Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[H-].[Na+].[CH2:11]([C:13]1[C:18]([OH:19])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12].O>CN(C=O)C>[CH2:11]([C:13]1[C:18]([O:19][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12]
Reactant: CN(C)CCCCl
Reactant: CCc1c(O)nc(C)c2sccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OCCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
3-(N,N-Dimethylamino)propylchloride hydrochloride (5.51 g, 34.9 mmol) and sodium hydride (60% in oil, 1.55 g, 38.8 mmol, prewashed with pentane) in DMF (30 ml) were stirred at room temperature for one hour. This solution was then added to a mixture of 4-ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.9 g, 15.0 mmol) and sodium hydride (60% in oil, 0.60 g, 15.0 mmol, prewashed in pentane) in DMF (30 ml) which had been allowed to react for two hours. The combination was stirred at room temperature for three days, poured into H2O (500 ml), extracted with CH2Cl2 (3×200 ml) and dried over MgSO4. The solvent was removed in vacuo and the product was purified by flash chromatography on silica gel 60 (120 g) using 8% MeOH in CH2Cl2 as the eluant to give the product (2.3 g, 55% yield) as a yellow oil; IR (neat) 1440, 1580 and 2980 cm-1 ; mass spectrum m/z 279 (MH+); 1H NMR (CDCl3) δ 1.20 (t, J=7 Hz, 3H, CH2CH3), 1.68 to 2.90 (m, 6H, CH2CH2N, CH2CH3), 2.27 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 4.43 (t, J=6 Hz, 1H, OCH2CH2), 7.27 and 7.53 each (d, J=6 Hz, 1H, thiophene-H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:15])=[CH:12][C:13]=1[NH2:14])(=[O:8])=[O:7])(C)(C)C>Cl>[NH2:14][C:13]1[CH:12]=[C:11]([Cl:15])[S:10][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N
Agent: Cl
Product: Nc1cc(Cl)sc1S(N)(=O)=O
Yield: 100.1 %

Procedure:
A solution of 3a (250 mg, 0.93 mmol) in concentrated HCl solution (10 mL) was heated at 55° C. for 2h. Removal of all solvents then afforded 3b (198 mg) as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2].C(=O)([O-])[O-:22].[K+].[K+].CS(C)=O.OO>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 169.4 %

Procedure:
Mix 4-(5-Formyl-indol-1-ylmethyl)-benzonitrile (0.73 g, 2.8 mmol), potassium carbonate (0.19 g, 1.4 mmol), and dimethylsulfoxide (14 mL) in a flask. Cool 10 minutes in an ice bath and add hydrogen peroxide (0.95 mL, 30% wt in water) dropwise. Remove ice bath and stir at rt for 4 hrs. Pour into water (30 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product as a white solid (0.66 g, 88%). 1H NMR (DMSO-d6) 9.95 (s, 1H), 8.17 (s, 1H), 7.89 (bs, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.69 (d, J=3.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.32 (bs, 1H), 7.23 (d, J=8.1 Hz, 2H), 6.73 (d, J=3.1 Hz, 1H), 5.54 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([F:26])[CH2:23][C@H:22]1[CH2:27][O:28][CH2:29][CH2:30][CH:31]=O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([F:26])[CH2:23][C@H:22]1[CH2:27][O:28][CH2:29][CH2:30]/[CH:31]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCC=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 86.2 %

Procedure:
Trimethyl phosphonoacetate (0.95 ml, 5.88 mmol) was dissolved in THF (40 ml). Under a nitrogen gas stream, sodium hydride (60% in oil, 235 mg, 5.88 mmol) was added in portions to the resulting solution, while stirring at 0° C. After stirring the reaction mixture at the same temperature for 10 minutes, a solution of 3-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)propionaldehyde (1.35 g, 4.90 mmol) in THF (40 ml) was added dropwise at 0° C. The reaction mixture was further stirred for 2 hours at 0° C. and poured in ice water (50 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (1.40 g, 86%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:23]([CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=1[CH3:33])([OH:25])=[O:24].N1CCCCC1>C(O)C>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([CH2:27][CH2:26][C:23]([OH:25])=[O:24])[C:29]=2[CH3:36])[C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(OCCc2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCOc4ccc(C(C)C)cc4)c32)c(C)c1CCC(=O)O
Temperature: 90 °C
Yield: 58.2 %

