Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3](=[C:9]([O:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/[N:12](C)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.C(O)(=[O:20])C>>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][NH:12][C:13](=[O:20])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:17]
Reactant: CCOC(=O)C(C#N)=C(/C=C/N(C)C)OCC
Reactant: CC(=O)O
Product: CCOC(=O)c1c(OCC)cc[nH]c1=O
Temperature: 100 °C
Yield: 58.5 %

Procedure:
(4E)-Ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (20 kg) and acetic acid (126 L) were charged to a reactor and heated to 100° C. for 3 hrs until the reaction was complete as characterized by HPLC. The reaction mass was cooled to 55° C. and acetic acid was removed by vacuum distillation at 65-75° C. After distillation, the mixture was cooled to room temperature and water (3 L) was added. The pH of the mixture was adjusted to 8 by addition of 100 L of a 30% sodium carbonate solution. The solids were filtered off and washed with 10 L of water. The combined aqueous layers were extracted three times with DCM (100 L). The combined DCM layers were washed with brine, then dried over sodium sulfate and concentrated to dryness. Ethyl acetate was added to the concentrate. The mixture was heated to 40° C. and then cooled to 25° C. The solids were filtered off, washed with petroleum ether and dried at room temperature for 12 hrs to yield ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (10.3 kg; 58.5% yield).
Reaction SMILES: [F:1][C:2]([F:31])([C:27]([F:30])([F:29])[F:28])[C:3]([F:26])([F:25])[C:4]([F:24])([F:23])[C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7](COS(C(F)(F)F)(=O)=O)([F:9])[F:8].[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.[CH3:44]N(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]([F:31])([C:27]([F:28])([F:29])[F:30])[C:3]([F:25])([F:26])[C:4]([F:23])([F:24])[C:5]([F:21])([F:22])[C:6]([F:20])([F:19])[C:7]([N:32]([CH3:44])[C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=1)([F:8])[F:9]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(N(C)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1

Procedure:
A solution of 45 g. of (pentadecafluoroheptyl)(trifluoromethanesulfonyloxy)methane and 28 g. of ethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is stirred at 120° C. for 72 hours, diluted with water, and filtered. A methylene chloride solution of the solid is dried over anhydrous magnesium sulfate and evaporated. The residue is recrystallized from acetonitrile to yield the product as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[CH3:27][O:28][CH2:29]C(Cl)=O.[C:33]1([CH2:43][NH2:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:29][O:28][CH3:27])[C@H:9]([C:24]([NH:44][CH2:43][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)=[O:26])[CH2:10]1
Reactant: NCc1cccc2ccccc12
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: COCC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NCc1cccc2ccccc12

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 91% purity by LC/MS. MS(ESI+): m/z=514.8.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was added portionwise, allowing for gas evolution, to a solution of 3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (0.7 g, 2.5 mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete, benzyl bromide (1.2 mL, 10.0 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (0.9 g, 93%) as an off white solid: MS (ES) m/e 385 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)=[O:27])#[N:2].C1COCC1>[C].[Pd].CO>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1[CH2:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)=[O:27])#[N:2]
Reactant: COc1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CCc2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1OC

Procedure:
A mixed solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(3,4-dimethoxyphenyl)prop-2-enamide (170 mg, 0.336 mmol), 10% palladium carbon (20 mg), THF (3 ml) and methanol (3 ml) was stirred under hydrogen atmosphere for 4 hours. Insolubles were filtrated off and the filtrate was concentrated to give the objective product as a solid material.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]([NH:29][C:27](=[O:28])[CH2:26][O:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: CC(C)NC(=O)CCl
Reactant: Cc1onc(-c2ccccc2)c1C(=O)c1cc2cccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)c1cc2cccc(OCC(=O)NC(C)C)c2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.5 %

