Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:28])C.Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:28]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccccc2)cc1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, 126 g (650 mmol) of 2-methyl-5-phenylbenzonitrile was dissolved in 700 ml of anhydrous toluene, and to the resulted solution was dropped 780 ml of a toluene solution of diisobutyl aluminum hydride (1.0 M solution; 780 mmol) at −10 to 0° C., and the mixture was stirred at room temperature overnight. To the reaction solution was dropped 25 ml of ethyl acetate, and this was poured into a mixture of 2.5 L of ice water and 270 ml of concentrated hydrochloric acid. After stirring at 70 to 75° C. for 1 hour, the mixture was cooled to room temperature, and separated. The organic layer was washed with water, saturated sodium bicarbonate solution, then, water, and concentrated to obtain 123 g of 2-methyl-5-phenylbenzaldehyde.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:43]2([CH3:44])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:25]=[CH:26]\[CH2:27][C:28]([O:31][Si](CC)(CC)CC)([CH3:30])[CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:43]2([CH3:44])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:25]=[CH:26]\[CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([OH:46])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C\OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C/C=C\OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 80 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-triethylsilyloxy-4-methyl-(2Z)-pentenyloxy}-20-methylpregna-5,7,16-triene (140 mg, 0.178 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (4 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (63 mg, 80%) as a colorless foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:8]([O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14])[CH3:9].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([N:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCN
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
Sodium carbonate (21.1 g, 199 mmol) was added to a suspension of β-alanine ethyl ester hydrochloride (10.2 g, 66.4 mmol) and benzyl bromide (16.2 mL, 136 mmol) in acetonitrile (265 mL). The reaction mixture was stirred at ambient temperature overnight and then filtered through a layer of CELITE filter aid. The filter cake was rinsed with acetonitrile (100 mL). The filtrate was concentrated under reduced pressure to provide 20.28 g of ethyl 3-dibenzylaminopropionate as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 79 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}-2-methylpropan-1-one (30 mg, 0.068 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.102 mmol) to afford the desired product (27.4 mg, 79%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.77 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.07-7.99 (m, 2H), 7.55-7.51 (m, 1H), 7.44 (dd, J=11.6, 2.2 Hz, 1H), 3.54-3.42 (m, 3H), 3.38-3.33 (m, 4H), 3.21-3.11 (m, 4H), 2.15-2.06 (m, 5H), 1.99 (d, J=11.0 Hz, 2H), 1.75-1.64 (m, 2H), 1.26 (d, J=6.9 Hz, 6H); ESI MS m/z 510 [C29H33ClFN3O2+H]+; HPLC 97.7% (AUC), tR=11.07 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[Na].[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [Na]
Product: CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
2.30 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine (prepared in example 1) in ethanol (5 mL) was added dropwise to 0.16 g of sodium metal in 10 mL of anhydrous ethanol, the reaction mixture stirred at the room temperature for 2 to 6 hours, then treated according to example 1 to obtain 0.68 g of 6-ethoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, at 98.0% purity, as a yellow viscous liquid, yield of 28.2%. GC-MS (M+) (EI, 70 eV, m/z) calc: 342. found: 342. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.100 (t, J=6.9 Hz, 3H, CH3), 1.322 (t, J=6.9 Hz, 3H, CH3), 3.189 (q, J=6.9 Hz, 2H, CH2), 4.295 (q, J=6.9 Hz, 2H, CH2), 4.754 (s, 2H, CH2), 6.108 (d, J=9.0 Hz, 1H, Py H), 7.397 (s, 1H, Thiazole H), 8.084 (d, J=9.0 Hz, 1H, Py H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])C1C=CC=CC=1.[H][H].Cl>C(O)(=O)C.[C].[Pd].C(OCC)(=O)C>[OH:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[C:10]([CH3:20])([CH3:19])[C:9](=[O:21])[NH:8]2
Reactant: Cc1ccc(O)c2c1N(Cc1ccccc1)C(=O)C2(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c2c1NC(=O)C2(C)C
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
