Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH2:32])[C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[C:21]([F:29])[CH:20]=3)=[N:16][C:15]=2[CH:30]=1)(=O)C.O1CCOCC1.Cl>O>[F:29][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[C:13]([CH:31]=[CH2:32])=[CH:12][C:11]([OH:10])=[CH:30][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Potassium carbonate (55 mg) was added into a solution of 2-[4-(acetyloxy)-3-fluorophenyl]-7-vinyl-1,3-benzoxazol-5-yl acetate (0.14 g, 0.39 mmol) and 1,4-dioxane (3 mL). The mixture was stirred at 90° C. for 1 h, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from EtOAc/hexanes, gave a white solid (0.06 g, 46% yield, m.p. 250-252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([O:34][S:35](=[O:40])(=[O:39])[NH:36][CH2:37][CH3:38])[C:31]([CH3:41])=[CH:30][C:29]=1[S:42]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[C:29]([S:42][C:10]2[C:11](=[O:13])[O:12][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:8][C:9]=2[OH:14])=[CH:30][C:31]([CH3:41])=[C:32]([O:34][S:35](=[O:39])(=[O:40])[NH:36][CH2:37][CH3:38])[CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Reactant: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (156 mg, 0.499 mmol; prepared in Example NN), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-ethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example VVV; 250 mg, 0.546 mmol), K2CO3 (303 mg, 2.195 mmol), and DMF (4 mL). The reaction was stirred at room temperature for 2.5 hours and then worked up in the usual manner. The crude product was flash chromatographed using CH2Cl2 :MeOH (98:2 to 97:3) to give the desired product as a amorphous solid. 1H NMR (CDCl3) δ 1.0-2.1 (m, 16 H), 1.55 (s, 9 H), 2.00 (s, 3 H), 2.6-2.7 (m, 3 H), 3.10 (d, 1 H), 3.3-3.4 (m, 2 H), 4.96 (t, 1 H), 6.70-6.78 (d, s, 3 H), 6.93 (d, 2 H), 7.29 (s, 1 H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:27]2[CH2:26][CH2:25][N:24]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:23]([CH3:22])[CH2:28]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2C(C)(C)C)cc1

Procedure:
136 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 2-methyl-1-m-tolylpiperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C#Cc2ccccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1cccc(C#Cc2ccccn2)c1

Procedure:
Deprotection of tert-butyl 2-(3-(pyridin-2-ylethynyl)phenoxy)ethylcarbamate with HCl-dioxane following the method used in Example 13 gave 2-(3-(pyridin-2-ylethynyl)phenoxy)ethanamine hydrochloride as a white solid.
Reaction SMILES: N1C2C(=CC=CN=2)C=C1.C([O:17][C:18]1[C:19]([F:36])=[C:20]([C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[C:21]([F:24])=[CH:22][CH:23]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[F:36][C:19]1[C:18]([OH:17])=[CH:23][CH:22]=[C:21]([F:24])[C:20]=1[C:25]([C:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:26]
Reactant: O=C(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncccc12
Agent: [Pd]
Agent: c1cnc2[nH]ccc2c1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ncccc12
Reaction time: 6 h

Procedure:
was prepared following the protocol of Scheme 43, substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with 7-azaindole. To a solution of (3-benzyloxy-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-1802, 0.5 g, 1.37 mol) in methanol (70 mL) and tetrahydrofuran (30 mL) was added palladium on carbon (120 mg, 10% wt., 0.58 mol). The mixture was stirred under hydrogenation (60 psi) for six hours. After removal of solvent, the residue was dried under vacuum, which provided (2,6-Difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone 651
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)C(OCC)=O)=[CH:5][CH:4]=1.[OH-].[Na+].S(=O)(=O)(O)O.[Na].N1C=CC=CC=1C>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(c1ccc(O)cc1)(c1ccc(OS(=O)(=O)O)cc1)c1ccccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccn1
Product: O=S(=O)(O)Oc1ccc(C(c2ccc(O)cc2)c2ccccn2)cc1

Procedure:
20 g. ethyl α-(4-hydroxyphenyl)-α-(4-sulphoxyphenyl)-2-pyridine-acetate monosodium salt were dissolved in 200 ml. 3% aqueous sodium hydroxide solution and the solution then boiled for 1 hour. After cooling, the pH was adjusted to 7.5 by adding diluted sulphuric acid and then distilled to dryness. The residue was treated with boiling ethanol and insoluble material was filtered off. The ethanol extract was concentrated to a small volume to give, by crystallisation, a high yield of the desired 4-hydroxyphenyl-4-sulphoxyphenyl-(2-pyridyl-methane monosodium salt in the form of colourless crystals which melted at 197° - 199°C. (decomposition).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:40])[CH2:31][N:32]([C:24](=[O:25])[C@H:19]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)CC

