Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Cl[CH:10]([CH:16]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[OH:8][C:6]1[CH:5]=[CH:4][N:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:1]=[C:2]2[CH:7]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(O)ccn1
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(O)ccn12

Procedure:
2-Aminopyridin-4-ol (3 g, 27 mmol) was dissolved in ethanol (90 mL) in 250 mL round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% in benzene; 130 mL; Commercial solution from Toronto Research Chemicals Inc.) was added and the mixture refluxed for 10 hours. Reaction was concentrated and triturated with ethyl acetate before drying under high vacuum to give ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate as a beige solid (829 mg).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[CH3:12][S:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)[N:10]2[N:9]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-n3cccn3)n2n1
Temperature: 110 °C

Procedure:
To a RB flask under argon were introduced 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (300 mg, 1 mmol), 1H-Pyrazole (88.5 mg, 1.30 mmol), Cesium carbonate (801 mg, 2.46 mmol), Copper(I) iodide (50 mg, 0.3 mmol) and DMF (5 mL). The mixture was degassed for few minutes and heated at 110° C. overnight under argon. Solvent was removed and the mixture was taken in EtOAc and was passed through a pad of celite. Solvent evaporation gave the crude product which was purified by flash chromatography (ISCO, hexane :EtOAc 3:1). 2-Methylsulfanyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine was isolated as a yellow syrup (23, 8%). LCMS (E/I+) 232 (M+H). 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (47.1 mg, 0.162 mmol), 2-Methanesulfinyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.08 mmol), N,N-Diisopropylethylamine (30 uL, 0.2 mmol) and 1-Methoxy-2-propanol (200 uL,) were combined in a microwave vial. The reaction was microwaved at 200° C. for 2.5 hours, taken up in DMSO, purified by Gilson RP-HPLC. The product, [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was isolated as a tan solid (8 mg, 21%). LCMS (E/I+) 475 (M+H). NMR 1H (DMSO-d6)-9.75 (br s, 1H), 8.94 (s, 1H), 8.58 (d, 1H, J=2.09 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (d, 1H, J=8.72 Hz), 6.94 (s, 2H), 6.70 (s, 1H), 6.60 (s, 1H), 6.52 (d, 1H, J=8.74 Hz), 4.04-3.13 (series of m, s along with the water peak, 14H), 2.71 (m, 2H), 2.15 (d, 2H, J=11.30 Hz), 1.72 (m, 2H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[B:22](OC)([O:25]C)[O:23]C.Cl>C1COCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[B:22]([OH:25])[OH:23]
Reactant: N#Cc1ccc(F)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
n-BuLi (1.9 M, 26.3 mL, 50 mmol) was added dropwise to a solution of diisopropylamine (7.71 mL, 55 mmol) in 100 mL anhydrous THF under N2 at 0° C. After 10 minutes, the reaction was cooled to −78° C. A solution of 4-fluorobenzonitrile (6.06 g, 50 mmol) in 20 mL anhydrous THF was added dropwise, at such a rate to maintain an internal temperature of −78° C. After stirring for 1 h at this temperature, trimethyl borate (8.41 mL, 75 mmol) was added dropwise at such a rate to maintain an internal temperature of −78° C. The reaction was stirred and gradually warmed to room temperature over 16 h. The reaction was cooled to 10° C. and 25 mL 6N HCl was added. After stirring at room temperature for 4 h, the reaction was partitioned between water and ethyl acetate. The organic layer was washed three times with 100 mL 2N NaOH. The aqueous layers were pooled and adjusted to pH 6 with 6N HCl. The white solid which forms was extracted by three washes of 100 mL Ethyl acetate. The organic layers were pooled, dried over sodium sulfate, concentrated and dried under high vacuum to give 2-fluoro-5-cyanophenyl boronic acid (5.74 g, 70%). 1H NMR (500 MHz, acetone-d6) 8.08 (1H, dd, J=2.14, 5.5 Hz), 7.90 (1H, m), 7.31 (1H, t, J=8.85 Hz). Anal. calcd. for C7H5BFNO2: C, 50.97; H, 3.05; N, 8.49. Found: C, 51.19; H, 3.19; N, 8.26.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[CH:8]#[C:9][C:10](=[O:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]=[C:10]([CH:9]=[CH:8][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:11]
Reactant: C#CC(C)=O
Reactant: Oc1cc(Cl)sn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cn1sc(Cl)cc1=O

