Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([C:23](OCC)=[O:24])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][OH:24])[CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)c1cc(CO)nn1-c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A solution of ethyl 5-[(4-fluorophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate (170 mg) in tetrahydrofuran (2.5 mL) was cooled to −78° C., and a 1.5 mol/L solution (1.2 mL) of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred at room temperature for 1 hr, treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (yield 135 mg, yield 89%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.CI.[C:37](=O)([O-])O.[Na+]>O1CCCC1>[CH3:37][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=C([O-])O
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](CO)Nc3ccccc3[C@@H]21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium hydride (60% in oil, 14 mg, 0.1 mmol) was suspended in tetrahydrofuran (1 ml), the compound (35 mg, 0.08 mmol) synthesized in Example 50 was added under ice-cooling, and the suspension was stirred for 1 hr. Methyl iodide (14 mg, 0.1 mmol) was added thereto, and the mixture was stirred under ice-cooling for 30 min., and then at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and eluted with hexane-ethyl acetate (4:1, v/v) to give the title compound (30 mg, 84%) as an amorphous form.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20](O)=[C:21]([C:23](=[O:25])[CH3:24])[CH:22]=1>N1C=CC=CC=1.C(OCC)C>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:20]1[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=1[C:23](=[O:25])[CH3:24])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)c1cc(F)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 101.4 %

Procedure:
Trifluoromethanesulfonic anhydride (8.6 mL, 51 mmol) was added dropwise at 0° C. to a stirring solution of 5′-fluoro-2′-hydroxy-acetophenone (6.4 g, 41 mmol) in pyridine (62 mL). The reaction was stirred overnight from 0° C. to ambient temperature. The reaction solution was diluted with diethyl ether (500 mL). The organic layer was washed with 1 N aqueous hydrochloric acid (1×300 mL), followed by a saturated, aqueous sodium chloride solution (2×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a maroon-colored liquid (11.9 g, 100% ). The product was further purified by Kugel-Rohr distillation to afford a yellow oil that solidified upon standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:31])[C@H:26]([C@@H:28]([CH3:30])[OH:29])[NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:31])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH:28]([OH:29])[CH3:30])[CH3:23]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O-])(=[O:25])C.[Na+]>CN(C)C=O>[CH2:6]([O:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([CH:23]=[O:25])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(COc2cccc3occc23)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(OCc2ccccc2)c2ccoc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Dry N,N-dimethylformamide (12.1 g, 166 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (11.4 g, 75 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min at 10° C., a solution of 4-benzyloxy-benzofuran (9.3 g, 41 mmol) in N,N-dimethylformamide (9 ml) was added dropwise within 30 min. The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 100° C. After 10 min at 100° C. the mixture was heated at 85° C. for 3 h, cooled to 10° C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate and water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 1.8 g (7 mmol, 17%) of the title compound as yellow oil.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8](C)=[CH:7][CH:6]=1)(O)(=O)=O.CNCCCCC=C.[C:20]([N:27]1C=CN=[CH:28]1)([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:21].C(N(CC)CC)C>CN(C=O)C>[CH2:6]([N:27]([CH3:28])[C:20]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:21])[CH2:7][CH2:8][CH2:10][CH:11]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C=CCCCCNC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)n1ccnc1
Yield: 94 %

Procedure:
Compound 2a (3 g, 1 eq.), carbonyldiimidazole (2.04 g, 1.2 eq.), and triethylamine (1.74 g, 1.2 eq.) in anhydrous DMF (60 mL) were stirred at room temperature for 2 days. The reaction mixture was then washed with water. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 3a as a pale yellow oil in 94% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.33 (quint, J=8.04 Hz, 2H), 1.61 (quint, J=8.04 Hz, 2H), 2.02 (q, J=7.46 Hz, 2H), 3.00 (s, 3H), 3.05 (t, J=7.46 Hz, 2H), 3.35 (t, J=7.46 Hz, 1H), 4.89-4.96 (m, 2H), 7.02 (m, 1H), 7.15 (m, 1H), 7.81 (s, 1H).
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC/C=C/CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C/COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2ccccc2n1

