Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27]#[N:28])[CH:21]=[CH:20]4)[CH:12]=2)[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].O>CO>[CH:29]1([CH2:32][N:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][C:11]([CH:14]4[CH2:16][CH:15]4[C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[CH:23]=[C:22]([C:27]#[N:28])[CH:21]=[CH:20]5)=[CH:10][CH:9]=3)[CH:4]2[CH:1]([CH3:3])[CH3:2])[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: CC(C)C1NCCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)C1c2cc(C3CC3c3ccc4cc(C#N)ccc4c3)ccc2CCN1CC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 20A (0.25 g, 0.95 mmol), cyclopropanecarboxaldehyde (71 mL, 0.95 mmol), and sodium cyanoborohydride (119 mg, 1.86 mmol), in methanol (3.5 mL) was heated to 50° C., stirred for 2 hours, cooled to room temperature, and treated with water. The resulting precipitate was collected by filtration, dried, and purified by flash column chromatography with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[C:31]([S:33]([O-:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1[CH3:37])([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]>CO.O>[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[C:31]([S:33]([O-:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1/[CH:37]=[CH:15]/[C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=2)([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)[O-])c[n+]1CCCCCC(=O)O
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Agent: C[N+](C)(C)CC(=O)O
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc2cc(/C=C/c3ccc(S(=O)(=O)[O-])c[n+]3CCCCCC(=O)O)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-2-methyl-5-sulfonato-pyridinium betaine are converted according to the general directions above. Column chromatography: SiO2 (RP18), eluent: methanol/water.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36](O)=[C:35]([F:40])[CH:34]=1)[CH3:26].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:35]([F:40])[CH:34]=1)[CH3:26]
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
Combine 1-(4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-ol (0.257 g, 0.76 mmol) and 3-(3-Fluoro-4-hydroxy-benzoylamino)-propionic acid ethyl ester (0.150 g, 0.59 mmol) in toluene (3.0 mL). Add 1,1′(diazocarbonyl)dipiperidine (0.223 g, 0.88 mmol) followed by tributyl-phosphane (0.22 mL, 0.88 mmol) under inert atmosphere. Stir at room temperature for 18 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-70% Ethyl acetate/hexanes gradient) to provide 0.305 g of title compound (90%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:15]([Cl:14])[C:20]=2[N+:21]([O-:23])=[O:22])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1

Procedure:
A solution of 1-[1,1-dimethylethoxycarbonyl]piperazine (1.88 g) in dichloromethane (30 ml) is added drop by drop over 1.5 hr to a solution of 4,6-dichloro-5-nitropyrimidine (1.94 g) and triethylamine (1.32 g) in dichloromethane (170 ml) at -78°. After stirring an additional hr at -78°, the reaction is diluted with aqueous sodium bicarbonate (10%). The phases are separated, the organic phase is concentrated to a liquid which solidified on standing at 20°-25°. The solid is dissolved in chloroform and flash chromatographed on silica gel eluting with methanol/chloroform (1/99), pooling and concentrating the appropriate fractions gives the title compound, Anal. Calc for C13H18N5ClO4 ; MW=343.77: C,45.42; H,5.28; N,20.37; Cl,10.31. Found: C,45.52; H,5.40; N,20.34; Cl,10.36.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[CH2:20]([O:19][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 2.1 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (130 ml) and the product from step (i) (10 g) added in three portions to the cooled (4° C.) stirred mixture. Stirring was continued for a further 15 minutes when tertiary butyl bromoacetate (7.0 ml) was added dropwise over 15 minutes. After 1 hour at 4° C., the mixture was stirred for 6 hours at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic phases washed with water and brine, then dried (MgSO4) and evaporated. The residue, after purification by flash chromatography on silica eluting with dichloromethane, gave tertiary butyl 4-(benzyloxycarbonylmethyl)phenoxyacetate, 7.5 g, as a colourless oil: NMR (CDCl3) d 7.31(5H, m), 7.20(2H, m), 6.85(2H, m), 5.12(2H, s), 4.49(2H, s), 3.60(2H, s), 1.48(9H, s); m/e 356 (M.)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)[NH2:33]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:24])[F:25])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:28][N:33]=[C:32]([C:34]4[CH:39]=[N:38][CH:37]=[CH:36][N:35]=4)[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cnccn1
Product: O=C(N1CCC(O)CC1)N1CC(c2cccc(OC(F)(F)F)c2)CC(c2nc(-c3cnccn3)no2)C1