Procedure:
A stirred solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 1-butyn-3-one (3.5 g, 0.05 mole) and p-toluenesulfonic acid (0.02 g) in 25 ml of toluene was heated at 80° C. for 24 hours. Upon cooling, the dark brown reaction mixture was concentrated and the residual oil was column chromatographed on silica gel, using diethyl ether/hexane as eluant. Compound 11 was obtained as a yellowish solid; 1.8 g; mp 137°-139° C.; IR (KBr) 1675, 1620 cm-1 ; NMR (CDCl3) δ8.2 (d,1H,J=13.9 Hz); 6.35 (s,1H); 5.85 (d,1H,J=13.9 Hz); 2.35 (s,3H).
Reaction SMILES: C([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([OH:14])=[O:13])[S:5][C:4]1=[O:15])C.[OH-].[Li+]>C1COCC1.O>[O:15]=[C:4]1[NH:3][C:7]([C:8]([F:11])([F:9])[F:10])=[C:6]([C:12]([OH:14])=[O:13])[S:5]1
Reactant: CCn1c(C(F)(F)F)c(C(=O)O)sc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(=O)[nH]c1C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 2,3-dihydro-2-oxo-4-(trifluoromethyl)-5-thiazolecarboxylic acid (Bionet Research, 2.0 g) in THF (20 mL) was added a solution of lithium hydroxide (0.696 g) in water (20 mL). The mixture was stirred at 50° C. for 72 h, cooled to room temperature and filtered. The filtrate was washed with ethyl acetate (10 mL), acidified to pH 3 using dilute hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extractions were washed with water (2×50 mL), saturated brine solution, dried (Na2SO4), filtered and concentrated in vacuo to give the subtitle compound as a colourless solid (1.583 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccccc1

Procedure:
Prepared from L-leucine methyl ester HCl and benzoyl chloride according to the procedure from Example 10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:22][C:21]=1[O:35]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:22][C:21]=1[OH:35])(=[O:18])=[O:19])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)NCCN(C)C)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)NCCN(C)C)cc1O
Yield: 99.7 %