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-L-isoleucine (1.36 g) and N-(benzyl)glycine ethyl ester (770 mg) were reacted in the same manner as in Preparation Example 52 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([C:18]1[O:22][C:21]([NH2:23])=[N:20][N:19]=1)[CH3:17].C(Cl)(=O)C(Cl)=O.OS([O-])(=O)=O.[K+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O.CN(C=O)C>[Cl:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[O:22][C:18]([CH2:16][CH3:17])=[N:19][N:20]=1)=[O:6]
Reactant: CON=Cc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: CCc1nnc(N)o1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CCc1nnc(NC(=O)c2ccc(Cl)c(C=NOC)c2Cl)o1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
400 mg (1.61 mmol) of 2,4-dichloro-3-[(methoxyimino)methyl]benzoic acid and 228 mg (2.0 mmol) of 5-ethyl-1,3,4-oxadiazole-2-amine were dissolved in 3 ml of pyridine, and 10 mg of 4-dimethylaminopyridine and a drop of DMF were added. At room temperature (RT), 255.83 mg (2.016 mmol) of oxalyl chloride were then added dropwise, and the mixture was stirred at 70° C. for 4 h. 0.5 ml of water was then added to the reaction, which had once more been cooled, and the mixture was stirred for about 30 min, acidified with a saturated KHSO4 solution and extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases were washed once with 20 ml of a saturated NaHCO3 solution, dried over MgSO4, filtered off and concentrated. The residue was purified chromatographically by preparative HPLC. Yield: 99.3 mg (18%) as colorless crystals.
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]3[N:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=3[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]>N1C=CC=CC=1.O>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:18](=[O:19])[CH3:13])[O:7][C@H:1]1[N:10]1[C:14]2[N:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[N:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: O=c1[nH]nnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]nnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
The compound from Step A (1.68 gr, 6.24 mmol) was stirred in pyridine (20 mL). The anhydride acetic (2.3 ml, 25 mmol) was added and the mixture was stirred at 20° C. for 16 hours. The mixture was evaporated to dryness to give a syrup which was dissolved in water. The aqueous layer was extracted by acetyl acetate. The organic layer was evaporated to dryness to give the title compound (1.5 gr) as a brown foam.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6]C1CCCCO1)[CH:2]=[CH2:3].C([Li])(CC)C.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1>[CH2:1]([C:4]1[C:5]([OH:6])=[C:13]([B:26]([OH:27])[OH:25])[CH:14]=[CH:15][CH:16]=1)[CH:2]=[CH2:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CCc1ccccc1OC1CCCCO1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=CCc1cccc(B(O)O)c1O
Reaction time: 0.17 h
Yield: 21 %