Procedure:
60 mg (0.14 mmol) of the compound from Example 194A and 30 mg (0.22 mmol) of N′-hydroxypyrazin-2-carboximidamide were reacted according to the General Method 2. Yield: 36 mg (48% of theory)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].I.CS[C:18]1[NH:19][CH2:20][C:21](=[O:23])[N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[NH:19][CH2:20][C:21](=[O:23])[N:22]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC1=NC(=O)CN1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC2=NC(=O)CN2)o1

Procedure:
2-(5-Dimethylaminomethylfuran-2-ylmethylthio)ethylamine (4.00 g), 2-methylthio-imidazolin-4-one hydroiodide (9.63 g) and triethylamine (7.27 g) were refluxed in ethanol (50 ml) for 6 hours.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COCCOCCO
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Product: COCCOCCOc1cc2ncnc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Yield: 42.2 %

Procedure:
Using an analogous procedure to that described in Example 91, 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reacted with 2-(2-methoxyethoxy)ethanol (70 mg) to give 4-(indol-5yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (50 mg, 42%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37].C(N(CC)CC)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chloro -hydrocinnamic acid and 1.09 g (0.007 mol) of 1,1'carbonyldiimidazole are stirred at room temperature for 1.5 hours in 20 ml of tetrahydrofuran and 1.04 g (0.007 mol) of ethyl L-alaninate hydrochloride and 0.94 ml (0.007 mol) of triethylamine are then added thereto. After stirring at room temperature for 2 hours, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetatemethanol (9:1) and then on aluminum oxide with ethyl acetate and subsequent crystallization from ethyl acetate/ hexane gives ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-alaninate as white crystals with melting point 106°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:12][CH2:13][N:14]([CH3:34])[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step V (5.340 g) in 1,2-dichloroethane (60 mL) is added formaldehyde (1.94 mL of 37% aqueous solution, 23.88 mmol), followed by sodium triacetoxyborohydride (2.403 g, 11.34 mmol) in portions over 20 min. The mixture is stirred at room temperature overnight, then water is added to the mixture, and it is extracted with CH2Cl2. Organic fraction is washed with aqueous NaHCO3 and brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel eluting with 0-10% of MeOH in CH2Cl2 to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Br[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].[H-].[Na+]>>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CCC(Br)CC
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) (440 mg, 1.221 mmol) in 3-bromopentane (3196 μL, 25.6 mmol) under nitrogen at rt was added a dispersion of 60% sodium hydride in mineral oil (244 mg, 6.11 mmol). Evolution of gas was observed. The reaction was stirred at room temperature for 10 min and then heated to 120° C. under N2 for 19 h. The reaction mixture was cooled to room temperature and quenched with sat. NH4Cl. The layers were separated and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound (375 mg, 71% yield) as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:26][CH2:27][OH:28].Cl>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[OH:28][CH2:27][CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: OCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
10 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (1.45 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is then stirred for 30 minutes at room temperature, 5.22 g of 2-iodoethanol are added dropwise thereto, and the mixture is then stirred for 15 minutes at room temperature and poured into a mixture of 30 ml of 2 N hydrochloric acid and 400 ml of ice-water. After being left to stand for some time the oil which separates crystallises and is taken up in 200 ml of methylene chloride. The solution is dried over magnesium sulphate and concentrated to dryness by evaporation. To crystallise, the residue is triturated with diethyl ether. 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 83°-84° is obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH2:24][C:25]2[N:26]=[C:27]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[S:28][CH:29]=2)=[O:23])=[C:17]([F:40])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl>C(Cl)(Cl)Cl.CO>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([NH:30][C:27]2[S:28][CH:29]=[C:25]([CH2:24][C:22](=[O:23])[NH:21][C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:16][C:17]=3[F:40])[N:26]=2)=[O:39])=[CH:37][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1
Yield: 75.8 %

