Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1.I[CH2:32][CH3:33]>C(#N)C.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:32]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1)[CH3:33]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(O[C@@H]3CCCNC3)ccnc21
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN1CCC[C@@H](Oc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 50 °C

Procedure:
To a solution of (R)-4-(piperidin-3-oxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (84 mg, 0.20 mmol) in acetonitrile (1.0 mL) was added iodoethane (24 uL, 0.30 mmol), and the mixture was heated at 50° C. for 18 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow oil, which was used in the next step without any further purification (46 mg, 51%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31]Br)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl>C(O)C.[OH-].[Na+].O>[CH:20]1[C:21]2[CH:22]([CH2:24][O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[O:27])[C:23]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccccc1S
Reactant: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCCCSc1ccccc1C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of thiosalicylic acid (500 mg) in ethanol (15 ml) and 2N sodium hydroxide aqueous solution (3.2 ml) was added 3-(9-fluorenylmethoxycarbonylamino)-propyl bromide at ambient temperature and the suspension was stirred for 2 hours. The resulting clear solution was diluted with water (20 ml) and acidified with 1N hydrochloric acid (6.5 ml). White crystals were collected by filtration and the solid was washed with ethanol-water (1:3, 15 ml) and then with n-hexane - diethyl and either (2:1, 15 ml) to give 2-[3-(9-fluorenylmethoxycarbonylamino)-propylthio]benzoic acid (1.07 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6][OH:7].Cl[C:14]1[C:15]2[N:16]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:17]=[CH:18][N:19]=1>C(#N)C>[CH3:23][C:21]1[N:22]=[C:15]2[C:14]([O:7][CH2:6][C:5]3[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:4]=3[CH3:3])=[N:19][CH:18]=[CH:17][N:16]2[C:20]=1[CH3:24]
Reactant: Cc1cccc(C)c1CO
Reactant: Cc1nc2c(Cl)nccn2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(C)c1COc1nccn2c(C)c(C)nc12
Yield: 50 %

Procedure:
Sodium hydride (0.15 g, 3 mmol) (50% in oil) was added to a stirred solution of 2,6-dimethylbenzylalcohol in acetonitril (10 ml). 8-chloro-2,3-dimethylimidazo[1,2-a]pyrazine (0.4 g, 3 mmol) was added and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was solved in methylene chloride and washed with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethylacetate:petroleum ether(40-60) 1:1 as eluent. Crystallization from petroleum ether gave 0.42 g (50%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12]C(=O)C)[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[ClH:16]>>[NH2:12][C:5]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:11][CH:3]([C:2]3=[O:1])[CH2:4]1)[CH2:6]2.[ClH:16]
Reactant: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: Cl
Product: NC12CC3CC(C1)C(=O)C(C3)C2

