise added at room temperature (1 hour). After stirred at 60° C. for 24 hours, this was cooled to room temperature. The reaction liquid was dried to solidness under reduced pressure, the residue was dissolved in methanol (100 ml), and this was poured into water (600 ml). After stirring at room temperature for 15 minutes, the precipitated crystal was washed and collected by filtration, and dried to obtain the entitled compound (35.36 g, 93%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Br-:17].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClCCl.CO>[NH2:1][C:2]1[C:6]([Br:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: [Br-]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)c(Br)c1N
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (2.33 g, 10 mmol) and phenyltrimethylammonium tribromide (9.4 g, 25 mmol) in dichloromethane (25 mL) and methanol (25 mL) was added calcium carbonate (4.03 g, 40 mmol) and the mixture stirred overnight. The solid was filtered off and the filtrate concentrated. The residue was purified by flash chromatography on silica gel using 1:10 ethyl acetate/hexanes to give 2.75 g of the title compound. 1H NMR (DMSO-d6) δ 7.62-7.65 (m, 2H), 7.47-7.51 (m, 3H), 3.80 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:12])=[O:13])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=3)[N:3]=2)[CH2:27][CH2:26]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCNCC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 116 °C
Reaction time: 20 h
Yield: 28.7 %

Procedure:
A mixture of tert-butyl 4-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (202 mg, 0.400 mmol), 4-aminobenzamide (82 mg, 0.60 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 116° C. in a sealed tube for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give 4-(4-(piperidin-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (58 mg).
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([O:14]CC)(=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[CH:20][C:19]=1[C:29]#[N:30]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:6](=[O:14])[NH:17][C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][C:19]=2[C:29]=1[NH2:30])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(N)c2cnn(-c3ccccc3)c2[nH]c1=O
Yield: 40.2 %

Procedure:
Sodium pellets (0.86 g, 37.4 mmol) were added carefully to dry ethanol (40 ml) in a round-bottomed flask with a condenser in place and under nitrogen. The resulting solution of sodium ethoxide was allowed to cool to room temperature before addition of diethyl malonate (4.74 ml, 31.2 mmol). 5-Amino-1-phenylpyrazole-4-carbonitrile (2.30 g, 12.5 mmol) was added portionwise and the mixture heated at reflux for 4 h. The mixture was cooled and the ethanol removed in vacuo. Water (25 ml) was added to the residue and the solid was filtered off, washing with water. 4-Amino-6,7-dihydro-6-oxo-1-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carboxylic acid ethyl ester (1.5 g, 40%) was obtained as a white solid. δH (400 MHz; DMSO) 1.35 (3H, t, J=7), 4.40 (2H, q, J=7), 7.30-7.34 (1H, m), 7.49-7.54 (2H, m), 8.04 (2H, br s), 8.09 (2H, br d, J=8), 8.44 (1H, s), 12.20 (1H, br s).
Reaction SMILES: C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:20][S:17]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([OH:21])=[O:5])(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)c1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1S(C)(=O)=O
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (0.366 g) in dichloromethane was added trifluoroacetic acid and the reaction mixture was stirred for 3 hours. The mixture was evaporated and trituration of the residue with diethyl ether gave the title compound (0.29 g; MS: APCI+(M+H) 279).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.5 g, 1.84 mmole) in THF (20 mL) at 0° C., is added a solution of benzyl magnesium chloride in tetrahedronfuran (2.0M, 1.0 mL, 2 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 2 hrs. The reaction is quenched with NH4Cl(aq), partitioned between ethyl ether and water. Extracted the aqueous layer with ethyl ether. The combined organic is washed with brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel yields the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12].O>C1(C)C=CC=CC=1>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: C1CCNC1
Reactant: O=C(Cl)c1cccs1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)N1CCCC1

