Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1C[CH2:23][CH:22](I)[C:21]1([CH3:27])[CH3:26].C[OH:29]>[C].[Pd]>[CH3:26][C:21]1([CH3:27])[CH2:22][CH2:23][O:29][CH:20]1[C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CCC(I)C2(C)C)c1
Reactant: CO
Agent: [Pd]
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2OCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 66.60E (0.388 g, 0.801 mmol) in MeOH (17 mL) (degassed by N2), was added palladium-carbon (0.0853 g, 0.801 mmol). The resulting mixture was stirred at room temperature under H2 for 23 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:19 EtOAc/hexane) and gave 65 mg of 69.43A. MS ESI (pos.) m/e: 376 (M+18)+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1)#[N:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[N:13]=1.CC([O-])=O.[Na+]>C1COCC1.O>[CH3:8][N:7]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[N:13]=1)[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CNc1ccc(C#N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N(C)c2ccc(C#N)cc2)c2ccccc2n1
Temperature: 23 °C
Reaction time: 96 h
Yield: 1 %

Procedure:
To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH2Cl2 150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]+). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH3 in Me2S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]+). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H2O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). 1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[OH:32][CH:33]1[C@H:38]2[CH2:39][NH:40][CH2:41][C@@H:34]1[CH2:35][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:40]5[CH2:39][C@H:38]6[CH:33]([OH:32])[C@H:34]([CH2:35][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]6)[CH2:41]5)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@@H](C1)C2O
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@@H](C4)C5O)cn3)nc2n1C1CCCC1
Yield: 77 %

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl was combined with (1R,5S)-tert-butyl 9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate which gave (1R,5S)-tert-butyl 7-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (158 mg) in 77% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.76 (s, 1H), 8.56 (d, J=8.59 Hz, 1H), 8.41 (s, 1H), 8.28 (br s, 1H), 7.92 (d, J=7.07 Hz, 1H), 6.47 (s, 1H), 4.80 (m, 1H), 4.67-4.29 (m, 2H), 4.14-3.68 (m, 3H), 3.48 (m, 1H), 3.24-2.99 (m, 7H), 2.60 (m, 2H), 2.26-1.54 (m, 10H), 1.49 (s, 9H); LCMS m/z 619.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22]([OH:24])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22]([Cl:27])=[O:24])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)n1c(C(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Product: CC(C)n1c(C(=O)Cl)c(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
A mixture of 4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4.9 g) and thionyl chloride (50 ml) was heated at reflux for 90 minutes. The excess thionyl chloride was then removed by evaporation in vacuo (15 mmHg/40° C.) followed three times by treatment with dichloromethane and evaporation in vacuo, to give 4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carbonyl chloride (4.35 g) in the form of a white solid, m.p.132°-134° C. [Elemental analysis: C,66.4; H,4.4; N,4.04; Cl,10.3%; calculated: C,66.4; H,4.40; N,4.08; Cl,10.31%].
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:23])[CH2:16][CH2:17][C:18](=O)[C:19]([CH3:21])([CH3:20])[C@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[OH:24].[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30]/[N:31]=[C:18]1/[C:19]([CH3:21])([CH3:20])[C@:2]23[O:1][C@H:3]2[CH2:4][C@@H:5]2[C@@H:14]([C@@:15]3([CH3:23])[CH2:16][CH2:17]/1)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C@@H:9]1[OH:24]
Reactant: NCCON
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Agent: Cl
Product: CC1(C)/C(=N/OCCN)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Yield: 68 %