Procedure:
A solution of 163 mg N-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide in 8 ml CHCl3/MeOH 3:1 was cooled to −10° C. A stream of HCl gas was passed over the stirred solution for 10 min. The reaction mixture was kept at 4° C. over night, then concentrated. The crude product was purified by chromatography on silica using a gradient from CH2Cl2 to CH2Cl2/MeOH 9:1 in 20 minutes to give 112 mg 4-chloro-N-{4-[(3-fluoro-2′-sulfamoyl-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-benzamide as white solid. MS 545.3 ([M+H]+)
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[CH:21][C:16]=3[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]2=[O:31])=[C:10]([O:34][CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37](C)[CH2:38]C(N)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:25]1([N:15]2[C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=3[N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH2:3][N:37]([CH3:38])[CH3:36])=[CH:9][C:10]=3[O:34][CH3:35])[C:14]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN(C)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)C)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)CN(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
A mixture of 1.5 g of the compound obtained in Example 15 Step B, 1 g of 2-dimethylamino-1,1-dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 12-14), 1.6 g of BOP and 2 g of DIPEA in 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/MeOH mixture (98/2; v/v). 0.15 g of the expected product is obtained after crystallization from iso ether, mp=161° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]C3CCCCO3)[C:9]=2[O:8][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[C:26]1([CH2:25][CH2:24][CH2:23][O:3][CH2:4][CH2:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=3[O:8][CH:7]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCc1coc2c(OC3CCCCO3)cccc12
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc2c(CCOCCCc3ccccc3)coc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (60%, 27 mg) was suspended in DMF (1 ml) and the obtained suspension was cooled to 0° C. To this solution, a solution of 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran (118 mg) in DMF (0.5 ml) was added dropwise and the obtained mixture was stirred at 0° C. for 10 minutes. To this solution, 1-bromo-3-phenyl-propane (0.27 ml) was added and the solution was stirred at 0° C. for 1 hour and then at room temperature for 45 hours. A catalytic amount of concentrated hydrochloric acid was added to the reaction solution and the solution was stirred for 2 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (15 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (106 mg, yield: 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:36])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (500 mg, 2.7 mmol) and triphenylphosphine (840 mg, 3.2 mmol) are dissolved in 12 mL of DCM and NBS (570 mg, 3.2 mmol) is added. The mixture is stirred for 4 hrs and the solvent is removed. The residue is purified by flash column chromatography to give 455 mg of 3-bromo-5-bromomethyl-pyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]Cl)([O-:31])=[O:30].Cl>O>[F:1][C:2]1[C:3]([NH:17][S:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N+:29]([O-:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1SNc1nc(OCc2ccc(F)cc2)ncc1F
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and a 1.0 M solution of KOtBu in tBuOH (1.0 mL, 1.0 mmol) was added nitrobenzene-sulfenyl chloride (0.044 g, 0.23 mmol) in one portion, and the resulting brown solution was stirred for 60 min. The reaction was diluted with water (2 mL) and neutralized to pH 7 with 1N HCl. The aq. phase was extracted with EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse phase chromatography to yield the title compound (0.020 g, 26%) as a yellow solid: mp 184° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=7.25 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.59 (m, 1H), 7.36 (m, 2H), 7.29 (m, 2H), 6.88 (m, 2H), 6.23 (bs, 1H), 5.19 (s, 2H); HPLC-MS (ESI) m/z 391 (M+H)+, 389 (M−H)−.