41.0 g (146 mmol) of 1-benzyl-2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one was dissolved in 11 of acetic acid. After the addition of 82 g of a 10% palladium-carbon catalyst, the reaction atmosphere was replaced with hydrogen and 40 ml (160 mmol) of 4N hydrogen chloride solution in ethyl acetate was added, following which the mixture was stirred for 2.5 hours over a water bath at 80° C. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 4:1 mixture of chloroform and methanol) and recrystallized (ether) to obtain 27.58 g (yield, 98.9%) of colorless prisms of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCN3C=CN=C3)[C@H]2[OH:42])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C@@H:12]2[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]2[N:8]2[C:9]3[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=3[N:6]=[CH:7]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](OCCCCn4ccnc4)[C@H]3O)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
A mixture of the 2,6-diamino-9-[2'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine and 2,6-diamino-9-[3'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine isomers in 0.1M tris buffer (pH 7.4), 0.1M NaSO4 buffer (pH 7.4) and DMS0 is treated with adenosine deaminase at RT for 5 days as per the procedure of Example 3. The product containing fractions are purified by silica gel chromatography and the product containing fraction evaporated to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([O-])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:14](=[O:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)[O-]
Reactant: O=C1CCCc2cc(O)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCc2cc(O)ccc2C1=O
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To 6-hydroxy-1-tetralone (10.4 g, 0.064 mol) and ethyl oxalate (17.4 mL, 0.128 mol) in THF (100 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M in THF, 130 mL). The slurry was stirred overnight and a solid was filtered. The solid was dissolved in water and made acidic to pH 2.5 with 3 N HCl, precipitating a waxy solid. The waxy solid was extracted into EtOAc, dried (MgSO4), and concentrated in vacuo leaving a dark solid (15.7 g). The solid was purified by chromatography on silica gel, eluting with 15% EtOAc/hexanes to give a yellow solid (5.9 g). The solid was recrystallized from EtOAc/hexanes to give the product as a yellow solid, 3.7 g (22% yield). FABHRMS m/z 263.0925 (M+H, C14H15O5 requires 263.0919). 1H NMR (CDCl3/300 MHz) 7.93 (d, 1H); 6.80 (d of d, 1H); 6.68 (s, 1H); 5.72 (s, 1H); 4.39 (q, 2H); 3.00-2.75 (m, 4H); 1.40 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C.ClCCl>[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
To 5 mL of dichloromethane solution containing 0.14 g of (7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.22 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 36 of acetic acid were added, then, 0.20 g of sodium triacetoxyborohydride was added to the reaction mixture, and stirred for 3 hours. To the reaction mixture, water, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1], to give 0.30 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [N:1]([C:4]([C:7]([C:10]([C:19]([F:22])([F:21])[F:20])([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[O:11][Na])([F:9])[F:8])([F:6])[F:5])=[N+:2]=[N-:3].S(OC)(O[CH3:27])(=O)=O>>[N:1]([C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([O:11][CH3:27])([C:19]([F:22])([F:21])[F:20])[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(F)(F)C(F)(F)C(O[Na])(OCC(F)(F)F)C(F)(F)F
Reactant: COS(=O)(=O)OC
Product: COC(OCC(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(F)N=[N+]=[N-]
Yield: 72 %

Procedure:
To demonstrate that the product was N3CF2CF2C(ONa)(OCH2CF3)CF3, the reaction mixture was stirred overnight with 56.7 g (0.45 mol) of dimethyl sulfate, then heated to 40° (0.5 mm, 0.1 kPa) to remove volatiles. Fractionation of the volatiles gave 101.4 g (72%) of 6-azido-4-methoxy-4-trifluoromethyl-1,1,1,5,5,6,6-hepta fluoro-3-oxahexane, bp 60°-61° (15 mm, 2.0 kPa). IR (CCl4): 3010, 2970, and 2660 (sat'd CH), 2150 (N3), 1300-1100 cm-1 (CF, C--O). NMR (CCl4): 1H 4.10 (q, JFF 7.8 Hz, 2H, CH2CF3) and 3.67 ppm (s, 3H, OCH3); 19F-73.8 (t of t, JFF 9.3, 7.9 Hz, 3F, CF3), -75.3 (t, JHF 7.8 Hz, 3F, CF3CH2), -89.3 (q or t, JFF 7.9, 3.4 Hz, 2F, CF2N3), and 117.7 ppm (q of t, JFF 9.3, 3.4 Hz, CF2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.[CH3:23][NH:24][O:25][CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH:6]=[CH:5]2
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
