Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].F[C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37]>>[Br:1][C:2]1[C:3]([C:8](=[O:9])[N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])=[N:4][N:5]([C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[CH:22][C:21]=2[C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Br
Reactant: O=C(OCc1ccccc1)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Yield: 40.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-bromo-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (Intermediate 163A, 268 mg, 0.85 mmol) and benzyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 122B, 300 mg, 0.77 mmol) were converted to the title compound (215 mg, 41%). 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.21 (dd, J=8.3, 1.9 Hz, 1H), 8.11 (d, J=2.0 Hz, 0.5H), 8.08-8.03 (m, 0.5H), 7.85-7.78 (m, 1H), 7.55-7.33 (m, 5.5H), 7.25-7.06 (m, 3H), 7.05-6.96 (m, 0.5H), 5.47-5.32 (m, 2H), 4.82-4.42 (m, 2H), 3.92-3.71 (m, 0.5H), 3.58-3.34 (m, 3H), 3.23-2.91 (m, 2.5H), 2.82-2.74 (m, 2H), 2.27 (s, 2H), 2.22 (s, 1 H), 1.59-1.13 (m, 4H), 1.07-0.80 (m, 7H), 0.72-0.59 (m, 3H); MS(ESI+) m/z 687.5 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH:5]1([NH:11][C:12]2[CH:13]=[C:14]([C@@H:18]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:5]1([NH:11][C:12]2[CH:13]=[C:14]([C@@H:18]([N:32]3[CH2:37][CH2:36][N:35]([CH2:1][CH2:2][CH3:3])[CH2:34][CH2:33]3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN1CCN([C@@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC3CCCCC3)c2)CC1
Reaction time: 8 h
Yield: 61498.2 %

Procedure:
To a room temperature solution of propionaldehyde (40.6 μL 0.56 mmol) and COMPOUND 27 (250 mg; 0.56 mmol) in 1,2-dichloroethane was added sodium triacetoxy borohydride (380 mg; 1.79 mmol) and acetic acid (31.9 μL; 0.56 mmol). The reaction mixture was stirred overnight then was washed with saturated sodium bicarbonate, followed by water. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 73 (169 g; 62% yield). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.99 (t, J=7.91 Hz, 2H), 1.10-1.16 (m, 3H), 1.28-1.33 (m, 4H), 1.61-1.65 (m, 4H), 1.75-1.79 (m, 4H), 1.83-1.90 (m, 4H), 2.97-3.01 (m, 2H), 3.13-3.15 (m, 2H), 3.17-3.28 (m, 8H), 3.42-3.46 (m, 2H), 3.52-3.54 (m, 1H), 5.08 (s, 1H) 7.24-7.29 (m, 3H), 7.48-7.51 (m, 3H), 7.55-7.57 (m, 1H), 7.62 (d, J=7.42 Hz, 1H). Found: C, 56.59; H, 7.89; N, 8.25. C31H46N4O×4.3HCl×0.6H2O has C, 56.56; H, 7.89; N, 8.51%. [α]D16=+14.5 deg [c 0.50, MeOH].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#N)[CH:5]=[CH:6][C:7]=1[F:8].CC(C[AlH]CC(C)C)C.C1C[O:26]CC1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCOC1
Reactant: CC(C)(C#N)c1ccc(F)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred solution of 2-(3-bromo-4-fluorophenyl)-2-methylpropanenitrile (29 g, 120 mmol) in THF (500 mL) at −78° C. was dropwise added DIBALH (1M in toluene, 360 mL, 3 eq) over 2 h. After the reaction mixture was stirred at same temperature for 30 minutes, it was allowed to warm to room temperature. After the reaction was complete, the mixture was quenched by 1N HCl and extracted with EA. The separated organic layer was dried over MgSO4 and evaporated in vacuo to give 2-(3-bromo-4-fluorophenyl)-2-methylpropanal (27 g, 92%). 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 7.47-7.44 (m, 1H), 7.19-7.15 (m, 1H), 7.12 (t, J=8.4 Hz, 1H), 1.45 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22]Cl)[CH3:19].[H-].[Na+]>>[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[CH3:19]
Reactant: CN(C)CCCCl
Reactant: c1ccc2c(c1)ccn2Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN(c1ccncc1)n1ccc2ccccc21

Procedure:
The title compound was prepared from N-(4-pyridinyl)-1H-indol-1-amine and dimethylaminopropyl chloride with the aid of NaH in substantially the same manner as in Example 4. The product was obtained as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 104 %