Procedure:
2-(2-allylphenoxy)tetrahydropyran (3.5 g, 16.03 mmol) was dissolved in dry THF (120 ml) and the solution cooled to −78° C. sec-Butyl lithium (1.3M in hexanes, 14.7 ml, 19.11 mmol) was added dropwise with stirring over 10 minutes, the reaction was stirred at −78° C. for 2 hours. Triisopropoxy borane (6.7 ml, 28.77 mmol) was added and stirring continued for 4 hours at −78° C. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (2×200 ml). The combined extracts were dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane and the solid filtered off to give the title compound (600 mg, 21%); MS 177 (M−H)−; HPLC retention time (system 1) 3.09 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=2)[O:3]1.Cl>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:6](=[O:7])[C:2]([CH3:1])([CH3:28])[O:3][C:4]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([F:27])[CH:18]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)c(F)c2)=C(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)c(F)c2)=C(c2ccc(N)cc2)C1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
To 200 mg of 2,2-dimethyl-4-(4-nitrophenyl)-5-{3-fluoro-4-(methylsulfonyl)-phenyl}-3(2H)-furanone (Example 287) in 7 ml ethanol and 1 ml water, were added 0.5 ml concentrated HCl and 0.2 g of iron powder. The mixture was stirred for 12 hours at 70° C. After the reaction mixture was cooled to room temperature, the unreacted iron was filtered off. The filtrate was concentrated in vacuo and the residue was neutralized with 1 N aqueous sodium hydroxide, which was followed by extraction with 30 ml dichloromethane. The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=1:1) to afford 102 mg of 4-(4-aminophenyl)-2,2-dimethyl-5-{3-fluoro-4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 199-200° C. NMR: δ1.54 (s, 6H), 3.24 (s, 3H), 3.80 (br s, 2H), 6.71 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.61 (dd, J=10.5, 1.8 Hz, 1H), 7.64 (dd, J=8.4, 1.8 Hz, 1H), 7.92 (dd, J=8.1, 7.2 Hz, 1H). IR (cm−1): 3468, 3374, 1694, 1517, 1386, 1320, 1159, 1147.
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[S:47])=[CH:29][C:28]=1[F:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH3:25])[CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:16]=1>C1COCC1>[CH3:7][CH:8]([CH3:25])[CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[CH:23][CH:24]=2)[N:16]=1
Reactant: CC(C)CCNc1nc(-c2ccc(C#N)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCNc1nc(-c2ccc(CN)cc2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Add lithium aluminum hydride (210 mg, 5.5 mmol) portionwise over 3 min to a solution of 4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzonitrile (500 mg, 1.8 mmol) in THF (20 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 1 h at 60° C. Cool the mixture, quench slowly with water (0.2 mL) and 1N NaOH (0.2 mL). Add sodium sulfate to absorb residual water, filter the mixture through Celite®, wash with DCM (50 mL) and concentrate in vacuo. Purify the residue by SCX chromatography to obtain the desired intermediate (493 mg, 97%). MS (ES+) m/z: 276 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][C:32]([O:31][CH3:30])=[O:42])=[CH:39][CH:38]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
[4-(3-Aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.39 g, 1.0 mmol) and (4-formyl-phenyl)-acetic acid methyl ester (0.17 g, 0.96 mmol) were mixed in THF (15 mL) and then treated with NaBH(OAc)3 (0.43 g, 2.0 mml) and acetic acid (0.5 mL). After stirring at 40° C. under a N2 atmosphere for 2 h the mixture was quenched with water and then extracted with ethyl acetate. The organic residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate as an orange solid (0.30 g, 54%): MS (EI) m/z 555.3 (M+H)+; 1H NMR (DMSO-d6): δ 3.61 (s, 3H), 3.66 (s, 2H), 4.12 (d, J=6.0 Hz, 2H), 6.40 (d, J=6.8 Hz, 2H), 6.49 (d, J=6.8 Hz, 2H), 6.98 (t, J=7.7 Hz, 1H), 7.18-7.22 (m, 4H), 7.36 (t, J=7.5 Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.72 (t, J=8.6 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 8.30 (d, J=7.3 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH2:44][CH2:43]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH2:53][C:51]2[N:52]=[C:48]([N:45]3[CH2:46][CH2:47][O:42][CH2:43][CH2:44]3)[S:49][CH:50]=2)[C:6]2[CH:7]=[C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)[O:9][C:5]=2[CH:4]=1
Reactant: OCc1csc(N2CCOCC2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCc2csc(N3CCOCC3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.10 g, 0.315 mmol), triphenylphosphine (0.124 g, 0.473 mmol) and (2-morpholinothiazol-4-yl)methanol (Example 5B, 0.086 g, 0.429 mmol) were added in a 25 mL round-bottom flask and purged under vacuum and nitrogen. Tetrahydrofuran (8 mL) was then added and the mixture was treated with DIAD (0.083 g, 0.410 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 22° C. for 1 hour and diluted with ethyl acetate. This was washed with sat. NaHCO3 (1×) and brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column chromatography (2.5×10 cm, 40% ethyl acetate in CH2Cl2) and the residue obtained after concentration was crystallized in ethyl acetate to give the title material as crystals (0.083 g, 53%) and as an amorphous impure solid from the mother liquor (0.169 g). LC (Method F): 2.466 min. HRMS (ESI) calcd for C22H22N5O5S2 [M+H]+ m/z 500.1057. found 500.1075. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.82 (s, 1H) 7.07 (s, 1H) 6.67 (d, J=2 Hz, 1H) 6.62 (s, 1H) 6.40 (d, J=1.5 Hz, 1H) 5.10 (s, 2H) 4.19 (s, 3H) 3.82 (s, 3H) 3.81 (m, 4H) 3.46 (m, 4H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]([NH:48][C@H:49](C(O)=O)[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[CH2:41][CH2:40]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[O:39]1[CH2:40][CH2:41][N:42]([CH2:45][C:46]([NH:48][C@H:49]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[CH2:43][CH2:44]1
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN1CCOCC1)C(C)(C)O
Yield: 77 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.18 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl) 3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)], 58 mg (0.20 mmoles) of N-morpholinoacetyl-L-phenylalanine, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, to obtain 101 mg (yield 77%) of the title compound as a white amorphous substance.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2>CS(C)=O>[C:1]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)#[N:2]
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCCc1ccc2c(c1)CC(=O)N2
Temperature: 90 °C
Yield: 42 %

Procedure:
Potassium cyanide (2.0 g) was added to 15 mL of dimethyl-sulfoxide and heated to 90° C. 5-Chloroethyl-2-oxindole (3.0 g) dissolved in 5 mL dimethyl sulfoxide was added slowly with stirring, and the reaction heated to 150° C. for 2 hours. The mixture was cooled, poured into ice water and the precipitate collected by vacuum filtration, washed with water, dried and then chromatographed on silica gel (5% methanol in chloroform) to give 1.2 g (42% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:26]([CH3:28])[CH3:27])[N:11](/[CH:20]=[CH:21]/[C:22](OC)=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:26]([CH3:28])[CH3:27])[N:11](/[CH:20]=[CH:21]/[CH2:22][OH:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/CO
Yield: 81.3 %

Procedure:
From methyl (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-yl]-2-propenoate (1.150 g) and diisobutylaluminium hydride (1M in dichloromethane, 6.62 ml) by the process as described for the preparation of Intermediate (8 a) to afford a white solid which was purified by FCC eluting with System A (2:3) to afford the title compound (0.866 g) as a white solid, λmax (EtOH) 255.2 (12,050) and 243.2 (inf) nm (ε10,915).