Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(NC2C=C(OC(C)C)NN=2)C([N+]([O-])=O)=CN=1.[Cl:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25]([N+:33]([O-:35])=[O:34])=[C:24](Cl)[N:23]=1.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>>[Cl:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25]([N+:33]([O-:35])=[O:34])=[C:24]([NH:43][C:40]2[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=2)[N:23]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Product: CCOC(=O)c1nc(Cl)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 30 using ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate and 5-methyl-1H-pyrazol-3-amine as the starting materials. LCMS: 327 [M+1].
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:46]=[CH:45][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)\[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:46]=[CH:45][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:36][CH:37]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (10 ml) was added to a solution of ethyl E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyrate(1.60 g) in tetrahydrofuran (20 ml)-methanol (10 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (10.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyric acid (1.50 g, yield 99%) as colorless crystals. m.p. 131-132° C.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11](N)=[O:12]>>[C:11](=[O:12])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH2:10]
Reactant: NC(N)=O
Reactant: CCCCCCCCO
Product: CCCCCCCCOC(N)=O
Reaction time: 1.5 h

Procedure:
A 1000 mL glass flask equipped with a reflux condenser, a gas-liquid separator, and a stirrer was charged with 522.4 g (4.01 mol) of 1-octanol and 60.07 g (1.00 mol) of urea. While the mixture was stirred at 500 rpm and nitrogen gas was allowed to flow at 30 mL per minute, the mixture was allowed to react at 165° C. After 90 min, 52.1 g (0.87 mol) of urea was added, and after 120 min, 49.34 g (0.82 mol) of urea was added, and the mixture was allowed to react at a reaction temperature of 165° C.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[CH:15]1.CN(C)[CH:25]=[O:26].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[S:14]1[C:15]([CH:25]=[O:26])=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 68.9 %

Procedure:
Butyllithium (54 mL, 134 mmol) is added dropwise to a solution of N,N,N',N'-tetramethylethylenediamine (15.57 g, 134 mmol) in tetrahydrofuran under nitrogen at 0° C. The reaction mixture is treated dropwise with a solution of benzothiophene (15.00 g, 112 mmol) in tetrahydrofuran, warmed to room temperature, treated with additional N,N,N',N'-tetramethylethylenediamine (15.57 g, 134 mmol) and butyllithium (54 mL, 134 mmol), stirred at room temperature for 13 hours, cooled to 0° C. treated with N,N-dimethylformamide (24.40 g, 336 mmol), warmed to room temperature, stirred for five hours, poured into one molar hydrochloric acid and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to obtain an orange oil. Flash chromatography of the oil using silica gel and a 15% ethyl acetate in hexane solution gives the title product as an orange oil (12.51 g, 69%).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][C:29]1[S:33][C:32]2=[CH:34][N:35]=[CH:36][N:31]2[C:30]=1[CH3:37]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:32]4[S:33][C:29]([CH2:28][OH:27])=[C:30]([CH3:37])[N+:31]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: Cc1c(CO)sc2cncn12
Product: Cc1c(CO)sc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 6.4 %

Procedure:
The same procedure as in Example 1 was repeated except that 135 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 186 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 9.3 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5][CH2:4]1.[C:13]([NH:20][CH2:21][C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]([NH:20][CH2:21][C:22]([N:5]1[CH2:4][CH:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:23])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC1CNCc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC1CN(C(=O)CNC(=O)OC(C)(C)C)Cc2ccccc21
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 4-methoxy-1,2,3,4-tetrahydroisoquinoline (5.88 g, 36 mmol) in 100 mL of CH2Cl2 were added Boc-glycine (12.6 g, 72 mmol), 4-dimethylaminopyridine (8.80 g, 72 mmol), and dicyclohexyl carbodiimide (14.9 g, 72 mmol). After stirring overnight, the resulting precipitate was filtered and the filtrate was evaporated. A SiO2 chromatography (EtOAc:hexane=1:1) of the residue gave 4.9 g (43%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)O
Reactant: CCNCC
Product: CCN(CC)C(=O)CCCCCCNC(=O)OC(C)(C)C