Procedure:
A solution of N-(4-oxoadamantan-1-yl)acetamide (1A) (20 mmol) in 200 mL of concentrated, aqueous HCl was heated in a sealed pressure tube at 130° C. for 20 h. The solvent was removed under reduced pressure to give amine 1B as an HCl salt in 90% yield as an off-white solid. Data: LC/MS (ESR) m/z 166 [M+1]+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)C>C1COCC1.C(OCC)(=O)C>[CH3:21][N:19]([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:22])[CH2:2][C:1]#[N:3])=[CH:18][CH:17]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.9 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 14.3 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of 4-dimethylamino-benzoic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is diluted with ethyl acetate and then extracted with 10% NaOH(aq). The aqueous layer is acidified (pH 6-7) with a 1 M HCl(aq) solution affording a white precipitate. The precipitate is filtered and washed with water. The filtrate is then extracted ethyl acetate. The organic layer is concentrated in vacuo. The organic extraction yields very little of the expected 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile, however, the precipitate isolated from the acidification of the original aqueous layer is indeed the desired 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile. Upon drying the precipitate in vacuo, the desired 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile is isolated as a light brown solid in the amount of 3.295 gms. (68% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][N:3]=1.[CH3:24][C:25]1[N:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:32][CH2:31][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[N:30]=3)=[O:14])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][N:3]=1
Reactant: Cc1cccc(CN)n1
Reactant: Nc1ncc(C2CCOCC2)cc1-c1ccc(C(=O)O)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CNC(=O)c2ccc(-c3cc(C4CCOCC4)cnc3N)cc2F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a vial were charged with 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (20 mg, 0.063 mmol), (6-methylpyridin-2-yl)methanamine (11.6 mg, 0.095 mmol), DIEA (28 μL, 0.158 mmol), PyBOP (65.8, 0.126 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 10 min. The reaction mixture was then purified by preparative HPLC, and product fractions were combined, frozen and lyophilized to afford 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-((6-methylpyridin-2-yl)methyl)benzamide as a white powder. LCMS (m/z) 421.3 (MH+) 0.41 min. 1H NMR (DMSO-d6) δ ppm 8.99 (d, J=3.1 Hz, 1H), 7.95-7.83 (m, 3H), 7.79 (t, J=7.6 Hz, 1H), 7.53 (d, J=11.7 Hz, 2H), 7.44 (dd, J=8.0, 1.4 Hz, 1H), 7.24 (d, J=7.4 Hz, 2H), 4.60 (d, J=5.5 Hz, 2H), 4.02-3.88 (m, 2H), 3.40 (td, J=11.2, 2.7 Hz, 3H), 2.88-2.71 (m, 1H), 2.51 (br. s., 3H), 1.82-1.58 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([CH3:13])[N:5]=1)=[C:2]=S.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@@:25]1([O:33][C:2]([NH:1][C:4]3[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([CH3:13])[N:5]=3)=[N:23][CH2:24]1)[CH2:26]2
Reactant: NCC1(O)CN2CCC1CC2
Reactant: Cc1cc(N=C=S)nc(C)c1C#N
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc(C)c1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To 6-isothiocyanato-2,4-dimethylnicotinonitrile (0.09 g, 0.48 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.17 mL, 1.19 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.11 g, 0.49 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.22 mL, 1.43 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2,4-dimethylnicotinonitrile (0.10 g, 0.32 mmol, 66% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.08 (s, 1H), 6.60 (s, 1H), 3.88 (d, J=10.38 Hz, 1H), 3.61 (d, J=10.38 Hz, 1H), 2.98 (s, 2H), 2.70-2.79 (m, 2H), 2.63-2.69 (m, 2H), 2.55-2.60 (m, 4H), 2.31-2.39 (m, 4H), 1.99 (s, 1H), 1.89 (s, 1H), 1.54-1.62 (m, 2H), 1.41-1.49 (m, 1H). MS (LC/MS) R.T.=0.78; [M+H]+=312.1.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: ClC1=NN(c2ccccc2)CC1
Solvent: ClCCl
Product: Clc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Yield: 36.9 %

Procedure:
3-Chloro-4,5-dihydro-1-phenylpyrazole (1.8 g) and 4-chloroaniline (3.8 g) were fused under N2 at 140° for 20 minutes. The melt was cooled and the solid dissolved in CH2Cl2, washed with 1% HCl (×3), water, dried (Na2SO4), then absorbed into silica and column chromatographed using first 1:1 petrol: ether and then ether to give the title product as a yellow powder (1.0 g), (37%), m.p. 144°-7°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
A solution of 2.0 g of 2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo [1,2-a][1,4]benzodiazepine in 50 ml of dioxan was treated with a solution of 0.62 g of sodium hydrogen carbonate in 18 ml of water and the mixture was stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with dichloromethane. The dichloromethane extracts were dried over magnesium sulphate and chromatographed over 100 g of silica gel. 1.7 g of the desired product were eluted with dichloromethane/ethanol mixtures containing 8 to 12% ethanol. After recrystallization from ethyl acetate/diethyl (sic) ether there were obtained 1.65 g of 8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C., which was converted into the hydrochloride (dec. above 300° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[OH:9])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OB(O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccccc1-c1cncc(Cl)n1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a mixture of 2,6-dichloropyrazine (1.00 g, 6.71 mmol), 2-hydroxyphenylboronic acid (972 mg, 7.05 mmol) and trans dichlorobis(triphenylphosphine) palladium (II) (471 mg, 0.671 mmol) were added acetonitrile (20 mL) and sodium carbonate (13.4 mL, 1.0 M in water, 13.4 mmol), and the resulting mixture was degassed by a nitrogen sparge. The reaction flask was equipped with a reflux condenser, then was placed in a pre-heated oil bath (75° C.) and was stirred rapidly. After 5 h, the reaction mixture was allowed to cool to room temperature, then was poured into water and extracted with EtOAc. The organic phase was separated and concentrated in vacuo. Purification by chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 207.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.64 (s, 1H), 9.11 (s, 1H), 8.53 (s, 1H), 7.85 (dd, J=8.0, 1.5 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:36])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](B(O)O)[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.OO.S(=O)(=O)(O)[OH:40]>[OH-].[Na+].O>[CH2:29]([NH:28][C:27]([NH:26][C:24]1[S:25][C:21]2[C:20]([OH:40])=[CH:19][C:18]([C:15]3[CH:16]=[N:17][C:12]([N:9]4[CH2:8][CH2:7][C:6]([CH3:36])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]4)=[N:13][CH:14]=3)=[CH:32][C:22]=2[N:23]=1)=[O:31])[CH3:30]
Reactant: O=S(=O)(O)O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(B(O)O)c2s1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(O)c2s1
Reaction time: 72 h
Yield: 78 %

