Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(N2C(S(CCC)(=O)=O)=NN=N2)[CH:6]=CC=C[CH:2]=1.[K].C[Si](C)(C)N[Si](C)(C)C.[CH:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1)=O.O>COCCOC>[CH:28](/[C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1)=[CH:2]\[CH2:1][CH3:6]
Reactant: CCCS(=O)(=O)c1nnnn1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: O
Solvent: COCCOC
Product: CC/C=C/[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-phenyl-5-propylsulfonyl-1H-tetrazole (3.34 g) and anhydrous ethylene glycol dimethyl ether (60 ml) at −60° C. was added 0.5 M hexamethyldisilazane potassium solution (in toluene, 26.6 ml), and the mixture was stirred for 30 minutes. Under the same condition, a solution of t-butyl trans-4-formylcyclohexylcarbamate (3.02 g) in anhydrous ethylene glycol dimethyl ether (15 ml) was added thereto and the reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added water, and the mixture was stirred for 1 hour, then extracted with diethyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.31 g of t-butyl trans-4-[(E)-1-butenyl]cyclohexyl-carbamate.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:3]=[O:4].C(O)(=O)C.[BH4-].[Na+].O>CO.C(OC)(C)(C)C>[CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][OH:4]
Reactant: CC(C=O)CC(C)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(CO)CC(C)Cc1ccccc1
Temperature: 20 °C
Yield: 99.8 %

Procedure:
Into a one liter flask equipped with a mechanical air stirrer, temperature probe, nitrogen inlet, autojack, and cooling bath was placed 50 mL methanol, 2,4-dimethyl-5-phenylpentanal (50.0 g, 0.26 mol), and acetic acid (11.0 g, 0.18 mol). To the stirred solution was added NaBH4 (70 g, 0.18 mol) in 50 mL of methanol over a period of two hours while maintaining the reaction temperature at 20° C. Water was then added until the all materials went into solution and 200 mL methyl t-butyl ether was then added. The organic phase was isolated, washed with three 50 mL portions of saturated NaCl solution, dried over magnesium sulfate, filtered, and rotovapped to give the product as a colorless liquid (49.9 g), odor—fresh, green herbal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[N:4]=[C:5]([S:26][CH3:27])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](O)[C:8]=1[F:16].FC1C([CH2:38][O:39][CH2:40][CH2:41][O:42][Si](C(C)C)(C(C)C)C(C)C)=CC(OC)=CC=1C=O>>[CH3:1][O:2][C:3](=[O:28])[N:4]=[C:5]([S:26][CH3:27])[C:6](=[N:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([CH2:38][O:39][CH2:40][CH2:41][OH:42])[C:8]=1[F:16]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(O)c1F
Reactant: COc1cc(C=O)c(F)c(COCCO[Si](C(C)C)(C(C)C)C(C)C)c1
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(COCCO)c1F

Procedure:
The same procedure was carried out as in Examples (163a) to (163b), except that 2-fluoro-5-methoxy-3-(2-triisopropylsilanyloxyethoxymethyl)benzaldehyde was used instead of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde in Example (163a), to give the title compound.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:42]([OH:44])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][C@H:36]([CH3:40])[CH2:35]1)=[CH:30][C:29]2=[O:41])[CH3:23].C(N(C(C)C)C(C)C)C.CNC>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:42]([N:7]([CH3:8])[CH3:6])=[O:44])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][C@H:36]([CH3:40])[CH2:35]1)=[CH:30][C:29]2=[O:41])[CH3:23]
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (2.38 g, 3.96 mmol) was added portionwise to 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (0.88 g, 2.64 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.380 mL, 7.92 mmol) suspended in DCM (15 mL) at 10° C. under nitrogen. The resulting mixture was stirred at RT for 2 hrs. Dimethylamine (3.96 mL, 7.92 mmol) was then added at 10° C. and the resulting mixture was stirred at RT overnight. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 0 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford a foam which crystallised from ethyl acetate, the solid was collected by filtration and dried to a constant weight in a vacuum oven to afford 8-(1-hydroxyethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (0.800 g, 84%) as a white solid. Mass Spectrum: M+H+ 361.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:17](CC3C=CC=CC=3)[CH:16]=[N:15][N:14]=2)[O:4]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[O:4]1
Reactant: CO[C@@H]1O[C@H](c2nncn2Cc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H](c2nnc[nH]2)[C@H]2OC(C)(C)O[C@@H]12
Reaction time: 24 h
Yield: 92.1 %