Procedure:
Prepare by a method similar to Example 70 using 7-(t-butoxycarbonyl)amino-heptanoic acid and diethylamine.
Reaction SMILES: [CH:1]1[C:17]2=[C:18]3[C:8]([C:9]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.O.[Cl:20]([O-])(=O)=O.[K+].Cl>C(O)(=O)C>[Cl:20][C:3]1[CH:2]=[CH:1][C:17]2[C:16]3[C:11]([C:9](=[O:10])[C:8]4[C:18]=2[C:4]=1[CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2-c2ccc(Cl)c3cccc1c23
Reaction time: 2 h

Procedure:
A 10g amount of benzanthrone was dissolved in a solvent mixture of 100g acetic acid and 100 g of water. 6 g of potassium chlorate was added to the solution and the mixture was heated and stirred at 90°-95° C for 2 hours. 12 g of conc. hydrochloric acid was added dropwise to the mixture during 1 hour and 20 minutes. After the addition, the mixture was stirred for 1 hour to complete the reaction. The reaction mixture was cooled, filtered, washed with water and dried. The product was recrystallized from chlorobenzene to obtain 3-chlorobenzanthrone having a melting point of 179°-190° C (orange needle crystals).
Reaction SMILES: [CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C:13]3[N:18]=[C:17]([C:19]#[N:20])[C:16]([O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.N.[OH:31]O>CO.C(Cl)Cl>[CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C:13]3[N:18]=[C:17]([C:19]([NH2:20])=[O:31])[C:16]([O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: CSc1ccc(Oc2ccc(C(=O)N3CCCN(C4CC4)CC3)nc2C#N)cc1
Reactant: OO
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CSc1ccc(Oc2ccc(C(=O)N3CCCN(C4CC4)CC3)nc2C(N)=O)cc1
Reaction time: 1.5 h
Yield: 26 %

Procedure:
A mixture of 6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carbonitrile (171.0 mg), 28% aq. NH3 (5 mL), and 30% aq. H2O2 (1.0 mL) in MeOH (4.0 mL) was stirred for 1.5 h. The mixture was diluted with DCM and washed with satd. aq. Na2S2O3. The organic layer was dried and concentrated. The residue was purified by reverse-phase HPLC followed by FCC to give the title compound (46.4 mg, 26%). MS (ESI): mass calcd. for C22H26N4O3S, 426.17; m/z found, 427.8 [M+H]+. 1H NMR (d6-acetone): 7.74-7.72 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (br s, 1H), 7.51-7.49 (dd, J=8.5, 1.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.82 (br s, 1H), 3.71-3.68 (m, 2H), 3.65-3.61 (m, 2H), 2.93-2.88 (m, 2H), 2.85-2.80 (m, 2H), 2.49 (s, 3H), 1.96-1.80 (m, 3H), 0.46-0.44 (m, 1H), 0.42-0.40 (m, 1H), 0.37-0.36 (m, 1H), 0.32-0.30 (m, 1H).
Reaction SMILES: C12C[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]O2.[CH:10]([CH:12]=[CH2:13])=[O:11].C=CC(=C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Mg]Br.CCCCCCC([OH:50])CC>CCOCC>[CH3:8][C:5]1[CH2:6][CH2:7][CH:13]([CH2:12][C:10]([OH:50])=[O:11])[CH2:3][CH:4]=1
Reactant: C=CC=O
Reactant: C1CC2CCC(CC2)O1
Reactant: CCCCCCC(O)CC
Agent: C[Mg]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CC(=C)C
Solvent: CCOCC
Product: CC1=CCC(CC(=O)O)CC1

Procedure:
When m is 1, n is 2 and p is 2, the ring system is a 2-oxabicyclo[3.2.2]nonane, another subclass of this invention. For example, compound XVp ##STR30## in which R2, R5 and R6 are methyl can be prepared by treating a Diels-Alder adduct of acrolein and isoprene with Ph3P=C(CH3)OCH3, hydrolyzing the resulting enol ether, treating the resulting ketone derivative with methyl magnesium bromide, and subjecting the resulting alcohol to epoxidation-cyclization to yield a 2-oxabicyclo[3.2.2.]nonan-7-ol, which is treated with WCH2X in which X is a halogen atom to yield the desired ether, XVp. Alternatively, 4-methyl-3-cyclohexene-1-acetic acid, as obtained by the method of Kugatova-Shemyakina et al., Chemical Abstracts, 65:10504c (1966) is treated with methyl Grignard followed by epoxidation-cyclization of the resulting alcohol to yield a 2-oxabicyclo[3.2.2]nonan-7-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:32]([CH3:34])[CH3:33])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:31])[CH2:23][C@@H:24]([OH:30])[CH2:25][C:26]([O:28]C)=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+:36]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:32]([CH3:34])[CH3:33])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:31])[CH2:23][C@@H:24]([OH:30])[CH2:25][C:26]([O-:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[Na+:36]
Reactant: COC(=O)C[C@H](O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Reaction time: 0.08 h