Procedure:
The title compound was prepared as described in Example 2 starting from 5α,6α-epoxy-17β-hydroxy-4,4-dimethylandrostan-3-one, (Preparation 8, 54 mg) and 2-aminoethoxyamine dihydrochloride (97 mg). The solution was evaporated, water was added and the aqueous phase was extracted with THF. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was triturated with diisopropyl ether/MeOH 95/5 and the precipitate was filtered to give the title compound (47 mg, 68%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=3)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]#[CH:32].O>CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:32][C:31]#[CH:30])[C:6]2[CH:8]=[C:9]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=3)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc3c(c2)NC(=O)CO3)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2ccc(-c3ncc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Then, 0.15 g of 3-(3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-1) was dissolved in 0.92 ml of N,N-dimethylformamide, to which 0.127 g of potassium carbonate and 70 μl of propargyl bromide were added, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.12 g (yield, 74%) of 3-(3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-13; m.p., 129.2° C.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]#[N:19])[N:8]=1.C(=O)([O-])[O-:24].[Na+].[Na+]>S(=O)(=O)(O)O>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[O:24])[N:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCCC/C=C/c1nccc(NC(N)=NCC(F)(F)F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)CCC/C=C/c1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A solution of trans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enenitrile (400 mg.) in concentrated sulphuric acid (2 ml.) was kept at 20° for 18 hours then added dropwise to saturated aqueous sodium carbonate. The mixture was extracted with EtOAc (2×15 ml.) and the extract dried (MgSO4) and evaporated in vacuo to give trans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enamide as an oil. The maleic acid salt was prepared in acetone (yield 205 mg; 36%), m.p. 177°-179°.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=O)[C:15]=2[F:23])[CH:11]=[CH:12][CH:13]=1)(C)C>C1COCC1>[NH2:22][CH2:20][C:16]1[C:15]([F:23])=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][OH:6])[CH:9]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cccc(C(N)=O)c2F)c1
Solvent: C1CCOC1
Product: NCc1cccc(-c2cccc(CO)c2)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-fluoro-3-biphenylcarboxamide (3.8 g, 10.6 mmol) in THF (40 mL) which was cooled to 0° C., BH3Me2S (14.0 mL, 21.2 mmol) was added dropwise. Then the reaction was stirred at 50° C. overnight. The reaction was quenched by adding HCl (10 mL, 3 N) and the result mixture was stirred for 2 h before THF was removed under vacuum. The aqueous layer was extracted with AcOEt (30 mL) then the pH was adjusted to around 9.0 by adding Na2CO3. The aqueous layer was extracted with AcOEt (50 mL×2), and dried over Na2SO4. After the solvent was removed, the crude product was purified on Al2O3 column chromatography, eluting with CH2Cl2/EA (10:1). 0.83 g of the product, [3′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol, was obtained (yield: 33%). 1H NMR (400 MHz, DMSO): δ 3.80 (s, 2 H), 4.56 (s, 2 H), 7.23-7.51 (m, 7 H); 13C NMR (400 MHz, DMSO): δ 62.8, 124.3, 125.8, 126.9, 127.2, 128.0, 128.1, 128.3, 128.4, 128.6, 131.6, 131.8, 135.6, 142.9, 155.6, 158.1; HPLC: retention time: 4.053 min; purity: 98.6% (HPLC).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10]O>C(Cl)(Cl)Cl.C[Si](C=[N+]=[N-])(C)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.33 h

Procedure:
1 g of dl-pyroglutamic acid was dissolved in a mixed solvent of 25 ml of methanol and 15 ml of chloroform, and 7.7 ml of trimethylsilyldiazomethane (2 M hexane solution) was added to it at room temperature, and then stirred for 20 minutes as it was. The solvent was evaporated away under reduced pressure, the residue was dissolved in chloroform, and washed with saturated saline water. After dried, the solvent was removed to obtain 1.03 g of the entitled compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:18]3)[C:7]=2[N:16]=1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (0.30 g, 1.36 mmol) was combined with phenylmethyl [(3R)-3-piperidinylmethyl]carbamate (for a preparation see Example 92(b)) (0.337 g, 1.36 mmol) in a 1:1 MeOH/DCM solution (30 mL). Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature for 16 h. NaBH(OAc)3 (0.86 g, 4.08 mmol) was added and the reaction was stirred an additional 2 h. The resulting solution was concentrated onto silica gel under vacuum and the crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off white solid (0.37 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:16]1(O)[CH:21]=CC=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([P:9]([O:13][C:14]2[CH:18]=[CH:17][CH:16]=[CH:21][CH:15]=2)[O:10][CH2:11][CH3:12])=[CH:7][CH:8]=1
Reactant: CCOP(OCC)c1ccc(OC)cc1
Reactant: Oc1ccccc1
Product: CCOP(Oc1ccccc1)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
113 g (0.496 mol) of diethyl 4-methoxyphenylphosphonite and 46.6 g (0.496 mol) of phenol were mixed and heated with stirring to 110° C. at 350-400 mbar. Ethanol distilled off during this via a small column. The temperature was then increased stepwise to 150° C., and the vacuum was simultaneously increased to 100 mbar. After completion of the reaction, the batch was cooled and distilled. 105 g were obtained having a boiling point of 159° C. at 0.4 mbar. The yield was thus 77% of theory.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21](Cl)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[Cl:23][C:19]1[CH:20]=[C:21]([NH:41][CH:38]2[CH2:40][CH2:39]2)[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=1
Reactant: NC1CC1
Reactant: COc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
N-Cyclopentyl-4-[5,7-dichloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (271 mg, 0.60 mmol) in cyclopropylamine (5 mL) was heated at 100° C. for 11 hours in a steel bomb. Cooled to room temperature. Ethyl acetate was added to the reaction mixture. The solution was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (4:1 hexanes/ethyl acetate) gave N-{4-[5-chloro-7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (201 mg, yield 71%) as a yellow foam. 1H NMR (CDCl3) δ 8.02 (d, 1H), 7.96 (s, 1H), 7.56 (d, 2H), 7.01 (d, 2H), 6.42 (s, 1H), 6.37 (d, 1H), 6.32 (d, 1H), 5.12 (d, 1H), 4.15 (m, 1H), 3.91 (s, 3H), 2.70 (m, 1H), 2.08 (m, 2H), 1.82-1.59 (m, 6H), 0.95 (m, 2H), 0.80 (m, 2H); MS m/z 475 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)[OH:7])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccc(OCc3ccccc3)cc2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 93.3 %