Procedure:
A solution of 3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-benzyl-4H-1,2,4-triazole (Preparation 19) (1.5 g, 4.5 mmol) in ethyl acetate (45 ml) and ethanol (5 ml) was hydrogenated over palladium black (0.4 g) at 2758 kPa (400 p.s.i) and 100 □C. for 24 hours. Additional palladium black (0.2 g) was then added and hydrogenation was continued for a further 72 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:7]=1)=[O:5])C.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CO>[CH2:21]([N:23]([CH2:24][CH3:25])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:7]=1)=[O:5])[CH3:22]
Reactant: CCNCC
Reactant: CCOC(=O)c1nc(C=Cc2ccc(OC)cc2)no1
Solvent: CO
Product: CCN(CC)C(=O)c1nc(C=Cc2ccc(OC)cc2)no1
Yield: 87.4 %

Procedure:
5-Ethoxycarbonyl-3-p-methoxystyryl-1,2,4-oxadiazole (1.25 g.) was suspended in dry methanol (5 ml.) and diethylamine (7.25 ml.) was added. The mixture was heated under reflux for 1 hour, when a solution was obtained. The solvent was removed under reduced pressure and the residual oil was dissolved in methanol and treated with charcoal. Evaporation of the filtrate left an oil, which was recrystallised from aqueous methanol to give the amide (1.199 g., 87.4%), m.p. 69°-70°, λmax. (EtOH) 225.5 300 (infl.) and 308 nm. (ε15400, 24400 and 25000), εmax. (CHBr3) 820 (C6H4), 970 (trans-CH=CH), 1650 (CO.N<),
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14](Cl)[C:13]3[N:20]=[C:21]([CH2:27][O:28][CH3:29])[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1.[OH-].[Na+].[BrH:32]>C(O)(=O)C>[Br:32][C:14]1[C:13]2[N:20]=[C:21]([CH2:27][O:28][CH3:29])[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=2[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCc1nc2c(Cl)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCc1nc2c(Br)nc3ccc(O)cc3c2n1CC(C)C