Procedure:
A stirred suspension of [5-[2-(4-ethoxycarbonyl-4-methyl-1-piperidyl)pyrimidin-5-yl]-2-(ethylcarbamoylamino)-1,3-benzothiazol-7-yl]boronic acid (166 mg, 0.286 mmol) in aqueous NaOH solution (2 M, 1.3 mL) was treated with excess hydrogen peroxide (27.5% aqueous solution, 0.45 mL) and kept at rt for 3 days by which time LCMS showed complete reaction. The resultant mixture was diluted with water (30 mL) and acidified by the addition of a small amount of conc. sulfuric acid. The precipitated solid was collected by filtration, washed with water (10 mL) and dried in vacuo to give Compound 26 as a white solid (102 mg, 78% yield). 1H NMR (DMSO-d6): δ 10.37 (1H, s), 8.67 (2H, s), 7.37 (1H, s), 6.85 (1H, s), 6.77 (1H, t, J=5.86 Hz), 4.30 (2H, dt, J=13.75, 4.56 Hz), 3.36 (2H, ddd, J=13.34, 9.92, 3.07 Hz), 3.22 (2H, p, J=6.69 Hz), 2.04 (2H, dt, J=13.63, 3.69 Hz), 1.42 (2H, ddd, J=13.55, 10.29, 3.91 Hz), 1.22 (3H, s), 1.13 (3H, t, J=7.19 Hz). m/z: 457 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(CCC=O)cc1
Yield: 51.8 %

