Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:33][CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)[CH3:32]>>[CH2:31]([O:33][CH:34]1[CH2:39][CH2:38][CH:37]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:35]1)[CH3:32]
Reactant: CCOC1CCC(=O)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-ethoxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11]C)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:1]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:8][C:9]2=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)Cc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 130.2 %

Procedure:
Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH2Cl2 under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO3. After stirring for 30 min, the organics were separated, dried (MgSO4), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50% EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25% EtOAc/hexanes): Rf=0.15. 1H NMR (400 MHz, CDCl3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].CS(O)(=O)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:30]2[CH:31]=[N:32][C:33]([F:36])=[CH:34][CH:35]=2)(N)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:20]=1>CO>[O-:9][N+:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:28][CH:26]([CH3:27])[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)([C:30]3[CH:31]=[N:32][C:33]([F:36])=[CH:34][CH:35]=3)[N:2]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1NC(c2cc[n+]([O-])cc2)=NC1(c1ccc(F)cc1)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-cyanopyridine N-oxide (100 mg) in methanol (4 mL) were added sodium methoxide (13.5 mg), and the mixture was stirred at room temperature for 24 hrs. To the reaction mixture was added methanesulfonic acid (104 mg), and the reaction mixture was stirred at room temperature for an additional 10 minutes. To the 3.5 ml of this solution was added to the solution (2 mL) of (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine described in Reference Example 5-1, and the mixture was stirred at room temperature for 15 hrs. After concentrating the reaction mixture in vacuo, the obtained residue was dissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; chloroform: methanol=9:1) to give 2-(1-oxido-pyridin-4-yl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline (172 mg) as colorless oil. To the solution (5 ml) of the obtained N-oxide compound in acetonitrile was added trimethylsilylcyanide (140 mg) and triethylamine (142 mg), and the mixture was stirred at 90° C. for 17 hrs. To the mixture was added trimethylsilylcyanide (140 mg) and triethylamine (142 mg), and the mixture was stirred at 90° C. for 2 hrs, and concentrated in vacuo. The obtained residue was dissolved in chloroform, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1) and treated with 4N hydrogen chloride—ethyl acetate solution to give the title compound (108 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+].C(OCC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])[N:5]=[CH:4][N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(Cl)ncn1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
4,6-Dichloropyrimidine (1.0 g, 6.71 mmol), bis(triphenylphosphine)palladium(II) chloride (0.094 g, 0.134 mmol) and tributyl[1-(ethyloxy)ethenyl]stannane (2.449 mL, 7.25 mmol) were added together in DMF (25 mL) and the resulting mixture was heated at 80° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of potassium fluoride (5.7 g in 57 mL water). Diethyl ether (80 mL) was added and the solid was filtered, washed with diethyl ether (×2) and discarded. The filtrate was separated and the organic layer was washed with water, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (564 mg);
Reaction SMILES: Br[C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)/C=C\C)[CH2:31][CH2:32]C>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([NH:16][S:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:2](/[CH:30]=[CH:31]\[CH3:32])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C/C=C\c1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (497.4 mg, 1.0 mmol, 1.0 eq), Pd(PPh3)2Cl2 (28.0 mg, 0.1 mmol, 0.1 eq) and Bu4NBr (321.1 mg, 0.1 mmol, 1.0 equiv.) was flushed with nitrogen. Anhydrous dioxane (10 mL) was added and the reaction mixture was flushed with nitrogen. (Z)-tributyl(prop-1-enyl)stannane (475.4 mg, 1.5 mmol, 1.5 eq) was added and the reaction mixture was stirred at rt for 2 h. The mixture was extracted with EtOAc and washed with water, brine. The organic layers were concentrated to afford the residue, which was purified by silica gel chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to afford (Z)—N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(prop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (375.6 mg, 82.1%) as white solid. LC-MS (m/z)=459 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]([C:11]2([CH2:21][C:22]#[N:23])[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)[N:4]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]([C:11]2([CH2:21][C:22]#[N:23])[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)[N:4]=1
Reactant: N#CCC1(n2cc(C(N)=O)c(N)n2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC1(n2cc(C(N)=O)c(N)n2)CCC(=O)CC1
Temperature: 80 °C

Procedure:
Aqueous hydrochloric acid (1 N, 36 mL, 36 mmol) was added to a solution of 3-amino-1-(8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-4-carboxamide (Intermediate 35-5) (5.5 g, 18 mmol) in THF (106 mL). The reaction vessel was capped with a reflux condenser and heated to 80° C. for 2 hours. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate, and neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated and then washed with brine. The washed solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to afford the title compound, which was used without further purification.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C:11]([O-:13])=[O:12])=O)(C)(C)C.[ClH:19].O1CCOCC1>>[NH2:8][C@H:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C:11]([O-:13])=[O:12].[ClH:19]
Reactant: CCOC(=O)[C@H](CC(=O)[O-])NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](N)CC(=O)[O-]
Reaction time: 0.25 h