To a DMF (1 ml) solution of 6-bromoquinoline-2-carboxylic acid (4000 mg, 15.9 mmol, US2005165049A1), triethylamine (6.64 ml, 47.6 mmol), N,O-dimethylhydroxyamine hydrochloride (1860 mg, 19.0 mmol) and HBTU (6620 mg, 17.5 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with saturated NaHCO3 aqueous solution and water, and the product was extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude residue was applied to a silica gel column chromatography and eluted with hexane/ethyl acetate (4:1) to furnish the title compound (4.29 g, 92% yield) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 3.47 (3H, s), 3.80 (3H, s), 7.68-7.80 (1H, brs), 7.81-7.85 (1H, m), 8.00-8.06 (2H, m), 8.17 (1H, d, J=8.1 Hz). MS (ESI): m/z 295, 297 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH:2]([CH3:4])[CH3:3].C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH2:1]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:21])=[O:23])[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2c(CC(C)C)nn3ccccc23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cc1nn2ccccc2c1-c1ccnc(S(C)=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
To a cold (0° C.) solution of 2-isobutyl-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (890 mg, 2.98 mmol) in dichloromethane (25 mL) was added sodium bicarbonate solid (500 mg), and m-chloroperbenzoic acid (734 mg, ˜70% pure, 2.98 mmol). The mixture was stirred at 0° C. for 20 minutes and then quenched by the addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The biphasic mixture was allowed to warm to room temperature and stirred vigorously for 15 minutes. The layers were separated and the organic layer washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration in vacuo provided 2-isobutyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (930 mg, 99%) as a yellow solid. 1H NMR (CDCl3) δ 8.73 (d, 1H), 8.63 (d, 1H), 8.47 (d, 1H), 7.48 (d, 1H), 7.43 (t, 1H), 6.94 (t, 1H), 3.00 (d, 2H), 2.99 (s, 3H), 2.16 (m, 1H), 1.01 (d, 6H); MS m/z 315 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[CH:9][CH:8]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:14](=[O:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([S:6][CH3:5])=[CH:8][CH:9]=2)=[CH:21][CH:20]=1
Reactant: Fc1ccccc1
Reactant: CSc1ccc(CC(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 40 %

Procedure:
Thereafter 174 g (1.3 moles) of anhydrous aluminum chloride was suspended in 600 ml of fluorobenzene. To the suspension was added dropwise a solution of 175 g of 4-methylthiophenylacetyl chloride obtained in the same manner as above in 120 ml of fluorobenzene at a temperature of 0° to 3° C. The resulting mixture was stirred at 20° C. for 3.5 hours. Then the reaction mixture was gradually poured into a mixture of ice water and hydrochloric acid, followed by extraction with dichloromethane. The dichloromethane layer was washed sequentially with a 5% aqueous solution of sodium bicarbonate and a saturated saline solution and dried over magnesium sulfate. The dichloromethane was distilled off and the resulting crystals were dissolved in 300 ml of a 2:1 mixture of ethyl acetate and isopropyl ether with heating. Ten grams of activated carbon was added and the solution was filtered. The separated crystals were collected by filtration, giving 92 g (40%) of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone as pale yellow solids.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[NH2:2].O=[C:16]([CH3:29])[CH:17]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:18](OC)=[O:19]>CCO.CC(O)=O.CCOC(C)=O>[CH3:13][N:12]([CH3:14])[S:9]([C:6]1[CH:7]=[N:8][C:3]([N:1]2[C:18](=[O:19])[C:17]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:16]([CH3:29])[NH:2]2)=[CH:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CN(C)S(=O)(=O)c1ccc(NN)nc1
Reactant: COC(=O)C(Cc1cccnc1)C(C)=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1[nH]n(-c2ccc(S(=O)(=O)N(C)C)cn2)c(=O)c1Cc1cccnc1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
A mixture of 400 mg (1.85 mmol) of 6-hydrazino-N,N-dimethylpyridine-3-sulfonamide and 383 mg (1.85 mmol) of methyl 3-oxo-2-(pyridin-3-ylmethyl)butanoate in 4 mL of EtOH/AcOH mixture (1:1) is heated for 4 hours at 80° C. and then concentrated under reduced pressure. The residue obtained is taken up in 20 mL of EtOAc, washed successively with water (2×20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is then solidified in 20 mL of an Et2O/pentane mixture (1/1), filtered and recrystallized from a cyclohexane/EtOH mixture. 188 mg of N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-sulfonamide are obtained in the form of white crystals.
