Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]([O:20][CH3:21])[C:11]=1[CH2:22][CH:23]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:26]([NH:25][CH2:23][CH2:22][C:11]1[C:12]([O:20][CH3:21])=[N:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CC=O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A mixture of [4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridin-3-yl]acetaldehyde (1.55 g, 4.26 mmol), aminodiphenylmethane (1.11 mL, 6.40 mmol), and powdered molecular sieves (4 Å, 2.80 g) in DCM (20 mL) was stirred for 30 min. Then sodium triacetoxyborohydride (132 mg, 0.625 mmol) was added. The resulting mixture was stirred overnight, diluted with DCM, filtered, and washed with sat. aq. Na2CO3. The layers were separated, and the aq. solution was extracted with DCM. The combined DCM layers were dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, 100% DCM) to yield N-benzhydryl-2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridin-3-yl]ethanamine (1.42 g, 62.8%). 1H NMR (CDCl3, 400 MHz): δ 7.48 (s, 1H), 7.18-7.38 (m, 10H), 4.84 (s, 1H), 4.78 (s, 2H), 3.81 (s, 3H), 2.77 (m, 4H), 1.62 (br s, 1H), 0.97 (s, 9H), 0.12 (s, 6H). LC-MS calc. for C29H37F3N2O2Si: 530.26; Found: 531 (M+H).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([Br:16])=[CH:11][C:10]=1[CH3:17])C.O1CCCC1.C(O)C>O>[Br:16][C:12]1[CH:11]=[C:10]([CH3:17])[C:9]([O:8][CH2:7][CH2:6][OH:5])=[C:14]([CH3:15])[CH:13]=1
Reactant: CCOC(=O)COc1c(C)cc(Br)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
Sodium borohydride (0.206 g) was added to a mixture of ethyl(4-bromo-2,6-dimethylphenoxy)acetate (0.782 g), tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to afford the title compound (0.645 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(OCC)C>[N:15]1([CH2:2][CH2:3][C:4]2[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]([NH:9][C:10](=[O:11])[C:5]=23)=[O:8])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCN3CCOCC3)cccc21
Temperature: 25 °C
Yield: 52.1 %

Procedure:
2-Bromoethylphthalimide (508 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). The mixture was allowed to stir at room temperature for 30 hours approx. The reaction was discontinued by solvent evaporation under reduced pressure. The obtained residue was purified by chromatography on silica gel (CH2Cl2 /MeOH 95:5) yielding 271 mg of pure product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=C(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Yield: 41.8 %

Procedure:
A stirring mixture of Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate (50 mg, 0.091 mmol) dissolved in dioxane (5 mL) was hydrogenated using an H-Cube hydrogenator (10% Pd/C, 30×4 mm, full hydrogen, 40° C., 1 mL/min). The reaction mixture was concentrated in vacuo to afford 21 mg (29%) of methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)propanoate as a yellow solid. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.7. found 553.0 [M+H]+, tR=1.85 min. (Method 8).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[C:8]2[N:13]([C:14]=1[Br:15])[N:12]=[CH:11][N:10]=[C:9]2[NH2:16])=[O:5])[CH3:2].C(N(CC)CC)C.C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=2)C=CC=CC=1>C1COCC1>[NH2:16][C:9]1[C:8]2=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:38]([NH:39][C:40]4[CH:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[CH:43]=[CH:42][N:41]=4)=[O:37])=[CH:21][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([Br:15])[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(N)cc2)c2c(N)ncnn2c1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1Br
Temperature: 70 °C
Yield: 88.8 %

Procedure:
Ethyl-4-amino-5-(4-aminophenyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.5 g, 3.99 mmol) was suspended in THF (20 mL) and treated with triethylamine (0.56 mL, 3.99 mmol) and phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (1.13 g, 3.99 mmol). The mixture was heated to 70° C. for 18 h. After cooling to rt, the mixture was concentrated then suspended in EtOAc. The product was collected by filtration to give 2.0 g of a tan solid (89%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H) 9.75 (s, 1H), 8.53 (d, J=5.4, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.60 (d, J=11, 2H), 7.37-7.31 (m, 3H), 5.15 (bs, 2H), 4.04 (q, J=7.1, 2H), 0.99 (t, J=7.2, 3H); MS [M+H]+=563.9, 565.9; LCMS RT=3.22.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26]O)=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].S(Cl)([Cl:31])=O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][Cl:31])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(c1ccc(C)c2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 1 h
Yield: 93 %