Procedure:
Combine the product of step A (1.14 g) with 6M HCl/dioxane (10 ml). Stir 15 minutes, decant the solution, and stir the residue with ether. Filter to obtain (S)-aspartic acid, α-ethyl ester, β-(6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazine-3methylamide) hydrochloride.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([CH2:18][C:19]([NH2:24])([CH3:23])[C:20]([NH2:22])=[O:21])=[O:17])[CH2:12][C:13](=[O:15])[OH:14])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O>[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44]([NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([CH2:18][C:19]([NH2:24])([CH3:23])[C:20]([NH2:22])=[O:21])=[O:17])[CH2:12][C:13](=[O:14])[OH:15])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Reactant: CSCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)CC(C)(N)C(N)=O
Agent: Cl
Solvent: O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)CC(C)(N)C(N)=O

Procedure:
When an equivalent quantity of L-methionyl-L-aspartyl-2-amino-2-methylpropionamide hydrochloride is substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-2-amino-2-methylpropionamide containing 1/3 mole of water of hydration per mole. This compound is represented by the following formula. ##STR15##Elemental analysis of this compound shows C: 54.45%; H: 6.69%; N: 12.69% and S: 4.96%. Theory is C: 54.36%; H: 6.71%; N: 13.11% and S: 5.00%.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[I:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>C(O)=O.Cl>[I:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: NNc1ccc(I)cc1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Solvent: O=CO
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(I)cc12

Procedure:
1-Oxo-indan-4-carboxylic acid (0.528 g, 2.99 mmol) and 4-iodophenylhydrazine hydrochloride (0.698 g, 2.58 mmol) were mixed together in a Teflon PFA vessel to form a paste in formic acid (2 mL, 96%) containing 3 drops of concentrated HCl. The vessel was irradiated at full power (760W) in a CEM Microwave (MDS2000) for one minute (T=140C, P<50 PSI), allowed to cool for 2 min, then irradiated again for one min (T=140C, P<50 PSI). The mixture was vacuum filtered hot. The solid was washed with formic acid, and dried on the frit. Chromatography (acetone/hexane) and trituration with diethyl ether have the title compound (0.059 g, 5%) as an tan solid: mp 251° C.; 1H NMR (DMSO-d6): δ 3.98 (s, 2H), 7.30-7.37 (m, 2H), 7.49 (t, 1H), 7.77-7.80 (m, 2H), 7.98 (d, 1H), 11.82 (s, 1H), 13.53 (s, 1H); MS [EI, m/z]: 375 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([NH:14][CH2:13][C:12]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:18][CH:19]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Temperature: 160 °C
Yield: 37.7 %

Procedure:
A mixture of C-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (530 mg, 2.6 mmol), methyl 6-chloronicotinate (440 mg, 2.6 mmol), N,N-diisopropyl ethyl amine (880 μL, 5.1 mmol) and DMSO (5.1 mL) was heated in the microwave to 160° C. for 2×0.5 h and 1 h. The mixture was then diluted with ice-water and extracted with ethyl acetate. The combined organic extracts were then washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (335 mg, 38%) as a yellow gum. MS: m/e=342.1 [M+H]+.
Reaction SMILES: O=[C:2]([CH3:12])[CH:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5].Br.[NH2:14][NH2:15]>CCO.O>[CH3:12][C:2]1[NH:15][N:14]=[C:4]([NH2:5])[C:3]=1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: CC(=O)C(C#N)c1cccnc1
Agent: Br
Solvent: O
Solvent: CCO
Product: Cc1[nH]nc(N)c1-c1cccnc1

Procedure:
3-Oxo-2-pyridin-3-yl-butyronitrile (step 1) (1.00 g, 6.49 mmol) was dissolved in EtOH (10 ml) and water (2 ml). Hydrazine hydrobromide (2.82 g, 24.97 mmol) was added and the reaction mixture was heated at reflux for 1 hour. The solvent was removed in vacuo and the residue was partitioned between EtOAc and sat. NaHCO3. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent was removed in vacuo to afford the title compound which was used without further purification; 1H NMR (d6-DMSO, 400 MHz) δ 11.51 (1H, br), 8.60 m), 8.40 (1H, m), 7.72 (1 h, m), 7.39 (1H, m), 4.60 (2H, br), 2.19 (3H, s).
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:20][C:19]([NH2:21])=[N:18][N:17]=2)[CH2:12][CH2:11]1>C(#N)C.CN(C=O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:20][C:19]([NH:21][C:7]([NH2:6])=[S:8])=[N:18][N:17]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)N=C=S
Reactant: CN1CCN(c2nnc(N)s2)CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCN(c2nnc(NC(N)=S)s2)CC1
Temperature: 80 °C