Procedure:
29.89 g of quinoline-2-carboxylic acid were heated under reflux for 51/2 hours in 450 ml of ethanol with the addition of 3.5 ml of sulfuric acid. The reaction mixture was worked up by evaporating it, taking up the residue in water and extracting the mixture with dichloromethane. The organic phase was washed with aqueous sodium bicarbonate solution and then with water until neutral, dried and evaporated. 32.23 g of crude ethyl quinoline-2-carboxylate were obtained as a green oil.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(O)C>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:7]([CH3:6])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccc(Br)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(Br)cc1)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium ethoxide was generated by the addition of sodium (9.45 g) to ethanol (370 ml). The resulting solution was cooled to 5° C. and diethyl 2-methylmalonate (68.8 ml) added over 2 minutes. The reaction mixture was stirred at 5° C. for 20 minutes and then 4-bromobenzyl bromide (97.0 g) was added over 20 minutes. The reaction mixture was then heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth and evaporated. The residue was partitioned between water (500 ml) and diethyl ether (1000 ml). The diethyl ether was separated and the aqueous layer was extracted with diethyl ether (2×500ml). The combined organic layers were dried (MgSO4) and evaporated to give an amber oil. This was purified by vacuum distillation, affording diethyl 2-(4-bromobenzyl)-2-methylmalonate (84.4 g), b.p.122°-125° C./0.1-0.2 mm Hg; mass spectrum (+ve CI): 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[CH:18]3)[CH:10]([NH2:13])[CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[CH:18]3)[CH:10]([NH:13][S:40]([CH:37]2[CH2:39][CH2:38]2)(=[O:42])=[O:41])[CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccnc(OC)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NS(=O)(=O)C1CC1)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccnc(OC)c1
Reaction time: 48 h

Procedure:
To a stirred solution of 1-[2-methoxypyridin-4-yl]-1-[(1-pyridin-2-yl-1H-indazol-5-yl)oxy]butan-2-amine (122 mg, 310 μmol) in dichloromethane (11 ml) was added triethylamine (100 μl), followed by cyclopropanesulphonic acid chloride (66 mg, 470 μmol) and DMAP (3.8 mg, 31 μmol). The stirring was continued for 48 h at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 10 mg (6.5%) as a racemic mixture of two diastereomeres.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:24]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([O:31][C:32]1[CH:37]=[C:36]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3cccc(OCc4ccccc4)c3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 150 mmol), 3-Benzyloxyphenylboronic Acid (70 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 0.5 microliters of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 60-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (9.7 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 5.21 (s, 2 H) 6.59 (d, J=2.27 Hz, 1 H) 7.27-7.32 (m, 1 H) 7.36 (d, J=7.33 Hz, 1 H) 7.39-7.44 (m, 1 H) 7.49-7.54 (m, 2 H) 7.49-7.57 (m, 1 H) 7.54-7.59 (m, 1 H) 7.60-7.67 (m, 3 H) 7.75-7.79 (m, 1 H) 8.01-8.06 (m, 3 H) 8.19 (d, J=2.27 Hz, 1 H) 11.26 (s, 1 H). ESI-MS: m/z 479.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23](Cl)[N:24]=1)[C:19]([NH2:21])=[O:20].CN(C(C(C)C)C)C.O>CCOC(C)=O>[NH2:21][C:19]([C:18]1[CH:17]=[C:16]([Cl:15])[N:24]=[C:23]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH:22]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC(=O)c1cc(Cl)nc(Cl)c1
Agent: CC(C)C(C)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1

