Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Reactant: O=Cc1cccc(F)c1
Product: O=C(C=Cc1cccc(F)c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
[1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula N-4), 2.34 g and 3-fluorobenzaldehyde were reacted using non-critical variations of the teachings Example 15 to give 3-(3-fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=3-fluoro), 3.08 g, m.p. 176-177°.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([N:11]1[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]1=[O:18])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:3]([OH:19])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCC1)N1CC(OC)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
To a solution containing (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (1.42 g, 5.20 mmol) in tetrahydrofuran (10 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (273 mg, 6.4 mmol) in water (10 mL). The mixture was stirred at 25° C. for 2.5 h, it was then acidified with 2N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×30 mL). The combined organic layers was dried over magnesium sulfate and concentrated to afford (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid, (855 mg, 65%), as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (m, 2H), 1.36-1.88 (m, 9H), 3.78 (s, 3H), 3.95 (J=17.7 Hz, 2H), 4.54 (dd, J=4.5 Hz, 11.0 Hz, 1H), 5.16 (s 1H), 12.80 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), 5-hydroxy-2-methylindole (74 mg, 0.5 mmol) and potassium carbonate (83 mg, 0.6 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling to ambient temperature, water (20 ml) was added. The precipitate was collected by filtration, washed with water and dried under vacuum at 60° C. to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (80 mg, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:42][O:43][CH2:44][CH2:45]Br>CN(C=O)C.O>[CH3:42][O:43][CH2:44][CH2:45][O:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: COCCBr
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
5-[1-(4-Hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (24.7 mg, 0.049 mmol) was dissolved in 1 mL of dry DMF. To the DMF solution was added Cs2CO3 (31.9 mg, 0.098 mmol), followed by methoxyethyl bromide (9.6 mg, 0.07 mmol). The mixture was stirred at 60° C. for 16 h and then diluted with water. It was extracted with EtOAc and the combined EtOAc extracts were washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (0-100% gradient CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc) to afford the title compound (21 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Oc1cc(Br)c2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cc(Br)c2[nH]ccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Combine 7-bromo-5-hydroxy-1H-indole and 0.2 N NaOH (1.1 eq.) in THF. Cool to about 0° C. before adding benzenesulfonyl chloride (1.10 eq.). Allow the reaction mixture to warm to ambient temperature. After 8 hours, pour into ethyl acetate, wash with water, dry the organic layer over Na2SO4 and concentrate. Purify to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH2:18]2)[CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[K+].O.[N:34]#[C:35]Br>CO>[CH2:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[CH2:21][CH2:22][CH2:23][N:17]1[C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:35]([NH2:34])=[N:1]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC1=N[C@@H](CCc2cc(N3CCCc4ccccc4C3)nc3ccccc23)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
To the stirred mixture of (2S)-2-amino-4-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]butan-1-ol (110 mg, 0.3 mmol), potassium acetate (90 mg, 0.91 mmol), methanol (8 mL) and water (2 mL) was added a solution of cyanogen bromide (32.3 mg, 0.3 mmol) in cold methanol (2 mL) at 0° C. After the addition, the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a residue which was purified by preparative HPLC to give 40 mg of product as a white solid (yield was 34.5%). MS obsd. (ESI+) [(M+H)+] 387. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J=7.2 Hz, 1 H), 7.56-7.43 (m, 3 H), 7.17-7.04 (m, 4 H), 5.91 (brs, 1 H), 4.84 (s, 2 H), 4.21 (t, J=8.0 Hz, 2 H), 4.13 (brs, 2 H), 3.87 (t, J=7.2 Hz, 1 H), 3.77 (t, J=7.2 Hz, 1 H), 3.01 (brs, 2 H), 2.94-2.89 (m, 1 H), 1.78 (brs, 2 H), 1.72-1.67 (m, 2 H).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.Cl>ClCCl.C(OCC)(=O)C>[C:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Heptanoyl chloride was added to a suspension of aluminum chloride in dichloromethane. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of indole in dichloromethane. The mixture was stirred at room temperature for 1 hour and poured into a mixture of hydrochloric acid and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ether to give 3-heptanoylindole as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13].C(OCC)(=O)C>CO.[Pd]>[NH2:13][C:5]1[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(N)c1N

Procedure:
2-Amino-3-nitro-benzoic acid methyl ester (50.7 g, 258.7 mmol) was suspended in methanol (441 ml) and ethyl acetate (441 ml) with palladium-on-active charcoal 10% (1.93 g, 1.81 mmol). The suspension was hydrogenated at room temperature under an H2 pressure of 2.5 bar. When the reaction was complete, the suspension was filtered over Celite and the residue was rinsed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and hexane (50 ml) was added. After addition of starting crystals, a precipitate precipitated out. Hexane (200 ml) was added to the suspension and the precipitate was filtered off, washed with hexane and dried in vacuo. Methyl 2,3-diaminobenzoate (D-01) was obtained (35.8 g, 83%).
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]=[C:23]=[S:24])=[O:21])=[CH:16][CH:15]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[C:41]=1[CH3:48].C1(C)C=CC=CC=1>C(O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]=[C:23]=[S:24])=[O:21])=[CH:18][CH:19]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:23]([NH:22][C:20](=[O:21])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[S:24])=[C:42]([CH3:47])[C:41]=1[CH3:48]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Methoxy-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were 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 (55 mg, yield 69%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([SH:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1.[CH3:23]I>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([S:18][CH3:23])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(S)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-mercapto-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (7.50 g), MeI (12.5 mL) in 1 M NaOH aqueous solution (100 mL) was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (5.75 g). This product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([S:68]([NH:71][CH3:72])(=[O:70])=[O:69])=[CH:64][CH:63]=1>CN(C=O)C>[CH3:72][NH:71][S:68]([C:65]1[CH:66]=[CH:67][C:62]([CH2:61][NH:60][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])=[CH:63][CH:64]=1)(=[O:69])=[O:70]
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CNS(=O)(=O)c1ccc(CN)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.05 g, 0.2 mmol) in DMF (10 mL) was added PyBOP (0.14 g, 0.30 mmol) and triethylamine (0.07 g, 0.6 mmol) at room temperature. After 15 minutes, 4-aminomethyl-N-methyl-benzenesulfonamide (0.04 g, 0.2 mmol) was added. After 5 hours, the mixture was quenched with water (30 mL) and diluted with ethyl acetate (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:13]=[C:14]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1.[O-]CC.[Na+]>C(O)C>[OH:5][C:4]([C:7]([F:9])([F:8])[F:10])([CH2:3][C:2]([CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH:13]=1)[CH3:11])[CH2:6][N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25](=[O:24])[CH:26]=[CH:27]1
Reactant: Oc1ccnc2ccccc12
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(C2(C)OCCO2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Temperature: 85 °C