Procedure:
Pyrrolidine (47 ml) was added to 2-thiophene carbonyl chloride (40 g) in toluene below 10°. After 11/2 hr, water was added. The product was extracted with ethyl acetate, crystallised from toluene and recrystallised from light petroleum (b.p. 60°-80°)/ethyl acetate to give white crystals (40 g) m.p. 66°-68°; TLC silica/ethyl acetate Rf 0.5.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][OH:15].CN(C=O)C>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][OH:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: OCCBr
Reactant: Cc1cc(I)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1OCCO
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Under an N2 atmosphere 2.34 g (10 mmol) 4-iodo-2-methyl-phenol are added to a suspension batchwise, cooled to 0° C., of 0.48 g (11 mmol) NaH in 50 mL THF and stirred for a further 30 min at this temperature. Then 0.85 mL (12 mmol) 2-bromoethanol, dissolved in 5 mL THF, are added dropwise and the mixture is stirred for 18 h at RT. 5 mL of DMF are added and the reaction mixture is heated to 70° C. for 8 h. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc and dried with Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (cyc/EtOAc 7:3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([OH:32])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of 57 mg (0.11 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step B) in DCM (359 μL) was added trifluoroacetic acid (415 μL, 5.38 mmol) at 0° C. After being stirred at 25 C. for 2 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure three times. Separation of the crude product by reversed phase HPLC (45 to 70% AcCN/H2O in 30 min, 3 time runs, tR=18.52 min) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[C:15]([CH:17]=O)[CH:14]=[C:13]2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1COCC1.[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[C:15]([CH2:17][NH:46][C:45]3[CH:47]=[CH:48][C:42]([N:39]4[CH2:38][CH2:37][O:36][CH2:41][CH2:40]4)=[CH:43][CH:44]=3)[CH:14]=[C:13]2[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(CNc3ccc(N4CCOCC4)cc3)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-p-methoxyphenylsulfonyl-2-(3,4,5-trimethoxyphenyl)pyrrole-4-carbaldehyde (50 mg, 0.12 mmol, Example 94a) in THF (1 ml) acetic acid (21 mg, 3 equiv.), 4-morpholinoaniline (21 mg, 1.05 equiv.) and NaBH(OAc)3 (61 mg, 2.5 equiv.) are added. The reaction mixture is stirred at room temperature for 16 h, and diluted with aqueous 1 M Na2CO3 solution and ethyl acetate. The organic layer is dried (MgSO4) and purified by flash chromatography and preparative HPLC. RT (program 2) 3.52. MS: 593.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][C:3]=1[CH3:27].[OH:28]O.O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:4][C:3]=1[CH3:27]
Reactant: Cc1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 9.2 gm (0.02 mol) of 6-[4-(4-bromo-3-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 100 ml of glacial acetic acid, and 2 ml (0.02 mol) of 30% hydrogen peroxide are added. The mixture is stirred for three hours at ambient temperature, poured onto 400 ml of water, and extracted three times with ethyl acetate. The organic phase is washed with water and dried with sodium sulfate, and the ethyl acetate is distilled off. The solid residue is recrystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:14])[CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17].CC(C)([O-])C.[Li+]>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]([CH3:14])[CH2:10][C:11]([NH:13][C:16](=[O:17])[O:18][CH:19]([CH3:21])[CH3:20])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@@H](CC(N)=O)Nc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)NC(=O)C[C@H](C)Nc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
(3S)-3-[(4-bromophenyl)amino]butanamide (for a preparation see Intermediate 13, 24.9 g, 97 mmol) was taken up in Ethyl acetate (850 mL) and cooled to <−9° C. (internal). Isopropyl chloroformate (116 mL, 116 mmol, Aldrich) was added followed by slow addition of Lithium tert-butoxide (18.61 g, 232 mmol) in Tetrahydrofuran (THF) (232 mL) keeping the temperature below 0° C. The reaction was stirred for 30 mins then checked by LCMS which showed a complete reaction. The mixture was partitioned between EtOAc (1000 ml) and 2N HCl (2000 ml). The organic layer was washed with brine (2000 ml) and then dried with Na2SO4, filtered and concentrated to yield the product as a brown oil (17.9 g) LCMS (Method B): Rt=1.09, MH+=343
Reaction SMILES: BrCCBr.[Mg].[CH2:6]1[O:14][CH:9]([CH:10]([CH3:13])[CH2:11]Br)[O:8][CH2:7]1.CON(C)[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]1[O:14][CH:9]([CH:10]([CH3:13])[CH2:11][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[O:8][CH2:7]1
Reactant: CON(C)C(=O)c1ccc(C)c(C)c1
Reactant: CC(CBr)C1OCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC(C)C2OCCO2)cc1C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
0.29 ml (3.4 mmol) of 1,2-dibromoethane was added to a suspension of 1.66 g (68.1 mmol) of magnesium in 5 ml of anhydrous tetrahydrofuran under a stream of nitrogen. 9.96 g (51.1 mmol) of 3-bromo-2-methylpropionaldehyde ethylene acetal [prepared as described in step (i) above] were then added dropwise to the resulting mixture, whilst ice-cooling, after which the mixture was stirred for 1 hour. A solution of 6.58 g (34.1 mmol) of N-methoxy-N-methyl-3,4-dimethylbenzamide in 30 ml of tetrahydrofuran was then added dropwise to the mixture, and the resulting mixture was stirred, whilst ice-cooling for 1 hour. A saturated aqueous solution of ammonium chloride was then added to the mixture, and the resulting mixture was extracted twice with ethyl acetate. The organic extracts were combined and washed with a saturated aqueous solution of sodium chloride, after which they were dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 6:1 by volume mixture of hexane and ethyl acetate, to give 3.26 g (yield 39%) of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:35]([NH:38][CH2:39][CH2:40][CH2:41][OH:42])(=[O:37])=[O:36])[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.C(N(C(C)C)CC)(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl>[CH3:52][S:53]([O:42][CH2:41][CH2:40][CH2:39][NH:38][S:35]([C:4]1[CH:5]=[C:6]([F:34])[C:7]([CH2:8][S:9][C:10]2[N:11]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=3)([CH3:16])[CH3:17])=[CH:13][N:14]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:37])=[O:36])(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-N-(3-hydroxypropyl)benzenesulfonamide (910 mg, 1.42 mmol) and diisopropylethylamine (0.74 mL, 0.74 mmol) in DCM (6 mL) was added methanesulfonyl chloride (0.13 mL, 1.706 mmol) at −10° C. After the reaction was slowly warmed to ambient temperature over 30 min, it was extracted with DCM (10 mL). The combined extracts were washed with water (10 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex:EA=1:2) to give 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenylsulfonamido)propyl methanesulfonate (0.80 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.39 (dd, J=8.27, 1.73 Hz, 1H), 7.27 (d, J=2.32 Hz, 2H), 6.89 (dd, J=10.97, 8.54 Hz, 1H), 6.84-6.74 (m, 2H), 6.58 (dd, J=8.09, 2.16 Hz, 1H), 6.53-6.45 (m, 1H), 6.41-6.33 (m, 2H), 5.26 (s, 1H), 4.42-4.29 (m, 2H), 4.23-4.08 (m, 3H), 3.78 (d, J=2.18 Hz, 4H), 3.21-3.10 (m, 2H), 3.10-2.99 (m, 4H), 2.00 (dd, J=11.78, 6.04 Hz, 2H), 1.65 (s, 7H).