Procedure:
A mixture of 4-[2-(4-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one (118 mg, 0.4 mmol), 4-carboxyethyl-3,5-dimethyl-2-formylpyrrole (78 mg, 0.4 mmol) and piperidine (0.3 mL) in 1.0 mL of ethanol was heated in a sealed tube at 90° C. for 18 hours and cooled to room temperature. The reaction mixture was concentrated and the residue was dissolved in methylene chloride followed by the addition of diethyl ether. The precipitate was filtered and washed with ethyl acetate to give 110 mg (58%) of 3-(5-{4-[2-(4-isopropyl-phenoxy)-ethyl]-2-oxo-1,2-dihydro-indol-3-ylidenemethyl}-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (piperidine salt).
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.CC1(C)C(C)(C)OB([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)O1>>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:55]3[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3ccncc3)cc12

Procedure:
Example 68 was synthesized according to the Suzuki coupling method described above for the synthesis of example 66, using ((S)-1-{5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methyl-butyl)-carbamic acid 9H-fluoren-9-ylmethyl ester and 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)pyridine, except that the crude product was purified by HPLC. 1H NMR (400 MHz, CD3OD): δ 8.48-8.59 (m, 3 H), 7.61 (d, J=2.0 Hz, 1H), 7.52 (dd, J=4.5, 1.5 Hz, 2H), 7.46-7.49 (m, 2 H), 7.20 (t, J=8.7 Hz, 1H), 5.34 (q, J=7.3 Hz, 1H), 1.91 (d, J=7.3 Hz, 3H). MS (ES+): m/z=386.19, 388.17 (100, 88) [MH+]. HPLC: tR=0.94 min (HPLC-ACQUITY, Purity).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[OH2:12].[Mn]([O-])(=O)(=O)=O.[Na+].[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:48])[NH:40][CH2:41][C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)=[CH:34][CH:33]=2)[N:29]=[C:28]([CH2:49][S:50][CH2:51][CH2:52][NH:53][C:54](=[O:56])[CH3:55])[CH:27]=1.[OH2:57]>O1CCOCC1>[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:48])[NH:40][CH2:41][C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)=[CH:34][CH:33]=2)[N:29]=[C:28]([CH2:49][S:50]([CH2:51][CH2:52][NH:53][C:54](=[O:56])[CH3:55])(=[O:57])=[O:12])[CH:27]=1
Reactant: CC(=O)NCCSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NCCS(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
meta-Chloroperbenzoic acid (156 mg, 0.90 mmol) dissolved in Dioxane (2 mL), and sodium permanganate monohydrate (192 mg, 1.20 mmol) dissolved in water (1 mL) were added dropwise to N-[2-[[6-[(3S)-3-methylmorpholin-4-yl]-2-[4-[(1-methylpyrazol-4-yl)methylcarbamoylamino]phenyl]pyrimidin-4-yl]methylsulfanyl]ethyl]acetamide (162 mg, 0.30 mmol) in dioxane (6 mL) and water (2 mL) at RT under nitrogen. The resulting solution was stirred at RT for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (61 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)OC(C)(C)C)c2ccccc21
Yield: 91.7 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline (109 mg, 0.41 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (10 mg) and a trace of conc. H2SO4 at rt for 7 h. Filtration over Celite™ afforded 93 mg (92%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.62 (d, J=8.1, 1H), 7.16 (d, J=7.8, 1H), 7.11 (ddd, J=7.8, 7.8, 1.6, 1H), 7.01 (ddd, J=7.7, 7.5, 1.0, 1H), 3.71 (m, 2H), 2.87 (ddq, J=6.8, 6.8, 6.8, 1H), 2.04 (dddd, J=7.4, 7.4, 7.4, 6.1, 1H), 1.61 (m, 1H), 1.51 (s, 9H), 1.3 (d, J=6.8, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].CC(C)([O-])C.[K+].Cl[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C(C)Cl
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 13.8 %