Procedure:
To (S)-3-{2-benzyloxy-4-[3-(2-dimethylamino-ethyl)-ureido]-benzenesulfonylamino}-4,4-diethoxy-butyric acid tert-butyl ester (1.80 g, 2.9 mmol) in ethanol (100 mL) was added 20% Pd on carbon (250 mg) and stirred under 1 atmosphere of hydrogen for 24 h. The reaction was judged complete by thin layer analysis and filtered. The filtrate was evaporated to give (S)-3-{4-[3-(2-dimethylamino-ethyl)-ureido]-2-hydroxy-benzenesulfonylamino}-4,4-diethoxy-butyric acid tert-butyl ester as a colorless foam 1.54 g (100%). MS (APCI) m/z 533.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=1>O1CCOCC1.C(OCC)(=O)C>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]3)=[CH:6][CH:7]=2)[CH:27]=1)#[N:29]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)c1
Temperature: 125 °C
Yield: 54.8 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.36 g) and 2-chloro-4-cyanopyridine (0.14 g) in dioxane (1 mL) was heated at 125° C. in a sealed tube for 5 days. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (methylene chloride to 2% ethanol/methylene chloride gradient gave the above-named compound (0.22 g) mp 152-153° C. NMR (CDCl3) 8.45 (1H, m), 7.86 (3H, m), 7.48 (2H, d), 7.20 (1H, br s), 7.07 (1H, s), 6.91 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (structure 68A of Scheme LI, where R1-2 =H) (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -78° C. was added 2.0M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at -78° C. for 15 min and iodomethane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0° C. and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4Cl (5 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone (structure 69A of Scheme LI, where R1-2 =H, R3 =methyl), 128 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (structure 70A of Scheme LII, where R1-2 =H, R3-4 =methyl) and 200 mg (40%) of recovered starting material. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolino 1H NMR (400 MHz, CDCl3) 7.99 (dd, J=7.9, 1.7, 1H), 7.77 (d, J=8.4, 1H), 7.48 (ddd, J=7.3, 7.3, 1.7, 1H), 7.13 (dd, J=7.4, 1.0, 1H), 4.32 (dd, J=13.4, 4.4, 1H), 3.69 (dd, J=13.3, 9.8, 1H), 2.76 (ddq, J=9.8, 7.0, 4.4, 1H), 1.56 (s, 9H), 1.24 (d, J=7.0, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][NH2:23]>O1CCOCC1>[NH:22]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:23]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NN
Solvent: C1COCCO1
Product: COc1ccc(N(C)c2nc(NN)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (100 mg, 0.33 mmol) in 2 ml of 1,4-dioxane was added 0.4 ml of hydrazine. The reaction mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was diluted with EtOAc (20 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum, yielding 20 mg (21%) of yellow solids. 1H NMR (CDCl3): 7.52-7.49 (m, 1H), 7.44-7.39 (m, 1H), 7.12-7.08 (m, 2H), 6.93-6.88 (m, 3H), 6.77-6.71 (m, 1H), 6.01 (brs, 1H), 4.11 (brs, 2H), 3.83 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:36](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:47][CH3:48].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:36][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:27][CH2:28]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:47][CH3:48]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3[nH]1)cn2C
Yield: 84.3 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.160 g of tert-butyl 4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}piperidine-1-carboxylate instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 0.95 cm3 of 5N potassium hydroxide. 0.104 g of tert-butyl 4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}piperidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:21][C@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:23])[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:44]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:44].[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([C@@H:22]([O:21][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:15][C@H:14]3[N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH3:23])[CH:25]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:27]=1
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](n3cnnn3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: C[C@H](O[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2n1cnnn1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-6-(1H-tetrazol-1-yl)-8-azabicyclo[3.2.1]octane (Example 135; 158 mg, 0.26 mmol) was dissolved in methanol (5 ml) and 2N hydrochloric acid (0.5 ml) and 10% palladium hydroxide (40 mg) added and the mixture hydrogenated at 50 psi for 30 minutes. The reaction mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by thin layer chromatography [5% methanol in dichloromethane] to give a white solid. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60° C. (41 mg, 28%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: C[C@@H]1CNCCN1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of 4-fluorophenyl methyl sulfone (2.00 g), (R)-2-methylpiperazine (2.30 g) and K2CO3 (3.20 g) in anhydrous DMF (80 mL) was heated at 100° C. for 5 hours. The reaction mixture was filtered to remove salts and the solvent was evaporated under reduced pressure to give a yellow oil. Purification by flash chromatography (CHCl3/MeOH) gave 1.36 g (47%) of the title compound as a pale yellow solid. M+(ESI): 255.2. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 100%).
Reaction SMILES: C(O)(=O)C.[CH:5]1([NH:8][NH2:9])[CH2:7][CH2:6]1.Cl.[CH:11](=O)[C:12]([CH3:14])=[O:13]>O>[CH:5]1([NH:8][N:9]=[CH:11][C:12](=[O:13])[CH3:14])[CH2:7][CH2:6]1
Reactant: NNC1CC1
Reactant: CC(=O)C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C=NNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Acetic acid (1.71 mL, 29.9 mmol) was slowly added to a solution of cyclopropylhydrazine.HCl (2.5 g, 18.1 mmol) in H2O (30 mL), and was then quickly added dropwise to a solution of pyruvaldehyde (40%, 2.36 mL, 14.5 mmol) in H2O (240 mL). This solution was stirred overnight at room temperature. The aqueous layer was salted and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 1.04 g of crude product as a reddish oil. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of ethyl acetate/hexanes (25:75 to 50:50) to afford 637 mg (35%) of 2-oxopropanal cyclopropylhydrazone as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:35](I)[CH3:36]>>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:35][CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cc1ccccc1
Reactant: CCI
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzyl-3-mercapto-5-sulfamylbenzoic acid (1.0 g), sodium hydrogen carbonate (0.3 g), sodium dithionite (0.3 g), ethyl iodide (1.0 ml) and saturated sodium hydrogen carbonate solution (8 ml) is stirred at 70° C for 3 hours. After cooling, the precipitated sodium 4-benzyl-3-ethylthio-5-sulfamylbenzoate is collected by filtration and washed with a minor amount of icecold water. After drying, the sodium salt is dissolved in hot water (10 ml), and the solution is clarified by the filtration hot in the presence of decolorizing carbon. The solution is acidified with conc. hydrochloric acid (0.5 ml) to precipitate the 4-benzyl-3-ethylthio-5-sulfamylbenzoic acid. The acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, the compound is obtained with a melting point of 234° -235° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>ClC(Cl)C>[CH3:5][CH:6]([CH2:14][CH2:15][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:12][CH:13]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under ice cooling, 24.86 g of anhydrous aluminum chloride was added to a dichloroethane suspension (250 ml) containing of [2-methyl-4-phthalimidobutyl]benzene and 9.29 g of succinic anhydride, and the mixture was stirred temperature for 2 hours. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The resulting crude crystal was recrystallized from ethyl acetate-hexane to obtain 16.11 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.IC[C:45]1[N:49](C)[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH3:45])[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(CI)nnc1S(C)(=O)=O
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1c(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)nnc1S(C)(=O)=O