Procedure:
N,N-Dimethyl-L-prolinamide (2.50 g, 17.58 mmol) was dissolved in a mixture of CH2Cl2 (50 mL) and water (50 mL), then solid sodium bicarbonate (2.95 g, 35.16 mmol) was added, followed by benzoyl chloride (2.1 mL, 18.45 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide N,N-dimethyl-1-(phenylcarbonyl)-L-prolinamide (4.502 g, >99%). LCMS: (M+H)+: 247.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>CO.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccc(Cl)cc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 47.2 mg, 0.150 mmol) in methanol (6.0 mL) was added neat 2,4-dichlorophenyl isocyanate (56.4 mg, 0.300 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a colorless film. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (74.8 mg, 99%) as a colorless film. MS cald. for C26H26Cl2FN2O3 [(M+H)+]: 503, obsd. 503.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C1CCNC1
Product: Cc1cc(Br)ccc1C(=O)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-methyl benzoic acid and pyrrolidine.
Reaction SMILES: [F:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:11]=[O:12]>>[OH:12][CH2:11][C:2]([F:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: C=O
Product: COC(=O)C(F)(CO)C(=O)OC

Procedure:
The process according to the invention is carried out in three stages: dimethyl α-fluoromalonate is first reacted with formaldehyde to give dimethyl α-hydroxymethyl-α-fluoromalonate, the latter is then hydrolyzed and the hydrolysis product is decarboxylated and dehydrated, and finally, the resuiting α-fluoroacrylic acid is esterified with a substituted phenol.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[NH:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[NH:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1)C(=O)O
Temperature: 96.5 °C
Yield: 59.6 %

Procedure:
8-(2-Chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid ethyl ester (0.11 g, 0.25 mmol) was added to a mixture of ethanol (15 mL), water (1.35 mL), and sodium hydroxide (0.07 g, 1.75 mmol). The mixture was heated to reflux (95-98° C. oil bath) for 11 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water (10 mL) was added to the residue and adjusted to pH=6 with 10 N hydrochloric acid. The product was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4. After filtration, the dichloromethane solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=3/7) to afford 8-(2-chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid (Compound Iq, 0.06 g, 59.8% yield) as a yellow oil. 1NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.60 (d, 1H, J=7.5 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.41-7.30 (m, 2H), 6.58 (d, 1H, J=2.7 Hz), 5.89 (d, 1H, J=2.7 Hz), 4.56-4.52 (m, 1H), 3.96 (d, 1H, J=13.5 Hz), 3.65 (d, 1H, J=13.5 Hz), 2.97-2.65 (m, 4H), 2.00-1.87 (m, 2H), 1.43-1.39 (m, 2H), 1.28-1.18 (m, 6H), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CD3OD/TMS) δ (ppm) 183.09, 136.97, 136.77, 131.03, 130.05, 130.31, 128.80, 124.29, 118.35, 113.24, 105.71, 65.49, 50.79, 49.81, 43.48, 42.01, 33.13, 30.39, 26.74, 26.19, 25.98, 23.34.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH3:31][NH2:32]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:32][CH3:31])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Product: CNC(=O)c1ccc2c(c1)[C@H](Nc1cccc(N3CCOCC3)c1)C[C@H](C)N2C(C)=O
Yield: 73 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 31 mg of (2S,4R)-1-acetyl-2-methyl-4-[(3-morpholinophenyl)amino]-1,2 3,4-tetrahydroquinoline-6-carboxylic acid (compound 179) and monomethylamine. Thus, 23 mg (73%) of the title compound was obtained as a light yellow oily substance.
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.NN>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH2:20][NH2:21])[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(OCc3ccccc3)cc2s1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc2ccc(OCc3ccccc3)cc2s1
Reaction time: 4 h
Yield: 107.2 %