Procedure:
To a solution of (7-hydroxy-2-benzofuranyl)(5-methyl-3-phenyl-4-isoxazolyl)methanone (example 4) (100 mg, 0.31 mmol) in DMF (5 mL) was added N-(chloroacetyl)isopropylamine (47 mg, 0.34 mmol) and potassium carbonate (173 mg, 1.25 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 1:1) afforded the title compound (37 mg, 28%) as a white solid. MS m/e: 419.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCO.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2COc2ccccc2)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Into a vial was added 4-(3-chloro-4-fluorophenyl)-3-[4-(phenoxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (9 mg, 23 mmol), EtOH (0.5 mL), and 2.0 M of sodium hydroxide in water (35 μL). Reaction was stirred for 2 hrs at rt. The reaction mixture was neutralized with acetic acid and then purified by preparative HPLC to yield the desired compound (7.6 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ: 11.58 (s, 1H), 9.05 (s, 1H), 7.32 (t, J=7.8 Hz, 2H) 7.19 (dd, J=9.1, 9.1 Hz, 1H), 7.0 (m, 1H), 6.97 (m, 2 H) 6.96 (m, 1 H), 6.72 (ddd, J=8.8, 4.0, 2.8 Hz, 1H), 5.43 (s, 2H); MF=C16H12ClFN4O3; LCMS calculated for C16H13ClFN4O3(M+H)+: m/z=363.066.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl[S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=O)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:78][CH2:79][C:80]1[CH:81]=[CH:82][C:83]([F:107])=[C:84]([C:86]2[CH:91]=[CH:90][CH:89]=[C:88]([CH2:92][N:93]3[CH2:98][CH2:97][N:96](C(OC(C)(C)C)=O)[C@@H:95]([CH3:106])[CH2:94]3)[CH:87]=2)[CH:85]=1>ClCCl.O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][S:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=3)[C:30]([NH:78][CH2:79][C:80]3[CH:85]=[C:84]([C:86]4[CH:91]=[CH:90][CH:89]=[C:88]([CH2:92][N:93]5[CH2:98][CH2:97][NH:96][C@@H:95]([CH3:106])[CH2:94]5)[CH:87]=4)[C:83]([F:107])=[CH:82][CH:81]=3)=[O:32])(=[O:25])=[O:26])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
A cooled solution (0° C.) of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine, (80 mg, 0.26 mmol) in dichloromethane (10 mL) was treated with 3-(chlorosulfonyl)benzoic acid (30 mg, 0.36 mmol) and diisopropylethylamine (0.09 mL, 0.52 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was then treated with PyBOP (100 mg, 0.31 mmol), diisopropylethylamine (0.15 mL, 0.86 mmol) and 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (107 mg, 0.26 mmol) and stirred at ambient temperature for 16 h. The mixture was treated with water (40 mL) and extracted with dichloromethane (25 mL) and the organic phase was then concentrated to dryness and the intermediate Boc-protected material purified by mass-directed automated preparative HPLC. Product-containing fractions were passed though a 5 g SCX solid-phase extraction cartridge and the product eluted off with a 10% solution of ammonia in methanol, product containing fractions were concentrated to dryness. The residue was dissolved in methanol, treated with aqueous hydrochloric acid (2M, 2 mL) and stirred at ambient temperature for 16 h. The mixture was then dried (hydrophobic frit), evaporated to dryness and the product purified by mass-directed automated preparative HPLC. Product-containing fractions were passed though a 2 g SCX solid-phase extraction cartridge and the product eluted off with a 10% solution of ammonia in methanol, product-containing fractions were concentrated to dryness to afford 16 mg of the title compound. LC-MS m/z 783 (M+H)+, 0.92 min (ret time).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([NH:31][C:32]3[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34](Cl)[CH:33]=3)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C=O)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([NH:31][C:32]3[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34]([O:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)[CH:33]=3)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3cc(Cl)ncc3[N+](=O)[O-])cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
A solution of 3-acetamidophenol (4.8 g, 32 mmol) in THF (200 mL) was cooled to 0° C. To the solution was added NaH (60% in oil, 1.3 g, 32 mol) and the mixture was warmed to rt and allowed to stir for 30 minutes. The product from Step 1 (˜8.5 g, ˜21 mmol) was added and the mixture was stirred at rt overnight then DMF (10 mL) was added and the solution was heated to 60° C. overnight. The reaction mixture was concentrated in-vacuo, then taken up in EtOAc and H2O and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude oil was purified chromatography to give the title compound (4.3 g, 39%). MS (ES+) m/e 521 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]([N+]([O-])=O)=[CH:9][NH2:10].[CH3:14][S:15][CH:16](SC)[CH2:17][N+:18]([O-:20])=[O:19]>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19]
Reactant: CSC(C[N+](=O)[O-])SC
Reactant: NC=C(SCc1ccco1)[N+](=O)[O-]
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Yield: 50.4 %