Reaction SMILES: CO[C:3]1([CH2:24]CCC)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:34]1COCC1>>[CH3:24][C:3]1([CH3:34])[CH:6]([OH:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]1[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: CCCCC1(OC)C(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Temperature: 0 °C

Procedure:
To a solution of Example 14 (100 mg) in THF (1 mL) at 0° C., was added LAH (1M, THF, 920 μL). The mixture was stirred at 0° C. for min., quenched with H2O, and diluted with EtOAc. The organic phase was washed with HCl 1N, brine, dried (MgSO4) and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (70:30)) to give the title compound as a white solid, m.p. 79°-81° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:30][CH2:31][C:32]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([O:9][CH:6]3[CH2:5][CH2:4][CH:3]([C:2]([F:1])([F:19])[F:20])[CH2:8][CH2:7]3)=[CH:18][CH:17]=2)[CH2:13][CH2:14]1)=[O:33]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-1H-indole (130 mg, 0.46 mmol) and DIEA (103 uL) in methylene chloride (2 mL) was added chloroacetyl chloride (47 uL, 0.59 mmol) at room temperature. The black solution was stirred for 30 min. The solvent was concentrated to give crude product. The crude was used directly for next step without further purification (80 mg, yield: 77%). ESI-MS: 362.10 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O-:19])(=O)=[O:17])=[CH:12][CH:11]=1>O>[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:2])(=[O:19])=[O:17])=[CH:12][CH:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
About 320 g of phosphorus pentachloride was taken in a three-neck round-bottomed flask. One neck was fitted with a mechanical stirrer, and a second neck was fitted with a plastic tube to collect hydrochloric acid produced by the reaction. About 190 g of p-styrenesulfonate sodium salt was added in small portions to the phosphorus pentachloride through the third neck while cooling the flask to 0° C. After the addition, the contents were allowed to stir at ambient temperature for 2 hours. Deionized ice water was then added dropwise to the flask, cooling the contents again to 0° C. The mixture was transferred to a separating funnel using additional water. An oily organic layer was collected and the remaining aqueous solution was extracted with dichloromethane. The organic layer was then combined and dried with anhydrous sodium sulfate. This solution was filtered through a small silica gel (100 g) column. The filtrate was collected and dichloromethane was removed under vacuum to obtain 125 g of p-styrenesulfonyl chloride blocked acid monomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=O.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:19][OH:20]
Reactant: CC1CCCCC1n1ccc(Cl)c(C=O)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CCCCC1n1ccc(Cl)c(C=NO)c1=O
Temperature: 75 °C
Yield: 92.1 %

Procedure:
A mixture of 4-chloro-1-(2-methylcyclohexyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (1.22 g), hydroxylamine hydrochloride (667 mg) and sodium acetate (787 mg) in methanol/water (4:1, 6.0 mL) was heated at 75° C. for 1 hr, and cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (1.19 g).