Procedure:
To a stirred solution of 1-methoxy-2-nitrobenzene (3 g, 19.59 mmol) in dimethylformamide were added potassium tert-butoxide (8.792 g, 78.36 mmol) and ethyl 2-chloropropionate (2.5 ml, 19.59 mmol) while maintaining temperature below −30° C. The reaction mixture was stirred for 5 min at −30° C., then ethyl 2-chloropropionate (0.25 mL, 1.959 mmol) was added to mixture. The reaction mixture was stirred for 10 min at room temperature. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(3-methoxy-4-nitrophenyl)propanoate (683 mg) was obtained as 14% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[OH:29]>CN(C)C=O.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1>[OH:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(OCCCCc2ccccc2)cc1
Reactant: Cc1ccc(O)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
One drop of N,N-dimethylformamide Was added to a solution of 1 g of p-(4-phenylbutoxy)benzoic acid in 5 ml of methylene chloride and 2 ml of oxalyl chloride was added to the mixture at -30° C. or lower. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude p-(4-phenylbutoxy)benzoyl chloride. This substance was dissolved in 5 ml of methylene chloride and the resulting solution was added to a solution of 1 g of 2-amino-4-methylphenol in 5 ml of pyridine under ice cooling followed by stirring at room temperature for 3 hours. The reaction mixture was poured into conc. hydrochloric acid-ice and then extracted with ethyl acetate. The extract was washed subsequently with water, an aqueous solution of sodium hydrogen carbonate and again water. After drying over anhydrous magnesium sulfate, the system was concentrated under reduced pressure to obtain 1.4 g of 2'-hydroxy-5'-methyl-4-(4-phenylbutoxy)benzanilide. Melting point: 138°~140 ° C.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[NH2-].[K+].N.[CH3:14]I>>[C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH2:9][CH3:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Reactant: CI
Agent: N
Agent: [K+]
Agent: [NH2-]
Product: CCc1ccc(C#N)c(=O)[nH]1

Procedure:
Boatman et al [J. Org. Chem. 30, 3593-7 (1965)] show the reaction of 3-cyano-6-methyl-2(1H)-pyridinone with potassium amide in liquid ammonia and subsequent reaction of the resulting salt with methyl iodide to produce 3-cyano-6-ethyl-2(1H)-pyridinone (p. 3596, 3a).
Reaction SMILES: [H-].[Na+].[CH:3]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]>CN(C)C=O>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[N:18]([CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: Clc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1N(c1nc2ccccc2[nH]1)C1CCCC1
Yield: 12.2 %

Procedure:
In analogy to example 1, (1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)amine (250 mg) was dissolved in dimethylformamide (2 ml) at room temperature, deprotonated with sodium hydride (48 mg) and alkylated with cyclopentyl bromide (136.7 mg) in a closed vessel at 100° C. for 8 h. Workup and chromatography resulted in 38 mg of the desired compound.
Reaction SMILES: [C:1]([C:5]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:8]([C:17]2[N:18]([C:38](Cl)=[O:39])[C:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[N:21]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:46][S:47]([CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:49])=[O:48]>C(N(CC)CC)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C@@:20]2([CH3:22])[C@:19]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)([CH3:30])[N:18]([C:38]([N:56]3[CH2:55][CH2:54][N:53]([CH2:52][CH2:51][CH2:50][S:47]([CH3:46])(=[O:48])=[O:49])[CH2:58][CH2:57]3)=[O:39])[C:17]([C:8]3[C:7]([O:41][CH2:42][CH3:43])=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[C:10]([S:11]([N:12]([CH3:14])[CH3:13])(=[O:15])=[O:16])[CH:9]=3)=[N:21]2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethyl-benzenesulfonamide was reacted with phosgene in the presence of triethylamine to give rac-(4S*,5R*)-2-(4-tert-butyl-5-dimethylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride. The carbamoyl chloride was then reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) in the presence of triethylamine to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H53N5O6S2Cl2 [(M+H)+] 834.2887, observed 834.2878.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[N-:50]=[N+:51]=[N-:52].[Na+].[I-].[Na+]>CCOC(C)=O>[N:50]([CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:16]2[S:15][C:14](=[C:11]3[S:10][C:9](=[N:28][C:29]4[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=4[NH:35][CH2:36][CH3:37])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]3=[O:13])[N:18]([CH3:19])[C:17]=2[CH:20]=1)=[N+:51]=[N-:52]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN=[N+]=[N-])cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 70 °C