Procedure:
A solution of methyl (3R,5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoate (34.4 mg) in dry THF (2 ml) was treated with aqueous sodium hydroxide solution (0.1M 0.660 ml). After 5 minutes, the solution was concentrated and the aqueous residue was diluted with water (9 ml) and the solution washed with ethyl acetate (4×). The solution was briefly evaporated and then freeze-dried to give the title compound (29.2 mg) as a white fluffy solid, [α]20 +16.7° (c 0.4, H2O); δ(D2O) 1.20-1.55, 1.55-1.85 (m, 2H, CH(OH)CH2CH(OH)), 1.34 (d, J 7 Hz, 6H, CH(CH3)2), 2.26 (d, J 7 Hz, 2H, CH2CO2Na), 3.30 (septet, J 7 Hz, 1H, CH(CH3)2), 3.67 (m, 1H, =CHCH(OH)CH2CH(OH)), 4.35 (m, 1H, CH=CHCH(OH)), 5.61 (dd, J 14 and 7 Hz, 1H, NCH=CH), 6.75 (d, J 14 Hz, 1H, NCH=CH), 7.01 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-(4-fluorophenyl)), 7.1-7.4 (m, 6H, aromatics).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:8]=2[N:7]=1
Reactant: COCCCc1nc2cccc(C(=O)OC)c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Product: COCCCc1nc2c(C(=O)OC)cccc2n1COCC[Si](C)(C)C

Procedure:
Analogously to Example 228e, 4.3 g of methyl 2-(3-methoxypropyl)-3-H-benzoimidazole-4-carboxylate and 3.54 ml of (2-chloromethoxyethyl)trimethylsilane are reacted. The title compound is obtained as a brown solid. Rf=0.33 (95:5 dichloromethane-methanol); Rt=4.26.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O.C1COCC1.CO>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Methyl 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylate (0.9 g, 3 mmol) was treated with the mixture of 2 M of sodium hydroxide in water (10 mL), THF (10 mL) and methanol (10 mL) at 50° C. for 1 h. After being neutralized with concentrated HCl (pH=3), the solution was concentrated. The resulting residue was azeotropically treated with benzene for 3 times to give the title compound which was used for the next reaction without purification. MS (M+H) 274.1.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:16])[CH3:15]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:16][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCN
Product: CCNC(=O)c1ccc(C(C)(C)C)cc1
Yield: 97 %

Procedure:
4-t-Butyl-N-ethylbenzamide (9 g, 0.044 mol) was prepared in 97% yield from 4-t-butylbenzoyl chloride (9 ml, 0.045 mol) and ethyl amine (70 wt % in water) using Method E2.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClC(Cl)C.C(O)(C)(C)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:8]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:3]=[C:2]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[S:10][C:9]=34)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ccnc2cc(Br)sc12
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: c1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Temperature: 85 °C
Yield: 38 %