Procedure:
A solution of 2-[(2-furanylmethyl)thio]-2-nitroethenamine (3.14 g.) and 1,1-bis-(methylthio)-2-nitroethane (13.2 g.) in dioxan (100 ml.) was heated at 100° for 11/2 hours. The solution was evaporated in vacuo and the residue suspended in warm ethyl acetate (70 ml.). The cooled suspension was filtered and the filtrate evaporated in vacuo. The oily residue was suspended in ether and the solid which separated was filtered and crystallised from ethanol to give the title compound (2.17 g.), m.p. 68°-70°.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([CH3:16])[C:8]=2[N+:13]([O-])=O)[N:3]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:13][C:8]1[C:7]([CH3:16])=[C:6]([CH3:17])[CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[N:3]2
Reactant: Cc1cc2nc(Cl)c(Cl)nc2c([N+](=O)[O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc2nc(Cl)c(Cl)nc2c(N)c1C
Yield: 83 %

Procedure:
A mixture of 2,3-dichloro-6,7-dimethyl-5-nitroquinoxaline, 8.33 g, 30.6 mmol) and stannous chloride dihydrate (34.54 g, 153 mmol) in ethyl acetate (300 ml) was heated at reflux for 11 hours. A further portion of stannous chloride dihydrate (13.82 g, 61.2 mmol) was added and the mixture was heated for 2 hours, cooled and diluted with ethyl acetate (500 ml). The mixture was added to saturated aqueous sodium bicarbonate (200 ml) and filtered, washing the filter cake well with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (3×100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with methanol/dichloromethane) to afford 5-amino-2,3-dichloro-6,7-dimethylquinoxaline (6.15 g, 83%), as an orange solid, mp 178°-180° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[N:13]=[CH:12][C:11]2[C:14]([NH:36][C:37](=[O:39])[O-:38])=[N:15][N:16](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:10]=2[CH:9]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C@H:47]([NH:49][C:50]([NH2:52])=[O:51])[CH3:48])=[CH:43][CH:42]=1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([SiH](CC)CC)C>O1CCOCC1>[F:40][C:41]1[CH:42]=[CH:43][C:44]([C@H:47]([NH:49][C:50](=[O:51])[NH:52][C:8]2[N:13]=[CH:12][C:11]3[C:14]([NH:36][C:37](=[O:39])[O:38][CH3:1])=[N:15][NH:16][C:10]=3[CH:9]=2)[CH3:48])=[CH:45][CH:46]=1
Reactant: O=C([O-])Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](NC(N)=O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccc(F)cc3)ncc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A 5 mL microwave vial was charged with cesium carbonate (71.7 mg, 0.220 mmol), (6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (40 mg, 0.085 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (23.3 mg, 0.128 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (3.21 mg, 5.97 μmol) and BrettPhos-G3-Pd (5.41 mg, 5.97 μmol). Dioxane (1 ml) was added, the vial was flushed with argon, capped and the contents heated to 100° C. with stirring for 16 h. The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added and the contents heated to 65° C. for 4 h with shaking. The reaction mixture was filtered, washing through with DCM (2 mL) and concentrated. The resulting residue was re-dissolved in TFA (1 mL) and stirred at room temperature for 30 minutes. Triethylsilane (0.014 ml, 0.085 mmol) was added drop wise and the reaction mixture was stirred for an additional 5 minutes. The volatiles were removed in vacuo, the resulting residue was re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered HPLC to afford (R)-methyl (6-(3-(1-(4-fluorophenyl)ethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate. TFA (5.4 mg, 0.011 mmol, 13.1% yield) as a white solid. MS ESI calc'd. For C17H18FN6O3 [M+H]+ 373. found 373. 1H NMR (ppm, 600 MHz, DMSO-d6): δ 10.39 (s, 1H); 9.26 (s, 1H); 8.94 (s, 1H); 7.76 (s, 1H); 7.43 (s, 1H); 7.35 (dd, J=8.4, 5.5 Hz, 2H); 7.13 (t, J=8.8 Hz, 2H); 4.84 (t, J=7.2 Hz, 1H); 3.68 (s, 3H); 1.37 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)(=[O:41])=[O:40])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)nc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 5-methyl-2-pyridinesulfonamide: 1H-NMR (CDCl3) δ 8.47 (1H, s), 7.90 (1H, d, J=7.9 Hz), 7.73 (1H, d, J=7.9 Hz), 7.47-7.24 (9H, m), 6.68 (1H, br.s), 3.54-3.44 (2H, m), 2.88-2.83 (2H, m), 2.43 (3H, s), 2.33 (3H, s), 2.27 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[CH3:11][S:12][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C=O)cc1F
Yield: 73.4 %

Procedure:
A solution of 3,4-difluorobenzaldehyde (2.8 g, 20 mmol) and sodium thiomethoxide (1.5 g, 20 mmol) in dimethylformamide (20 ml) was heated at 80° C. under an argon atmosphere for 2 hours. The reaction was cooled, poured into water (125 ml) and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and evaporated. The residue was distilled (bp 110-111° C., 0.5 mm Hg) to give 2.5 g (75%) of the desired aldehyde: Anal. Calc'd. for C8H7FSO (MW 170.21): C, 56.45; H, 4.15; S, 18.84. Found: C, 56.40; H, 4.00; S, 18.90.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[CH3:7][C:8]1([CH3:21])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([CH3:20])[CH:11]=[CH:10][C:9]1=2.[OH-:22].[Na+]>N1C=CC=CC=1>[CH3:7][C:8]1([CH3:21])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]([OH:1])=[O:22])[CH:11]=[CH:10][C:9]1=2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Temperature: 95 °C
Reaction time: 5 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The KMnO4 in the reaction path stands for potassium permanganate. To 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-methylnaphthalene (3.52 g, 17.4 mmol) were added pyridine (12 mL), potassium permanganate (6.70 g, 42.4 mmol), and sodium hydroxide (1.00 g, 25.0 mmol) followed by stirring at 95° C. for 5 hours. The reaction solution was filtrated by celite and the filtrate was made acidic by adding hydrochloric acid. After extraction by ethyl acetate, the liquid was dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (4/1) as an elution solvent. The yield was 141.6 mg (3%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12]I.O>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][CH3:12])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCc1cccc(Br)n1
Temperature: 2.5 °C
Yield: 93 %

Procedure:
Add dropwise a solution of (6-bromo-pyridin-2-yl)-methanol (9.6; g, 51; mmol) in anhydrous tetrahydrofuran (29; mL) to a stirring suspension of sodium hydride (60% dispersion in oil, 2.45; g, 61; mmol) in anhydrous tetrahydrofuran (96; mL) cooled to 0-5° C. under nitrogen. After gas evolution ceases, add dropwise methyl iodide (10.9; mL, 77; mmol) and warm to room temperature over 1; hour. Add iced water (100; mL), dilute with brine (100; mL) and ethyl acetate (200; mL). Separate the layers. Extract the organic layer once with brine (100; mL), dry over sodium sulfate and decant the liquid. Concentrate to a pale yellow oil (11.1; g) and distill using a Kügelrohr apparatus to give the title product as a colorless liquid (10.1; g, b.p.=140-150° C. at 2.4; mbar, 93%). MS (m/z): 202, 204; (M+1).