Procedure:
2.34 g (14.10 mmoles) of 3-(4-methoxyphenyl)-1-propanol were dissolved in 20 ml of dry dichloromethane and slowly added to a suspension of 4.56 g (21.15 mmoles) of pyridinium chlorochromate in 25 ml of dichloromethane. Once the reaction was completed, which was followed by thin layer chromatography, 3 ml of diethyl ether were added in portions and the mixture was filtered over celite. The ether phase was washed three times with water and left to dry over anhydrous sodium sulphate for an entire night. The 3-(4-methoxyphenyl)-propanal was purified by column chromatography using as eluent ethyl acetate: dichloromethane in increasing polarity, with 1.20 g of an oil being obtained (52% yield).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9])[NH2:2].C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>CO>[NH2:18][C:17]1[N:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH3:9])[N:2]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: Cc1cnccc1NN
Reactant: CCOC=C(C#N)C#N
Solvent: CO
Product: Cc1cnccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Hydrazinyl-3-methylpyridine (CAS no. 114913-51-8) (700 mg, 5.68 mmol) was suspended in MeOH (30 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (694 mg, 5.68 mmol) was added portionwise over 2 mins and the mixture stirred at ˜0° C. for 0.5 hours then heated at reflux for 2 hours. The mixture was allowed to cool and was then evaporated under reduced pressure to afford the crude 5-amino-1-(3-methylpyridin-4-yl)pyrazole-4-carbonitrile which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 2.09 (3H, m), 7.07 (1H, d), 7.87 (2H, m), 7.98 (1H, d), 10.22 (1H, s).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].[C:14](=O)([O-:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O:23]C(C)(C)C.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4](=[O:13])[C@H:5]([NH:6][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([OH:23])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(−)-2-phenylglycine methyl ester hydrochloride (2.17 g, 10 mmol) and di-t-butyl di-carbonate (2.62 g, 12 mmol) were combined in tetrahydrofuran (100 ml). Triethylamine (1.60 ml, 22 mmol) was added to the mixture via syringe at room temperature. The reaction mixture was stirred at room temperature overnight. The THF in reaction mixture was then removed in vacuum. Saturated aqueous NH4Cl and ethyl acetate were added to the mixture in a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated aqueous NH4Cl, dried over MgSO4, filtered and concentrated to give a white solid (3.08 g, crude product): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (d, J=8.1 Hz, 2H), 6.77 (m, 2H), 5.73 (br. s., 1H), 5.56 (br. s., 1H), 5.25 (d, J=6.6 Hz, 1H), 3.73 (s, 3H), 1.46 (s, 9H) LCMS (ESI) m/e 282.1 [(M+H)+, calcd for C14H20NO5 282.3].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[OH-].[K+].[C:17](=S)=[S:18]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:17]([SH:18])=[N:14][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: S=C=S
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine (18 g, 94.7 mmol) in ethanol (230 mL) and water (63 mL) was added KOH (5.63 g, 100 mmol), followed by CS2 (12 mL, 198 mmol). The mixture was stirred and heated to reflux for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1 N aqueous sodium hydroxide and the insolubles were filtered off. The filtrate was acidified to pH 2-3 with 1 N aqueous HCl. The resulting precipitate was collected, washed with water, and dried in vacuo to provide 17.7 g of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (80.5% yield): 1H NMR (DMSO-d6) δ 3.95 (s, 3H), 7.73 (d, 1H), 8.13 (s, 1H), 8.16 (d, 1H), 8.53 (s, 1H), 14.7 (s, 1H); MS (m/z) 233 [M+H]+.
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:22]1[CH:26]=[N:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[Cl:21])[CH3:10])C1C=CC=CC=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:8][C@H:9]([C@H:11]([N:22]1[CH:26]=[N:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[Cl:21])[CH3:10]
Reactant: CCOC(=O)c1ncn([C@H](CCc2cccc(Cl)c2Cl)[C@H](C)OCc2ccccc2)n1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncn([C@H](CCc2cccc(Cl)c2Cl)[C@H](C)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of ethyl 1-[(2S,3R)-2-(benzyloxy)-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxylate (103 mg) and iodotrimethylsilane (0.08 ml) in chloroform (4 ml) was stirred at room temperature for 2 hours. The mixture was poured into cold methanol and the whole was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with water, aqueous sodium bisulfite and sodium bicarbonate, successively, and dried. The residue left after evaporation of solvent was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (50:1) to give a gummy oil of ethyl 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxylate (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)c(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(F)c(F)c2)s1

Procedure:
prepared by reaction of 5-(3,4-difluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][CH2:13][CH2:14][Cl:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][CH2:13][CH2:14][Cl:15])[N:6]=[CH:5]2
Reactant: ClCCCBr
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: ClCCCn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
To a solution of 5-bromo-1H-indazole (3.0 g, 15 mmol) in DMSO (15 mL) was added 1-bromo-3-chloropropane (2.0 mL, 20 mmol) and K2CO3 (6.33 g, 45.9 mmol). The reaction was stirred at room temperature for 72 h; then the reaction was diluted with methylene chloride (100 mL) and washed with a 5% LiCl solution (4×). The organics were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (40 g ISCO column, hexanes/EtOAc, 95:5 to 65:35) gave the title compound (2.14 g, 51%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J=0.5, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.48-7.45 (dd, J=8.9, 1.8 Hz, 1H), 7.38 (d, J=8.9 Hz, 1H), 4.54 (t, J=6.4 Hz, 2H) 3.47 (t, J=6.0 Hz, 2H) 2.42-2.37 (m, 2H); ESI MS m/z 273 [M+H]+.