Procedure:
N-Ethyl-N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}thiophene-2-sulfonamide (0.27 g) was dissolved in absolute tetrahydrofuran (10 ml). This solution was ice-cooled, thionyl chloride (0.080 ml) and N,N-dimethylformamide (one drop) were added, and the mixture was stirred for 1 hr under ice-cooling, and then at room temperature for 2 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil was crystallized from ethyl acetate-hexane to give the title compound (0.26 g, yield 93%) as pale-yellow prism crystals. melting point 177-178° C.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[N-:8]=[N+:9]=[N-:10].[Na+].CC(C)=O>O>[N:8]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7])=[N+:9]=[N-:10]
Reactant: C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1CCCCC1O
Temperature: 75 °C

Procedure:
A solution of cyclohexene oxide (10.1 g, 103 mmol) and sodium azide (16.7 g, 257 mmol) in 100 mL of a 1:1 mixture of acetone:water was heated to reflux at 75° C. for 14 h. The mixture was cooled to rt, concentrated in vacuo to 50 mL, and extracted 3× with dichloromethane. The combined organic fractions were washed 2× with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-azidocyclohexanol that gave a proton NMR spectra consistent with theory.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[O:22][CH:23]=2)[N:3]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[O:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: OC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(SCc2coc(-c3ccc(Cl)cc3)n2)nc(N2CC(O)C2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.170 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 37 mg (0.340 mmol) of azetidin-3-ol hydrochloride and 44 mg (0.340 mmol) of N-ethyl-N-(1-methylethyl)propan-2-amine, were dissolved in 1 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 40 mg (46% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[N:12]1([CH2:18][CH2:19]O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:19][CH2:18][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: OCCN1CCOCC1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(Br)cn2CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.860 mmol), 2-(4-morpholinyl)ethanol (0.316 mL, 2.58 mmol) and triphenylphosphine (451 mg, 1.721 mmol) was added Tetrahydrofuran (THF) (5 mL). To the reaction was then added by dropwise DEAD (0.272 mL, 1.721 mmol). The solution was then let stir overnight at room temperature. The reaction was then concentrated and diluted with water (10 ml) then extracted by EtOAc (3×10 ml). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated. The yellow crude residue was then loaded onto a 25 g Biotage SNAP column and purified with 0 to 8% MeOH in DCM gradient over 30 minutes to afford 5-bromo-4-chloro-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (245 mg, 82% yield) as a light yellow solid. LC-MS (ES) m/z=347.2 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.05 (s, 1H), 4.39 (t, J=6.19 Hz, 2H), 3.48 (t, J=4.29 Hz, 4H), 2.71 (t, J=6.32 Hz, 2H), 2.42 (br. s., 4H).
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][S:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:5]4[CH:4]=[C:3]([CH2:1][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[S:7][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)[CH2:21][CH2:22]1)(=[O:27])=[O:28]
Reactant: C1CCNC1
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.9 %

Procedure:
To 5-(5-formyl-3-thienyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.08 mmol) in a mixture of dichloromethane (1.25 mL) and methanol (0.5 mL), pyrrolidine (0.07 mL, 0.8 mmol) and 2 drops of acetic acid were added. After the reaction mixture was stirred at room temperature for 6 hours, NaBH4 (30.26 mg, 0.8 mmol) was added. Then the reaction mixture was stirred at room temperature for 30 minutes. All the solvent was evaporated and purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) to give title compound (6.5 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH:8]([CH3:11])[CH2:7][C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].[C:17](O)(=O)C.[CH:21]([NH2:23])=[NH:22]>C(O)CCC>[CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[C:8]([CH:7]([CH3:17])[CH2:6][C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15])=[CH:11][N:23]=[CH:21][N:22]=3
Reactant: CC1CC(=O)C2=C(C1)C(C)(C)C(C)C2(C)C
Reactant: CC(=O)O
Reactant: N=CN
Solvent: CCCCO
Product: CC1CC2=C(c3ncncc31)C(C)(C)C(C)C2(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 1,1,2,3,3,6-hexamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (prepared as described in U.S. Pat. No. 3,927,083) (10 g, 0.045 mol), formamidine acetate (23 g, 0.22 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 1,1,2,3,3,5-hexamethyl-2,3,4,5-tetrahydro-1H-7,9-diaza-cyclopenta[a]naphthalene (˜5 g) is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:4](=[C:6]([C:8](=[CH:10][CH:11]=1)[CH3:9])[CH3:7])[CH3:5].[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19].[Na]>>[CH3:5][C:4]1[C:3]([CH3:2])=[CH:11][CH:10]=[C:8]([CH3:9])[C:6]=1[CH2:7][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1ccc(CBr)c(C)c1C
Agent: [Na]
Product: Cc1ccc(C)c(CSc2cccc[n+]2[O-])c1C
Yield: 50 %