Procedure:
To an ethanol (5 mL) solution of 2-(6-benzyloxy-benzo[b]thiophen-2-ylmethyl)-isoindole-1,3-dione (144 mg, 0.36 mmol) described in Production Example 77-1-4 was added hydrazine monohydrate (18.7 mg, 0.374 mmol). The mixture was stirred for 4 hours while heating under reflux. The reaction mixture was allowed to cool on standing followed by the addition of water and concentrating under a reduced pressure until the total volume of the solution was reduced by half. The solution was distributed between ethyl acetate and water. The organic layer was separated followed by washing with 2 N aqueous sodium hydroxide solution and water, drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure to obtain the title compound (104 mg, quantitative). This amine was used in the subsequent reaction without purifying.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:10])[N:4]=[CH:3]1
Reactant: CC(C)(C(=O)O)c1c[nH]cn1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)(C(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 60 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-imidazol-4-yl)-2-methylpropanoic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 161, (S)-2-(2-(1H-imidazol-4-yl)-2-methylpropanamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (92.2 mg, 60%). 1H-NMR (400 MHz, CDCl3): δ 9.31 (s, 1H), 8.32 (br s, 1H), 7.49-7.45 (m, 3H), 7.38 (d, 1H), 7.22-7.18 (m, 2H), 7.02-6.88 (m, 7H), 6.83 (s, 1H), 4.72-4.68 (m, 1H), 4.51 (d, 1H), 4.44 (d, 1H), 4.04 (dd, 1H), 3.63 (dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H). MS (EI) for C29H29F2N4O4 found 535 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1.C(N(CC)CC)C>ClCCl>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH3:60])[C:9]([C:3]5[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=5[Cl:1])=[O:11])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)c(Cl)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (40 mg, 0.231 mmol) in dichloromethane (2.0 mL) at 25° C. was treated with triphenylphosphine (72 mg, 0.28 mmol). The reaction was cooled to 0° C. and then was treated with N-chlorosuccinimide (37 mg, 0.28 mmol). This mixture was stirred at 0° C. for 5 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and triethylamine (0.04 mL, 0.28 mmol). This mixture was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:99 methanol/dichloromethane) afforded 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (54 mg, 48%) as a white solid: LR-MS for C30H29ClFN7O3 (M+H)+ at m/z=590.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)#[N:15].Cl>O1CCOCC1>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:18][CH:17]=1)#[N:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Diethyl malonate (0.49 mol) was added at approximately 60° C. over 2 hours to a suspension of sodium hydride (0.51 mol) in 140 ml of 1,4-dioxane. After stirring for a further 10 min, 0.05 mol of CuBr were added. After 15 min, 0.25 mol of 4-cyanobromobenzene in 10 ml of dioxane were added. The reaction mixture was maintained at 100° C. for approximately 14 hours and then, at approximately 15° C., 35 ml of 12N hydrochloric acid were slowly added. The precipitate was filtered off and the filtrate was extracted with diethyl ether. After phase separation, the organic phase was dried and then freed from the solvent. 32 g of the title compound remained.
Reaction SMILES: [CH:1]([PH:5][O:6]CC)([CH2:3][CH3:4])[CH3:2].[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11].OS(O)(=O)=O>O1CCCC1>[CH2:9]([PH:5](=[O:6])[CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C[Mg]Br
Reactant: CCOPC(C)CC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCC(C)[PH](=O)CC(C)C

Procedure:
A solution of ethyl sec-butylphosphinite (25g., 0.17 mole) in tetrahydrofuran (50 ml.) was added dropwise to a cooled solution of iso-butyl magnesium bromide (0.4 mole) in tetrahydrofuran (150 ml.). The mixture was then heated under reflux for 18 hours. The mixture was then cooled, hydrolysed with 2N H2SO4, and extracted with methylene dichloride. The combined extracts were washed with NaHCO3 solution and then dried (MgSO4). The solvent was removed by distillation and the residue was distilled under reduced pressure to give isobutyl sec-butyl-phosphine oxide bp. 81°-3°/0.03 0.03 mm as a colourless liquid (yield 20g., 72%).
Reaction SMILES: [Li].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[CH3:18][C:19]([CH3:21])=[O:20].C(O)(=O)C>O1CCCC1>[CH3:18][C:19]([OH:20])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:21]
Reactant: CC(C)=O
Reactant: COc1cc(CCCBr)cc(OC)c1OC
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(CCCC(C)(C)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.7 %

Procedure:
To anhydrous tetrahydrofuran (10 ml) stirred in an ice bath under nitrogen were added 104 mg (15 mmol) of lithium, 3.9 g (14 mmol) of 1-bromo-3-(3,4,5-trimethoxyphenyl)propane (1), and a solution of 0.95 ml (13 mmol) of acetone in tetrahydrofuran (10 ml). After the mixture was stirred for 17 hours at room temperature, a 2% aqueous solution of acetic acid (50 ml) chilled with ice was added to conduct extraction with diethyl ether. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (4.1 g) was purified by column chromatography on silica gel, thereby obtaining 860 mg (yield: 24%) of 2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 50 °C

Procedure:
A mixture of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indol-1-yl)butanoate (840 mg, 2 mmol), as described in Example 3 step C, and 2 M LiOH (5 mL) in methanol (5 mL) was heated to 50° C. for 5 h. The reaction was acidified with 1M HCl and the volatile was removed under reduced pressure. The residue was dissolved in ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with brine (10 mL) and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as colorless solid. LC/MS 407.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([NH:12][C:13]([C:15]2[N:16]([CH3:25])[N:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=2[Cl:20])=O)[CH:6]=[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[N:4]=1>CC(O)=O.[Fe]>[C:21]([C:18]1[C:19]([Cl:20])=[C:15]([C:13]2[NH:9][C:8]3[C:3]([O:2][CH3:1])=[N:4][C:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[CH:6][C:7]=3[N:12]=2)[N:16]([CH3:25])[N:17]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1nc(-c2ccccc2C(F)(F)F)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (149 mg, 0.291 mmol, prepared as described in STEP A above) in AcOH (10 mL) was treated with iron powder (81.3 mg, 1.46 mmol), and the resulting mixture was heated to 100° C. for 1.5 h. The cooled mixture was concentrated in vacuo, taken up in saturated aqueous NaHCO3 (50 mL), and extracted twice with EtOAc (40 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine as a white solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C22H21N5OClF3: 464.1 (M+H); Measured: 464.2.