Procedure:
8-Benzyloxy-4-chloro-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline (2.73 g, 6.65 mmol) was stirred for 1 hour in 25 mL of 30% hydrogen bromide in acetic acid at 65° C. The reaction was cooled in an ice bath and aqueous NaOH (50%) was added to adjust the pH to 7. The precipitate was recovered by filtration and air dried to provide 2.75 g of 4-bromo-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-8-ol as a brown solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:11]1[CH:12]=[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottom flask cooled to 0° C., dry dimethylformamide (2 ml) was added. To the above mixture, compound tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2 ml) was slowly added at 0° C. After 30 min, 2-chloro-N,N-dimethylethylamine (200 mg) in DMF (1 ml) was added to the above mixture. Reaction mixture was allowed to stir at room temperature for overnight, quenched with ice and extracted with ethyl acetate. The organic layer was washed with water (10 ml), brine and dried over sodiumsulphate. The organic layer was filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using 6% Ethyl acetate in hexane as eluant afford tert-butyl 4-(1-(2-(dimethylamino)ethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate as half white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4]2[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][N:2]=1
Reactant: II
Reactant: N#Cc1cccc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cccc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 1H-indazole-4-carbonitrile (1.65 g, 11.1 mmol), KOH (1.86 g, 33.3 mmol), and I2 (5.6 g, 22.2 mmol) in DMF (30 mL) was stirred at RT overnight. The reaction mixture was filtered. The filtrate was diluted with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was concentrated in vacuo to afford 3-iodo-1H-indazole-4-carbonitrile as white solid (2.01 g, 64.7%). MS (ESI): m/z=270 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[F:11][C:10]1[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: C1CCNCC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1
Solvent: ClCCl
Product: NC(=O)c1cc(F)c(N2CCCCC2)nc1Nc1ccc(F)cc1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
A solution of 6-chloro-5-fluoro-2-(4-fluorophenylamino)nicotinamide (50 mg, 0.176 mmol) and piperidine (1 mL, 10.12 mmol) was sealed in a small microwave vial and heated in a heating block at 100° C. for 2 hrs. The reaction mixture was diluted with CH2Cl2 and washed with bicarbonate and water. The reaction mixture was concentrated and the dark crude material was chromatographed (ISCO Companion 40 g silica gel column and eluted with (90:9:1 CH2Cl2:MeOH: NH4OH)t/CH2Cl2 gradient (20-100%)) to give 50 mg of 5-fluoro-2-(4-fluorophenylamino)-6-(piperidin-1-yl)nicotinamide as a brown solid. LCMS: (M+H)+=333.21. 1H NMR (400 MHz, CDCl3) δ ppm 10.68 (1H, s), 7.52-7.57 (2 H, m), 7.22 (1H, d, J=14.06 Hz), 6.94-7.00 (2H, m), 5.47 (2H, br. s.), 3.64 (4H, d, J=6.15 Hz), 1.62-1.72 (6H, m).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[S:3])[NH2:2].[Br:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>C(O)C>[Br:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]2[N:2]=[C:1]([C@@H:4]3[CH2:8][CH2:7][CH2:6][N:5]3[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[S:3][CH:22]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=S
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)cs1
Yield: 84 %

Procedure:
A solution of (S)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (compound 11a, 2.2 g, 9.6 mmol) and 4-bromophenacyl bromide (2.9 g, 10.5 mmol) in ethanol (50 ml) was stirred at room temperature for 3 hours. The resulting mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered and concentrated to give crude product. The crude product was purified with column chromatography (ethyl acetate:n-hexane=1:3) to yield pure product 12a (3.3 g).
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:31])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]=3[NH2:29])=[CH:18][C:17]2=[O:30])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.O.[OH-].[Li+].Cl.O[C@@H:39](CO)CN1C=CC(NC(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=N1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1.O>[OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:31])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[C:23]4[N:29]=[CH:39][O:28][C:24]=4[CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17]2=[O:30])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(O)c2N)=CC1=O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc3ocnc23)=CC1=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 29.4 %

Procedure:
A solution of (S)-2-[4-(benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (prepared as in Example 241, 0.137 g, 0.40 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide monohydrate (0.033 g 0.77 mmol) and the resulting mixture stirred at room temperature for 1.25 h. The mixture was concentrated in vacuo and the residue treated with acetonitrile, and concentrated in vacuo (repeated 2 additional times). The residue was treated with N,N-dimethylformamide and to this mixture was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.156 g, 1.00 mmol), N,N-diisopropylethylamine (0.180 g, 1.39 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.616 g, 1.39 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 18 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with aqueous saturated ammonium chloride, brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18, 20×150 mm column, 30% to 100% acetonitrile/water) to afford (S)-2-[4-(benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.055 g, 31%) as a tan solid: HR-ES-MS m/z calculated for C24H29N5O5 [M+H]+ 468.2242, observed 468.224; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.36-1.64 (m, 2H), 1.68-1.86 (m, 1H), 3.89 (s, 2H), 4.25 (d, J=18.4 Hz, 1H), 4.65 (d, J=18.4 Hz, 1H), 4.68 (s, 1H), 4.86-4.95 (m, 1H), 4.88 (s, 1H), 6.45 (d, J=2.1 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 8.81 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].[OH-].[Na+]>Cl>[N:1]1([C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(=O)Cl
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)COC(=O)N1CCNCC1
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of piperazine (8.61 g, 0.1 mol) in 1M HCl (200 mL) at room temperature was treated with isobutyl chloroformate (13.66 g, 13 mL, 0.1 mol), adjusted to pH 3 with 1M NaOH over 1 to 2 hours, stirred for 18 hours, quenched with 4M KOH, and extracted with dichloromethane (2×100 mL). The combined extracts were dried (MgSO4), filtered, and concentrated to provide 10.9 g (59%) the desired product. MS (ESI(+)) m/e 187 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]#[N:19])[C:15]3[N:20]=[CH:21][N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:14]=3[CH:13]=2)=[CH:8][C:7]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:42][S:43]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]#[N:19])[C:15]3[N:20]=[CH:21][N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:14]=3[CH:13]=2)=[CH:8][C:7]=1[C:29]([F:31])([F:30])[F:32])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1nc(-c2ccc(OCCCO)c(C(F)(F)F)c2)cc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCCOc1ccc(-c2cc3c(ncn3C3CCCCO3)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (670 mg) and DIPEA (1.4 ml) in NMP (7.5 ml) at 0° C. was added methanesulphonyl chloride (0.2 ml). The mixture was allowed to stir for 45 minutes at room temperature, then diluted with EtOAc (75 ml) and washed with saturated sodium bicarbonate (70 ml), followed by water (2×40 ml). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure to yield 3-(4-(4-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl methanesulfonate (720 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2cc(Cl)cc(Cl)c2)s1)OC