Procedure:
The intermediate 2-(2,3,6-trimethylphenylmethylthio)pyridine N-oxide is prepared from α2 -bromoprehnitene with 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Yield 50% theory. Melting point 108° - 110° C. Structure confirmed by IR and NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[N:11][N:12]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:21]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:23])[CH3:22])=[N:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nnco2)cc1
Reactant: CC(=O)c1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1nnc(-c2ccc(F)cc2)o1
Reaction time: 0.33 h
Yield: 4 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-1,3,4-oxadiazole (0.8 g, 2.4 mmol) in THF (10 mL) was added LDA (2.9 mmol) at −78° C. (0.308 g, 2.9 mmol) and mixture was stirred for 20 min. A solution of 4-acetyl pyridine (0.377 g, 3.1 mmol) in THF (10 mL) was added at −78° C. and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), extracted with ethyl acetate (3×60 mL), washed with brine solution (60 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh; using 90% ethyl acetate in hexanes) to obtain 1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (combined yield for 2 batches: 0.051 g, 4% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 2H), 7.99 (t, 2H), 7.48 (d, 2H), 7.04 (d, 2H), 6.98 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for [M+H]+ 286.09, found 286.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.CO.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[O:12][CH:26]=[N:25][CH:24]=1)=[CH:5]2
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Product: Fc1ccc2[nH]c(-c3cnco3)cc2c1
Yield: 26 %

Procedure:
To a 100 mL round-bottom flask was added 5-fluoro-1H-indole-2-carbaldehyde 47 (0.627 g, 3.84 mmol), methanol (40 mL), p-toluene sulfonylmethyl isocyanide (0.826 g, 4.23 mmol), followed by potassium carbonate (0.68 g, 4.92 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq. NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (2×20 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-(5-fluoro-1H-indol-2-yl)oxazole 48 (0.202 g, 72% yield). MS (ES) m/z 203 (M+H+).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:25]([C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=1)[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Boc-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (2.35 g) was dissolved in CH2Cl2 (60 mL) and TFA (20 mL) was added. After stirring for 1 h at RT, the mixture was concentrated in vacuo to yield 2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine as an oil that solidified upon standing. The material was used as is without further purification.
Reaction SMILES: N[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.ClCC[S:21](Cl)(=[O:23])=[O:22].C([N:27]([CH2:30][CH3:31])CC)C>>[CH:2]([CH:3]1[CH2:4][C:5]2[C:31](=[CH:9][CH:8]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:6]=2)[CH:30]1[N:27]=[S:21](=[O:22])=[O:23])=[CH2:10]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCN(CC)CC
Product: C=CC1Cc2cc(C3=NNC(=O)CC3)ccc2C1N=S(=O)=O

Procedure:
2-Amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane was treated with chloroethanesulfonyl chloride in the presence of two equivalent amounts of triethylamine in the same manner as in Example 2 to obtain 2-vinyl sulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[C:24]([O:30]C(=O)CCCC)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]>O>[C:24]([OH:30])(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CCCCC(=O)OC(=O)CCCC
Agent: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: O
Product: CCCCC(=O)O

Procedure:
In a manner similar to Example 12, a mixture of 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and valeric anhydride were heated on the water bath to give 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine valerate (ester).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[S:11])[NH:7][C:6]=2[CH:5]=[C:4]([F:12])[C:3]=1[F:13].[H-].[Na+].[N+]([C:19]1[O:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=1)([O-])=O>O1CCCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][C:19]3[O:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=3)[NH:7][C:6]=2[CH:5]=[C:4]([F:12])[C:3]=1[F:13]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Fc1cc2[nH]c(=S)[nH]c2c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3c(F)c(F)c(F)cc3[nH]2)o1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
4,5,6-Trifluoro-1,3-dihydro-benzimidazole-2-thione (0.72 g, 3.52 mmol) is suspended into 40 mL of tetrahydrofuran under argon. Then, 0.3 g (7.1 mmol) of sodium hydride are added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.5 g, 3.5 mmol) is then added and the reaction mixture is stirred at room temperature for 88 h, upon which it is poured on 40 mL of ice-water and extracted 3 times with 60 mL of ethyl acetate. The organic extracts are combined, washed with 150 mL of brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is diluted into 50 mL of water and 100 mL of dichloromethane. The aqueous phase is extracted twice with 100 mL of dichloromethane. The organic extracts are combined, washed with 100 mL of water, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 30 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 100/0 to 98/2 v/v; rate: 30 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is taken up in diethyl ether and concentrated to dryness under reduced pressure. 0.28 g of 5-(4,5,6-trifluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow meringue. mp: 152° C.