Procedure:
tert-Butyl piperidin-4-ylcarbamate (500 mg, 2.62 mmol), was dissolved in anhydrous N,N′-dimethyl acetamide (4 ml). 2,6-Dichloroisonicotinamide (522 mg, 2.62 mmol) was added, followed by N,N-dimethyl isopropylethylamine (465 μl, 2.62 mmol). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 20 minutes. H2O (50 ml) and EtOAc (100 ml) were added, the EtOAc layer was washed (4×50 ml), dried over Na2SO4 and concentrated in vacuo to give the title product as a brown solid. (760 mg).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni].[Mo]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Agent: [Mo]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A solution of (4R-cis)-1,1 dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate (Example 2), 8.2 kg (30.5 mol) in 100 L of methanol containing 15 kg of anhydrous ammonia is reacted with hydrogen gas under 50 pounds per square inch (psi) at 30° C. in the presence of a slurry of 8 kg of Raney nickel doped with 1% molybdenum. After 6 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, and the slurry is filtered, concentrated by distillation and distilled under vacuum to give 7.8 kg of 96% pure (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate as a clear oil; bp 125°-135° C. @0.5 mm Hg. 200 MHz 1H-NMR (CDCl3) 1.0-1.2 (m, 1H), 1.22 (s, 3H), 1.31 (s, 12H), 1.35-1.45 (m, 3H), 2.15 (dd, 1H, J=15.1 Hz, J=6.2 Hz), 2.29 (dd, 1H, J=15.1Hz, J=7.0 Hz), 2.66 (t, 2H, J=6.6 Hz), 3.82 (m, 1H), 4.12 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=O)[CH2:3][C:4]([O:6]CC)=[O:5].P(Cl)(Cl)(Cl)=O>S1(CCCC1)(=O)=O>[CH3:12][C:2]1([CH3:1])[CH:9]=[CH:10][O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(C)CC=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: CC1(C)C=COC(=O)C1
Temperature: 200 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of 16.98 g (0.10 mole at 93% purity) of ethyl 3,3-dimethyl-5-oxopentanoate and 9.44 g (0.062 mole) of phosphoryl chloride in 10 g of sulfolane was added to 250 g of sulfolane and the whole heated to 200° C. in an oil bath during 50 minutes. The reaction mixture was stirred at 200° C. for 1 hour, then subjected to distillation to give 9.71 g of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one in 2 fractions: fraction 1, 7.49 g, bp 55° C./400 Pa (3 mm Hg), 95.9% purity (glpc); fraction 2, 2.22 g, bp 55°-120° C./400 Pa, 71.1% purity (glpc).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:28]=[N:27]C=2C=1.O.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH:27][NH2:28])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: O
Product: NNC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 160.2 %

Procedure:
To a round-bottom flask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (40 mL). EDC.HCl (7.50 g, 39.1 mmol, 1.50 equiv), HOBT (5.20 g, 38.5 mmol, 1.50 equiv), and hydrazine hydrate (2 mL, 2.00 equiv, 99%) were added to the reaction. The resulting solution was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo to furnish 5.38 g (80%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl-].[Cl-].[O:7]=[C:8]1[NH:16][C:11]2=[NH+:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][NH2+:20][CH2:19][CH2:18]1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[O:7]=[C:8]1[NH:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:1]([Cl:4])=[O:2])[CH2:19][CH2:18]1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]c2[nH+]cccc2n1C1CC[NH2+]CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Phosgene (20% wt. in toluene; 1.8 mL, 3.43 mmol) was added to a suspension of 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (100 mg, 0.343 mmol) and 2,6-lutidine (0.50 mL, 4.293 mmol) in dichloromethane (5 mL) at 0° C. After 2 h, the solution was added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Dichloromethane (10 mL) was added, and the mixture was filtered to give the title compound as a solid (48 mg). MS 281 (M+1). 1H NMR (500 MHz, (CD3)2SO) δ 11.58 (s, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.01-6.99 (m, 1H), 4.52-4.46 (m, 1H), 4.31-4.23 (m, 2H), 3.38-3.33 (m, 1H), 3.19-3.14 (m, 1H), 2.32-2.24 (m, 2H), 1.84-1.81 (m, 2H).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:8]=1[NH2:9])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[C:24](=N)(OC)[CH3:25].C(=O)([O-])O.[Na+]>CO>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:7]2[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:24]([CH3:25])=[N:9][C:8]=2[CH:10]=1
Reactant: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: COC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(C)(C)C
Yield: 74.7 %

Procedure:
To a methanol (5 mL) solution of 2-(2-neopentylaminoanilin-5-yl)benzoxazole (see Working Example 81-2) (192 mg, 0.650 mmol) was added methyl acetimidate hydrochloride (107 mg, 0.975 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (155 mg, 75% yield) as white crystals.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][CH3:6])=O)[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[NH2:45])[CH:22]=1>ClCCl.N>[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:37])([F:38])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[N:45]=[S:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[CH:22]=1
Reactant: CCS(=O)CC
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCS(CC)=Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
To a solution of diethyl sulfoxide (0.47 g, 4.4 mmo) in dichloromethane at −60° C. under argon was added drop-wise trifluoroacetic anhydride (0.93 g, 4.4 mmol). The solution was stirred for 20 min at this temperature. Then the 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.76 g, 2 mmol) was added and the solution stirred at −60 C for 1 h. The reaction was diluted with aqueous ammonia; the organic layer was separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (270 mg; 29%).