Procedure:
3.8 grams (0.032 mole) of methylaminoacetaldehyde dimethylacetal was added to a 50 milliliter benzene solution containing 10.0 grams (0.032 mole) of the 5-[1-(3,5-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was heated to reflux, 50 milliliters of hexane was added, and the solution cooled. The crystals were filtered off, and dried in a vacuum oven at 80° C. to give 7.9 grams of fluffy waxy crystals of 3-[5-[1-(3,5-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 149°-152° C.).
Reaction SMILES: C[O-].[Na+].[CH:4]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[O:5].[BH4-].[Na+].Cl>CO>[OH:5][CH2:4][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)Oc1cccc(C=O)c1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COC(=O)C(C)Oc1cccc(CO)c1
Temperature: 5 °C
Yield: 91.2 %

Procedure:
Into 100 ml of methanol was dissolved 52 mg of sodium methoxide; the solution was cooled to 5° C. To the solution was added 1 g of methyl 2-(3-formylphenoxy)propionate was added; after adding 55 mg of sodium borohydride below 8° C. under stirring, the mixture was stirred for 2 hours at the same temperature. The reaction solution was poured into ice-cooled 2N hydrochloric acid and the mixture was extracted twice with diethyl ether. The organic layers were combined, washed once with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure to give 0.921 g of methyl 2-[3-(hydroxymethyl)phenoxy]propionate.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Ni]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 320.5 %

Procedure:
To a solution of methyl 2-chloro-3-nitrobenzoate (25 g, 116 mmol) in MeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H2 atmosphere (50 psi at 25° C.) for 3.5 h. The catalyst was filtered, and the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc to afford the title compound (69 g, 83.5% yield, four batches combined). 1H NMR (400 MHz, CDCl3) δ ppm 6.70-7.25 (m, 3H), 4.40-4.50 (br, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([C:9]([O-])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:15])=O>>[Cl:15][C:9]([C:3]([O:2][CH3:1])([CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:10]
Reactant: CCOC(=O)C(C)(OC)C(=O)[O-]
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(C)(OC)C(=O)Cl
Yield: 100 %

Procedure:
Mon-ethyl methoxy(methyl)malonate (14.52 grams, 0.08 mole) was reacted with thionyl chloride (19.61 grams, 0.16 mole) at 50° C. for a 13-hour reaction period with an additional holding period of approximately 32 hours at room temperature. Vacuum evaporation of the excess thionyl chloride gave 15.2 grams (0.08 mole) of ethyl 2-(chlorocarbonyl)-2-methoxypropionate. NMR analysis of the product indicated the following: