Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10]/[C:11](/[N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:28][CH:29]=2)[CH:24]1[C:43]1([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)=[N:12]\C(=O)OCC1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].Br[CH2:59][CH:60]([O:63][CH3:64])[O:61][CH3:62]>C(O)C>[CH3:62][O:61][CH:60]([O:63][CH3:64])[CH2:59][NH:10][C:11]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:38])=[O:39])=[CH:28][CH:29]=2)[CH:24]1[C:43]1([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)=[NH:12]
Reactant: COC(CBr)OC
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)NCC(OC)OC)CC2
Temperature: 120 °C
Reaction time: 1.33 h

Procedure:
1-[1-(4-Fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinoline-2(1H)-carboximidamide acetate (140 mg, 0.255 mmol, cf. example 72) was suspended in ethanol (2 mL). Sodium methylate (138 mg, 0.142 mmol) and 2-bromo-1,1-dimethoxyethane (65 mg, 0.383 mmol) were added. The reaction mixture was stirred at 120° C. in the microwave (80 W) for 80 min. The solvent was evaporated in vacuo and the crude product was used without further purification for the next step.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]2[C:5]=1[CH2:6][CH2:7][C@@:8]([CH3:32])([CH2:16][CH2:17][CH2:18][C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[O:9]2)[CH:2]=[CH2:3].C(#N)C.[O:36]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>O>[CH2:1]([C:4]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[C:10](=[O:9])[C:5]=1[CH2:6][CH2:7][C@@:8]([OH:36])([CH3:32])[CH2:16][CH2:17][CH2:18][C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C)c2c1CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C=CCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A 50 mL RBF flask was charged with (R,R,R)-5-allyl-2,8-dimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol (Ex-1E-3) (280 mg, 0.63 mmol) and ACN (14 mL), then cooled to 0° C. A solution of CAN (710 mg, 1.30 mml) in water (2 mL) was added dropwise over 1 min to the reaction resulting in a bright orange solution. After 15 min, the reaction was deemed complete (TLC—5:1 hept:EtOAc). The reaction was extracted with MTBE (3×15 mL). The combined MTBE layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield (R,R,R)-2-allyl-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-[1,4]benzoquinone (Ex-1E-4) as an orange oil (270 mg, 96%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.59 (d, J=1.4 Hz, 1H), 5.82 (ddt, 1H), 5.10-5.06 (m, 2H), 3.27 (d, J=6.2 Hz, 2H), 2.60-2.56 (m, 2H), 2.06 (s, 6H), 1.59-1.04 (m, 21H), 0.89-0.85 (m, 15H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](OCC)=[O:27])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][OH:27])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 2.6 g of ethyl 2-tritylaminothiazole-4-carboxylate and 10 ml of tetrahydrofuran was added dropwise under ice-cooling to a mixture comprising 0.24 g of lithium aluminum hydride and 30 ml of tetrahydrofuran, under a stream of nitrogen. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 3 hours, and then with heating under reflux for one hour. Ethyl acetate and then water were added to the reaction mixture under ice-cooling, the organic layer was separated off, and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extract was washed with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography, using as eluent a 1:1 by volume mixture of benzene and ethyl acetate. The product was recrystallized from a mixture of ethyl acetate, acetone and n-hexane. giving the desired compound as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=3)[N:10]=[C:9]([NH2:26])[CH:8]=2)[CH:4]=[N:3]1.[CH3:27][C:28]([O-])=O.[Na+].ClCC=O.C([O-])(O)=O.[Na+]>P([O-])([O-])([O-])=O.CCO.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[CH:17]=3)[N:10]3[CH:27]=[CH:28][N:26]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)[O-]
Reactant: Cn1cc(-c2cc(N)nc(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Agent: O=C([O-])O
Agent: O=CCCl
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 95 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (2.0 g, 5.4 mmol) was suspended in a mixture of 40 mL of pH 7 phosphate buffer and 16 mL of EtOH. To the milky white mixture was added NaOAc (0.79 g, 9.7 mmol) followed by 2-chloroacetaldehyde (1.0 mL, 8.1 mmol). The reaction mixture was then heated to 95° C. After 5 hours, the reaction was incomplete and another portion of 2-chloroacetaldehyde (0.10 mL, 0.81 mmol) was added and stirred for another 1 hour. After cooling, the reaction mixture was diluted in EtOAc and saturated NaHCO3. After separation, the organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was diluted in diethyl ether, sonicated, and filtered to afford 0.88 g of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine as an off-white solid. Additional product was obtained by concentration of the filtrate and purification by silica chromatography using 0-10% MeOH/EtOAc. This afforded another 0.80 g of the intermediate. MS (apci) m/z=396.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[C:4]([F:29])[CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:49])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[C:4]([F:29])[CH:3]=1
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 300 mg (0.70 mmol) of the compound from Example 290 in analogy to the synthesis of the compound from Example 296. 258 mg (83% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.[ClH:32]>C(O)C.C(OCC)(=O)C>[ClH:32].[ClH:32].[NH2:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl[(1S)-1-benzyl-2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl]carbamate (800 mg) in ethanol (30 mL) was added 4N hydrogen chloride in ethyl acetate (5 mL) and the mixture was stirred at 60° C. for 1 hour. The solvents were removed by evaporation in vacuo and the residue was recrystallized from 2-propanol to afford (2S)-2-amino-3-phenyl-N-[4-(4-pyridinyl)phenyl]propanamide dihydrochloride (625 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[N:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13]([CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[N:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2F)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A mixture of 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene (7.65 g), 6-(methylsulfonyl)pyridin-3-ol (5.0 g) and potassium carbonate (4.4 g) in N,N-dimethylformamide (40 mL) was stirred at 90° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with successively water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=25:75 to 40:60, volume ratio) to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (8.4 g, 69%) as pale yellow crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:30])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:17](=[O:19])[CH3:18].[F:31][C:32]([F:36])([F:35])[S:33]Cl>CCCCCC.O1CCCC1>[CH3:30][N:14]([CH3:13])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)[C:17](=[O:19])[CH2:18][S:33][C:32]([F:36])([F:35])[F:31]
Reactant: FC(F)(F)SCl
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)C=C(C(=O)CSC(F)(F)F)c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Two hundred ml. of dry tetrahydrofuran was combined with 8.1 g. of diisopropylamine, and the mixture was chilled to -70° under a nitrogen stream. A 36 ml. portion of 2.2-molar n-butyllithium in hexane was added, and the mixture was stirred for 5 minutes. Then a suspension of 18.8 g. of 1-dimethylamino-2-(3-trifluoromethylphenyl)-1-butene-3-one in 100 ml. of tetrahydrofuran was added at a rate such that the temperature of the mixture remained below -60°. The mixture was then stirred for 30 minutes more, and to it was added 10 g. of trifluoromethylsulfenyl chloride in 40 ml. of tetrahydrofuran, maintaining the temperature of the mixture below -60°. After the addition was complete, the reaction mixture was stirred for 15 minutes more, and was then allowed to warm to 10° over a period of 1 hour. The reaction was then quenched by the addition of saturated potassium dihydrogen phosphate solution and was diluted with water and diethyl ether. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness under vacuum to obtain a dark oil which solidified on standing. The oil was chromatographed on a 500 g. silica gel column, with 1:9 ethyl acetate:dichloromethane as the eluting solvent. The product-containing fractions were combined and evaporated to dryness under vacuum to obtain 4.3 g. of the expected product, which was identified by nmr (CDCl3): δ7.3-7.7 (m, 5H); 3.7 (s, 2H); 2.65 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)OCCC2N
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)c1ccc2c(c1)OCCC2NC(=O)OCc1ccccc1

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using 4-aminochromane-7-carboxylic acid methyl ester (1.4 g) and benzyloxycarbonyl chloride (2.0 ml), the objective 4-(benzyloxycarbonylamino)chromane-7-carboxylic acid methyl ester (1.9 g) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.C(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2nccs2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2nccs2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(1,3-thiazol-2-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (220 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:2 to give the title compound as colorless crystals (yield 82.8 mg, 44%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][N:24](CC5C=CC(OC)=CC=5)[C:17]=34)[C:12]([CH3:34])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.FC1C(C2C=C(NC3C4C(=CN(CC5C=CC(OC)=CC=5)N=4)N=CC=3)C(C)=CN=2)=NC(C)=CC=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:34])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2ncc3nccc(Nc4cc(-c5nc(C)ccc5F)ncc4C)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4cc(-c5nc(C)ccc5F)ncc4C)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Temperature: 70 °C
Yield: 72.8 %