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole and isolated as white solid. MS(m/e): 456.3 (MH+).
Reaction SMILES: [C:1]([N:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(=O)(=O)(O)O.[CH:22](O)([CH3:24])[CH3:23]>>[CH:22]([O:14][C:13](=[O:15])[CH2:12][CH2:11][N:10]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:16])([CH3:24])[CH3:23]
Reactant: CC(C)O
Reactant: CCCCCCCC(=O)N(C)CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCC(=O)N(C)CCC(=O)OC(C)C

Procedure:
Fifty-seven(57) grams of N-octanoyl-N-methyl-β-alanine and 500 ml of isopropanol were charged into a 1,000-milliliter flask, and 1 ml of conc. sulfuric acid was further added thereto as the catalyst. The mixture was heated under reflux reaction for 8 hours.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:11][O:10][C:9]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])=[N:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:9]1[O:10][CH2:11][CH:7]([C:5]2[S:6][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)[N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)s2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccccc3)s2)CO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 100 mg (0.3 mmol) of the product of Step D of Example 2 in 0.6 mL toluene was added successively 10.4 mg (0.009 mmol) of Pd (PPh3)4, 0.3 mL of 2.0 m sodium carbonate, and 44 mg (0.36 mmol) of phenylboronic acid in 0.15 mL of methanol. The mixture was stirred at 80° C. for 2 h. It was cooled and partitioned between 25 mL of 2.0 m sodium carbonate containing 2.5 mL of ammonium hydroxide solution and 25 mL of methylene chloride. The methylene chloride layer was washed with brine, dried (MgSO4), and concentrated. The residue was passed through a silica gel flash column eluting with ethyl acetate: hexanes (1:4) to give 85 mg of an oil. 1H-NMR (CDCl3) δ6.90-7.20 (m, 10H), 5.70 (dd,1H), 4.80 (t, 1H), 4.45 (t, 1H).