Procedure:
To a 50 mL flask was added the product of Example 145 (225 mg, 345 μmol), anhydrous DMF (8 mL), sodium azide (112 mg, 1.73 mmol), and sodium iodide (15 mg, 103 μmol). The reaction slurry was heated at 70° C. for 6 h under N2. The reaction mixture was diluted with EtOAc (70 mL), washed with H2O (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. MS(ESI): 658(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].Cl[CH2:18][C:19]1[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:18][C:19]3[CH:24]=[N:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=4)=[CH:21][C:20]=3[C:35]([F:36])([F:38])[F:37])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(CCl)cn2)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)cc3C(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 7 a], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyridine in the presence of cesium carbonate and potassium iodide, using acetonitrile as solvent, to obtain the title compound as white solid.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:16]1([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([S:1][C:9]3[CH:14]=[CH:13][C:12]([O:15][S:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:24])=[O:23])=[CH:11][CH:10]=3)=[CH:3][CH:4]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(Sc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A 100 ml 3-necked oven-dried flask is equipped with a magnetic stirring bar and a CaCl2 -Drierite drying tube and is charged with 4,4'-thiodiphenol (5.3 grams, 24.3 mmol), benzenesulfonyl chloride (6.5 ml, 50.9 mmol), 4-dimethylaminopyridine (0.59 grams, 4.8 mmol), and anhydrous pyridine (40 ml). The mixture is stirred at ambient temperature for 18 hours, and at reflux for 4 hours, then is poured into ice-cold water (100 ml) with vigorous stirring, and the yellow oil that separates is extracted into CH2Cl2 (100 ml), and washed with water (100 ml). Drying (MgSO4), filtration and concentration affords a yellow oil. Purification by filtration through a column packed with flash-grade silica gel (5"×2" i.d.), eluting with CH2Cl2 (ca. 0.5 1), gives after solvent removal under vacuum 11.8 grams (98 percent yield) of the title compound as a faintly yellowish, thick glass material.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl>C(Cl)Cl.O.CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
In methylene chloride (183 kg) was suspended 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid [Compound A] (480 kg) obtained in Reference Example 8. To the suspension was added triethylamine (13.8 kg) to dissolve Compound A. To the solution was added triphenylmethylchloride (34.9 kg) in methylene chloride solution (50 L) and the solution was heated for about 6 hours under reflux (40° C.). To the solution was added methylene chloride (273 kg) and the solution was allowed to stand at room temperature for one night. The reaction solution was heated at 30-35° C., to which was added methanol (81.4 kg). To the solution was added water (205 kg) and the solution was adjusted to pH 3.1±0.2 with 1N hydrochloric acid. The organic layer was separated and concentrated to 288 kg. The concentrate was stirred at room temperature for about 30 minutes, to which was dropped hexane (68 kg) for 20±5 minutes. The resulting mixture was stirred at room temperature for about 30 minutes, followed by at 5±5° C. for about 1 hour. The crystals were separated and washed with a mixture of hexane-methylene chloride (5:1) (205 L). The wet crystals were dissolved in DMF(183 L) and the solution was evaporated to about 138 kg or less to give 2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid [Compound A(T)] solution (89%).