Procedure:
A mixture of 2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-2-methyl-[1,3]dioxolane (0.514 g, 1.55 mmol), 4-hydroxyquinoline (0.433 g, 2.98 mmol), and sodium ethoxide (21 wt. % solution in ethanol, 0.55 mL, 1.49 mmol) in ethanol (4.2 mL) was heated at 85° C. for 14 hours, cooled to room temperature, quenched with water, and concentrated in vacuo to remove most of the ethanol. The residue was diluted with half saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes as the eluent. The product-rich fractions were concentrated in vacuo to afford 1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one. Yield: 0.35 g.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[BH4-].[Na+].Br[CH2:16][CH2:17][CH:18]1[O:24][C:23]([C:29]#[C:30][CH:31]2[CH2:33][CH2:32]2)([C:25]([F:28])([F:27])[F:26])[C:22]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:21]=2[NH:20][C:19]1=[O:39]>C1COCC1.C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:21]2[NH:20][C:19](=[O:39])[C@H:18]([CH:17]=[CH2:16])[O:24][C@:23]([C:29]#[C:30][CH:31]3[CH2:33][CH2:32]3)([C:25]([F:26])([F:27])[F:28])[C:22]=2[CH:34]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)OC1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1 h

Procedure:
To a room temperature solution of 409 mg (1.8 mmol) of 2-nitrophenylselenocyanate in 5.0 mL of THF was added 16 mL of ethanol and 90 mg of sodium borohydride. After stirring 1 h, a solution of 260 mg of rel-3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 8 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 2 h, at which time an additional 20 mg of sodium borohydride was added and stirring was continued for an additional 2 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 130 mg of the title compound as a pure solid: HRMS: Calcd. for C17H14NO2F3Cl (M+H)+ : 354.0508. Found: 354.0487.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([NH:21][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[S:19][CH:20]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2OCc2ccccc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3OCc3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A mixture of 0.5 g of 4-(2-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.29 g of p-toluenesulfonyl chloride was stirred for 2 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was chromatographed on 60 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated and yielded 0.28 g of N-[4-(2-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as a colorless, amorphous solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:46])[C:8]2[N:9]=[CH:10][N:11]([C:44]=2[N:45]=1)[C@@H:12]1[O:43][C@H:17]([CH2:18][O:19][C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:16])[C@H:13]1[OH:14])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:56]([CH2:58][CH2:59][O:60][CH2:61]Cl)#[N:57].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:46])[C:8]2[N:9]=[CH:10][N:11]([C:44]=2[N:45]=1)[C@@H:12]1[O:43][C@H:17]([CH2:18][O:19][C:20]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C@@H:15]([OH:16])[C@H:13]1[O:14][CH2:61][O:60][CH2:59][CH2:58][C:56]#[N:57])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(C)=O)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(C)=O)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
N2-Acetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (627 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and then 365 mg of dibutylstannyl dichloride (1.2 mmol) was added. And then, the reaction solution was reacted at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) guanosine (450 mg, yield 63%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[Si:29]([O:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[Si:29]([O:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:7]3[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:4][CH:3]=2)=[CH:45][CH:44]=1)(=[O:42])=[O:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1

Procedure:
Compound 2b was subjected to Suzuki coupling reaction conditions as described in Example 1, Step G, with (4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)sulfamoyl)phenyl)boronic acid to obtain compound 33a. Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H42N6O4SSi: 671.3 (M+H). Found 671.3.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:34][C:35]1[CH:40]=[C:39]([NH2:41])[CH:38]=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:35]1[CH:40]=[C:39]([NH:41][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:16][CH:15]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Reactant: Cc1cc(N)ccn1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccc(-c3noc(C(F)(F)F)n3)cc2)ccn1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To compound 12b, 4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzoic acid, (40 mg, 0.155 mmol) in DMF (516 μL) was added TFFH (82 mg, 0.310 mmol), 2-methylpyridin-4-amine (33.5 mg, 0.310 mmol) and DIPEA (81 μL, 0.465 mmol). The reaction was stirred at 50° C. for 1.5 h. The reaction mixture was subjected to purification by reverse phase prep-HPLC (gradient elution, water/MeCN both containing 0.1% TFA). Fractions containing the desired compound were combined and freeze-dried. The resulting material was dissolved in a mix of ACN/MeOH. They were loaded on a PL-HCO3 MP cartridge (from StratoSpheres™ SPE) and eluted with ACN (3 ml). The eluate was diluted with water (10 ml) and freeze-dried to yield the final compound.