Procedure:
Ethoxycarbonylisothiocyanate (0.346 ml, 2.96 mmol) is added dropwise to a stirred suspension of 5-(4-Methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-ylamine (63b) (0.59 g, 2.96 mmol) in acetonitrile (15 ml) and DMF (5 ml). The reaction is heated at 80° C. for 7 h followed by removal of the solvent. The residue heated in 2M aqueous NaOH (80 ml) at reflux for 30 minutes. After cooling to room temperature the solution is neutralised by addition of 6M aqueous HCl and the titled product is removed by filtration and dried under vacuum.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:16])=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCCN1
Reactant: Clc1c(Br)cccc1SCc1ccccc1
Product: O=C1COCCN1c1cccc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 16 (10 g, 31.38 mmol) was treated with morpholin-3-one (389 mg, 3.85 mmol) according to the procedure described in 1.6).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.ClC(Cl)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([CH3:23])[CH3:22].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34]#[N:35])[CH:25]=1>O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:15]=1[CH2:20][C:21]([CH3:23])([CH3:22])[N:35]=[C:34]2[C:26]1[CH:25]=[N:24][C:33]2[C:28]([CH:27]=1)=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: CC(C)=Cc1ccccc1F
Reactant: N#Cc1cnc2ccccc2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CC(Cl)Cl
Product: CC1(C)Cc2c(F)cccc2C(c2cnc3ccccc3c2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
Trifluoromethane sulfonic acid (0.52 mL) were added while cooling with ice to a dichloroethane (0.58 mL) solution of an about 4:7 mixture of 1-fluoro-(2-methylpropen-1-yl)benzene and 1-fluoro-(2-methylpropen-2-yl)benzene (87.3 mg, 0.58 mmol) and quinoline-3-carbonitrile (89.6 mg, 0.58 mmol), and after stirring for 18 hours at room temperature, the solution was poured into water followed by extraction with ethyl acetate and applying the resulting residue to chromatography to obtain 82.2 mg of the target compound (yield: 47%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#N.S(=O)(=O)(O)[OH:27]>C1C=CC=CC=1.C(OCC)C>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:27]
Reactant: O=S(=O)(O)O
Reactant: N#CCCCCCCOC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CCCCCCCOC1CCCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (19.4 g.) in dry benzene (50 ml.) was added dropwise at 10° C. to a stirred solution of 7-(2-tetrahydropyranyloxy)heptanenitrile (20.6 g.) in dry diethyl ether (200 ml.). The solution was stirred at 10° C. for 30 minutes and was then added to 2N aqueous sulphuric acid (300 ml.) at 0° C. The mixture was heated at 30° C. for 30 minutes, and then saturated with sodium chloride and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with aqueous sodium bicarbonate, and then aqueous sodium chloride, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanal (12.7 g.), b.p. 78°-106° C./0.1 mm.Hg, nD25 1.456.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:11]>[Pd].C(O)C.O1CCCC1>[ClH:11].[F:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ncc(F)cc1F
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of 3,5-difluoropicolinonitrile (1.4 g, 10 mmol), conc. HCl (12 ml) and 10% Pd—C (200 mg) in 1:1 ethanol/tetrahydrofuran was shaken under a hydrogen atmosphere (50 psi) for 5 h. The reaction mixture was filtered and the ethanol removed in vacuo. The remaining solution was lyophilized to afford an off-white solid (2.16 g, 100% yield). LCMS (M+H) calcd for C6H7F2N2: 145.06; found: 145.12.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>C1COCC1>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
1-(Hydroxyethyl)imidazole (5.30 g; 47.3 mmol) was dissolved in anhydrous THF (50 mL) and cooled in an ice-bath. Sodium hydride (2.08 g of a 60 wt % dispersion in oil, 52.0 mmol) was added in portions over 10 min. The ice-bath was removed, and the mixture was stirred at room temperature for 20 min. A solution of 1-fluoro-4-nitrobenzene (5.0 mL, 47.2 mmol) in anhydrous THF (10 mL) was added over 5 min and the mixture stirred for a further 1.5 hr. Water (a few mL) was cautiously added and the mixture concentrated under reduced pressure. The residue was partitioned between EA (75 mL) and water (75 mL), and the phases separated. The aqueous phase was extracted twice with EA and the combined organic layers extracted three times with 1N hydrochloric acid. The pH of these acidic extracts was then adjusted to 7 with 5N aqueous sodium hydroxide and the resulting milky solution extracted three times with EA. The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 1-(2-(4-nitrophenoxy)-ethyl)-1H-imidazole (5.46 g) as a brown oil. A solution of 1-(2-(4-nitrophenoxy)ethyl)-1H-imidazole (5.46 g; 2.34 mmol) in ethanol (60 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.40 g) at room temperature for 20 hr. The mixture was filtered through diatomaceous earth and then concentrated under reduced pressure to give 4-[2-(1H-imidazol-1-yl)ethoxy]benzenamine (4.56 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=[O:21])C>CN(C1C=CN=CC=1)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol produced in Example XV in dry CH2C12 at 0 degree C. there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine solution, dried over Na2SO4, and concentrated in vacuo to a yellow oil. Purification by SiO2 column chromatography yielded the p-toluenesulfonate.