Procedure:
An anhydrous tetrahydrofuran (20 ml) solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (3.65 g, 0.015 mol) was added dropwise under ice cooling to a Grignard reagent (30 ml tetrahydrofuran solution) prepared from 4-(benzyloxy)bromobenzene (8.00 g, 0.030 mol) and magnesium (0.81 g, 0.033 mol), and the resulting solution was stirred for 2 hours. The reaction solution was poured in an aqueous solution of saturated ammonium chloride and extracted with ether. The extract was washed with saturated brine and then dried. The reaction solution was filtered, the filtrate was concentrated and the obtained crude product was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (5.93 g, 0.014 mol, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[N:13]O)[CH3:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([NH2:13])[CH3:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1
Reactant: CC(=NO)c1cc(F)cc2[nH]cnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1cc(F)cc2[nH]cnc12
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanone oxime (351 mg, 1.82 mmol), Zn powder (1.18 g, 18.2 mmol), and NH4Cl (973 mg, 18.2 mmol) in MeOH (50 mL) and HOAc (10 mL) was heated at 80° C. for 4 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. To the residue was added NH4OH (50 mL), and the mixture was extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude mixture was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (10:1:0.2) to afford 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanamine (121) as a yellow solid (318 mg, 97.7%). MS (ESI): m/z=180.1 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 74 h

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (6 ml), and thereto are added ethyl 4-bromobutanate (7.94 ml) and potassium carbonate (6.4 g), and the mixture is stirred at room temperature for 74 hours. The reaction mixture is poured into water, and the colorless precipitates are collected by filtration and washed with water to give the title compound (9.5 g).
Reaction SMILES: [C:1]1([S:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20]>>[C:1]1([S:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCN(CCS(=O)c2ccccc2)CC1
Agent: Cl
Product: O=S(CCN1CCC(=NO)CC1)c1ccccc1

Procedure:
1-(2-Phenylsulfinylethyl)-4-piperidone oxime is prepared from 1-(2-phenylsulfinylethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].ClC(Cl)(Cl)C(=N)O[C:19]([CH3:22])([CH3:21])[CH3:20].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl.C1CCCCC1>[C:5]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=1[CH2:4][C:1]([O:3][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:2])([CH3:13])([CH3:6])[CH3:4]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 166.7 %

Procedure:
To a suspension of 2-carboxymethyl-5-methyl-benzoic acid (2.544 g, 13.1 mmol) in anhydrous dichloromethane (70 ml) held at 0° C. was added tert-butyl 2,2,2-trichloroacetimidate (11.47 mg, 52.4 mmol, 2 equivalents) in cyclohexane (85 ml). BBr3 (0.52 ml) was then added, and the reaction mixture was raised to room temperature and stirred for 16 hr. Solid NaHCO3 was added to quench the reaction, the solid precipitate was filtered off and washed with ether. The combined organic washing was evaporated to dryness, and the residue obtained was purified by silica gel chromatography to obtain 2-tert-butoxycarbonylmethyl-5-methyl benzoic acid tert-butyl ester 3.345 g (83.3%) as an oil. 1H NMR (CDCl3): 7.718 (1H, s), 7.227 (1H, d, J=7.57 Hz), 3.910 (2H, s), 2.362 (3H, s), 1.584 (9H, s), 1.443 (9H, s). FABMS (+Ve), m/z 307 [MH+], 251 [MH+−C4H8], 195 [MH+−2C4H8]. Anal. calcd. for C18H26O4: C, 70.6; H, 8.6. Found: C, 70.82; H, 8.53.
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (6.73 g, 25.29 mmoles), title B compound, in dry N,N-dimethylformamide (100 mL) was treated with sodium azide (3.79 g, 50.57 mmoles) and stirred at room temperature under argon for four hours. The reaction mixture was partitioned between 100 mL ethyl acetate and 200 mL distilled water. The organic layer was separated and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organics were washed successively with distilled water, saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was evaporated under vacuum to obtain an orange gum (5.62 g) which was triturated with penme to provide the title compound (4.50 g, 78%) as an off-white solid, m.p. 63°-64° C.
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:11]1([CH2:17][C@@H:18]([NH2:33])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(N(CC)CC)C>[CH:11]1([CH2:17][C@@H:18]([NH:33][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:9])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ccccc2O)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Product: CC1(C(=O)N[C@H](CC2CCCCC2)CN2CCN(c3ccccc3O)CC2)CCCCC1

Procedure:
A solution of 1-methylcyclohexanecarbonyl chloride, triethylamine and {(1R)-1-cyclohexylmethyl-2-[4-(2-hydroxyphenyl)-piperazin-1-yl]-ethyl}-amine is stirred at 0° C. under a nitrogen atmosphere for 1 hour. The mixture is then concentrated on a rotary evaporator and partitioned between ethyl acetate and saturated aqueous NaHCO3. The combined organic layers are washed with brine, dried and concentrated on a rotary evaporator to yield the desired product, which is purified by chromatography on alumina.