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and TFA (6.2 mL) were combined and heated at 70° C. for 3 hours. The reaction mixture was cooled, concentrated, and the residue combined with dichloromethane (20 mL). To this mixture was added saturated sodium bicarbonate (20 mL) and the reaction was let stand for 10 minutes to give a solid which was collected by filtration, subsequently dissolved in EtOAc (500 mL), and washed with brine (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated to give N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (0.15 g, 0.449 mmol, 72.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (3H, s) 2.44 (3H, s) 7.04 (1H, d, J=5.05 Hz) 7.34 (1H, dd, J=8.59, 3.28 Hz) 7.63-7.71 (2H, m) 8.24 (1H, s) 8.34 (1H, d, J=5.05 Hz) 8.43 (1H, s) 8.48 (1H, s) 13.04 (1H, s). MS [M+H] found 335.2.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:18]1[CH:17]=[C:16]2[C:21]([N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C@@H:13]([CH2:24][CH3:25])[C:14](=[O:23])[N:15]2[CH2:31][CH3:32])=[CH:20][CH:19]=1
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccc(Br)cc3NC(=O)[C@@H]2CC)cc1
Reactant: CCI
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CC[C@H]1C(=O)N(CC)c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-6-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl ethyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-7-bromo-1,3-diethyl-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−780 (c=0.005 G/ML, DMSO); MS (ESI) m/z 439/441 ([M+H]+); MS (ESI) m/z 437/439 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C1COCC1.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c(N)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) in acetic acid (10 mL) and THF (10 mL) was added zinc (2.59 g) at 0° C., and the mixture was stirred at 0° C. for 2 h. After stirring at room temperature overnight, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with AcOEt, washed with sat. NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% AcOEt in hexane) to give N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) as a blue solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.CCCP(=O)=O.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][C:17]=5[CH3:16])[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccn2ccnc(N3CC[C@H](N)C3)c12
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)n1
Agent: CCCP(=O)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccn2ccnc(N3CC[C@H](NC(=O)c4ccn(-c5ccc(F)cc5)n4)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (0.04 g, 0.19 mmol, 1.5 eq) in 1 mL of DCM was added (S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.036 g, 0.13 mmol, 1 eq), propylphosphonic anhydride (0.3 mL, 0.47 mmol, 2.5 eq), and N-methylmorpholine (0.15 mL, 1.36 mmol, 10.5 eq). The reaction mixture was stirred at room temperature for 1 h then quenched with H2O and extracted with ethyl acetate. The combined organic layers were concentrated and purified by HPLC to afford (S)-1-(4-fluorophenyl)-N-(1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1H-pyrazole-3-carboxamide (0.030 g, 0.074 mmol, 57%). 1H NMR (400 MHz, CDCCl3) δ 7.91 (d, J=7.3 Hz, 1 H), 7.82 (s, 1 H), 7.68 (dd, J=4.4, 8.8 Hz, 2 H), 7.33 (d, J=4.8 Hz, 1 H), 7.19 (t, J=8.8 Hz, 3 H), 7.00 (m, 2 H), 6.50 (s, 1 H), 4.75 (s, 1 H), 3.90-3.56 (m, 4 H), 2.57 (s, 3 H), 2.42-2.38 (m, 1 H), 2.02-1.80 (m, 1 H); MS: (ES) m/z calculated for C22H21FN6O[M+H]+ 405.2, found 405.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:8]([CH3:10])[CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:11]([N:6]1[C:5]([CH2:3][OH:2])=[CH:9][C:8]([CH3:10])=[N:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(C)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
To a stirring solution of 833 mg (3.61 mmol) of 2-Benzyl-5-methyl-2H-pyrazole-3-carboxylic acid methyl ester, prepared as in Part B, in 5 mL of THF at 0° C. is added dropwise over 5 min a solution of 5.5 mL (5.5 mmol, 1.5 equiv) of a 1.0M solution of LiAlH4 in THF. The resulting solution is stirred at RT for 48 h. The reaction mixture is cooled to 0° C. and worked up by carefully quenching first with 0.20 mL of H2O, then 0.20 mL of 15% NaOH, then 0.60 mL of H2O. The resulting slurry is filtered and the filter cake triturated with 20 mL EtOAc and refiltered. The filtrates were combined, dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by Kugelrohr distillation gave 710 mg of (2-Benzyl-5-methyl-2H-pyrazol-3yl) methanol as a clear oil: 1H NMR (CDCl3, 300 MHz) δ7.41-7.29 (m, 3H), 7.16 (m, 2H), 6.07 (s, 1H), 5.37 (s, 2H), 4.55 (s, 2H), 2.30 (s, 3H); low resolution MS (FAB)m/e 203 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:20].[C:21]([C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31]O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:31][CH2:30][CH2:29][C:25]1[CH:24]=[C:23]([C:21]#[N:22])[CH:28]=[CH:27][CH:26]=1
Reactant: [Br-]
Reactant: N#Cc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CC#N
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromide in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The filtrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.