Procedure:
In a sealed tube 2-bromo-7-chloro-thieno[3,2-b]pyridine (1.01 g, 4.08 mmol) was dissolved in 15 mL of dichloroethane and 15 mL of t-butylalcohol. 5-Amino-indole (540 mg, 4.08 mmol) was added, the tube was sealed, and the contents were heated at 85° C. for 36 hours. The solution was cooled and filtered, the solid washed with methylene chloride, and dried in vacuo to afford 1.96 g of crude product. A portion of the material (100 mg, 0.29 mmol) was coupled with benzeneboronic acid in a procedure analogous to example 2 to afford 37.1 mg (38%) of (1H-indol-5-yl)-(2-phenyl-thieno[3,2-b]pyridin-7-yl)-amine. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 8.69 (s, 1H), 8.15 (d, 1H), 7.78 (m, 3H), 7.41 (m, 6H), 6.98 (d, 1H), 6.53 (d, 1H), 6.41 (s, 1H); LC-MS: 342 (MH+); HPLC RT: 4.81.
Reaction SMILES: O.[C:2]1([CH3:8])C=CC=CC=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:18])=[O:17])=[CH:12][C:11]=1[N+:19]([O-])=O.C1(C)C=CC(S(O)(=O)=[O:29])=CC=1>C(O)CO>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH3:18])[O:29][CH2:2][CH2:8][O:17]2)=[CH:12][C:11]=1[NH2:19]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCO
Product: Cc1ccc(C2(C)OCCO2)cc1N
Yield: 94 %

Procedure:
To a flask mounted with Dean-Stark water removing apparatus (Dean-Stark trap) were added toluene (200 ml), 4-methyl-3-nitroacetophenone (9.77 g, 54.53 mmol), ethylene glycol (4.6 ml) and p-toluenesulfonic acid.monohydrate (0.79 g), and the mixture was heated under reflux for 100 min. The reaction mixture was cooled, washed with diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a crude brown oil (13.0 g). Using the crude oil and according to the method of Reference Example 61, step B, the title compound (9.89 g, yield 94%) was obtained as a pale-yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[S:18][C:17]3=[CH:19][N:20]=[CH:21][N:16]3[CH:15]=2)[CH2:11][C@@H:10]([O:23][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C.O>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[S:18][C:17]3=[CH:19][N:20]=[CH:21][N:16]3[CH:15]=2)[CH2:11][C@@H:10]([OH:23])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2cncc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1cn2cncc2s1
Reaction time: 0.33 h

Procedure:
Concentrated hydrochloric acid (0.85 ml) is added dropwise to a solution of 899 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine in 20 ml of dry acetonitrile under ice cooling, and the mixture is stirred at that temperature for 20 min. The reaction solution is diluted with 50 ml of ethyl acetate, water is added thereto, and the mixture is rendered weakly alkaline by addition of a saturated aqueous sodium hydrogencarbonate solution. The mixture is then extracted three times with ethyl acetate, and the organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate and filtered. The solvent is removed by evaporation under reduced pressure to give a crude product of (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine. Triethylamine (0.46 ml) and 0.24 ml of methanesulfonyl chloride are successively added to a solution of this compound in 20 ml of THF, and the mixture is stirred under an argon stream at −14° C. for 50 min. Water is added to the reaction solution, and the mixture is extracted four times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 472.6 mg of (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]-3-methanesulfonyloxypyrrolidine (a diastereomer mixture) as a yellow viscous material.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2cc(I)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(I)cc21
Yield: 77.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 130 mg 5-iodo-2-oxindole, and 75 L piperidine in 2 mL ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 162 mg (77%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:39]([C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)(=[O:41])=[O:40])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene sulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 1.25 (s, 9H, 5.76 (s, 2H, 7.05-7.15 (m, 4H, 7.20-7.30 (m, 5H, 7.30-7.45 (m, 3H, 7.50-7.60 (m, 5H; MS (ESI) m/z 537 [M-H]−; HRMS calcd for C32H31N2O4S: 539.2002; found (ESI+): 539.1999.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH:18]=O)[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12.[CH3:20][NH:21][CH3:22].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH2:18][N:21]([CH3:22])[CH3:20])[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12
Reactant: CNC
Reactant: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture of the aldehyde 111 (344 mg, 1.18 mmol) and dimethylamine (0.7 mL, 1.41 mmol) in methanol (24 mL) and acetic acid (few drops) were stirred at RT overnight. Sodium cyanoborohydride (237 mg, 3.77 mmol) was added and the reaction mixture was allowed to stir at room temperature until completion of the reaction. The solvents were evaporated and water was added to the residue and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 2.5% MeOH/97.5% DCM to 10% MeOH/90% DCM) to afford title compound 112 as a yellow solid (129 mg, 34% yield). MS (m/z): 321.1 (M+H).