Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([OH:21])=O.Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][OH:36])[CH2:26][CH2:25]1>>[OH:36][CH2:35][C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH:27]1[CH2:28][CH2:29][N:24]([C:19]([C:3]2[N:4]([CH3:18])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:17])[F:16])[CH:8]=3)=[N:6][C:2]=2[I:1])=[O:21])[CH2:25][CH2:26]1
Reactant: OC[C@H]1CCCN1C1CCNCC1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)O
Agent: Cl
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 19) and ((R)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 2) gave the title compound as light red amorphous solid. MS: 579.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.[C:29]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH:30]=1.[F-].[Cs+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]1([C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:5]3[N:15]=[C:16]([C:18]4[C:27]([CH3:28])=[N:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:17]=[C:4]3[N:3]=2)[CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Reactant: OB(O)C1=CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3=CCCC3)cc(NC3CCOCC3)n2n1
Temperature: 80 °C

Procedure:
A suspension of 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Example 1.001 (g)) (97 mg, 0.246 mmol), cyclopenten-1-ylboronic acid (55 mg, 0.491 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.0493 mmol), and cesium fluoride (112 mg, 0.737 mmol) in 1,2-dimethoxyethane (2.0 mL) was heated at 80° C. for 3 h. After being cooled to ambient temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 2:3) to give 5-cyclopent-1-en-1-yl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 1.011 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.73-1.86 (2H, m), 2.03-2.21 (4H, m), 2.60-2.66 (2H, m), 2.86-2.93 (2H, m), 3.05 (3H, s), 3.61 (2H, ddd, J=11.8, 11.8, 2.4 Hz), 3.77-3.87 (1H, m), 4.10 (2H, ddd, J=11.8, 3.3, 3.3 Hz), 6.19 (1H, s), 6.33 (1H, d, J=8.2 Hz), 6.68 (1H, s), 7.08 (1H, s), 7.72-7.79 (2H, m), 8.04-8.08 (1H, m), 8.17-8.21 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)=[CH:31][CH:32]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)=[CH:10][CH:11]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)NC(=O)c1ccccc1OCc1ccc(-c2ccccc2)cc1
Yield: 13.5 %

Procedure:
(S)-2-[2-(biphenyl4-ylmethoxy)-benzoylamino]-3-[4-(biphenyl-4-ylmethoxy)-phenyl]-propionic acid methyl ester (48 mg) was prepared from (S)-2-(2-hydroxy-benzoylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester (175 mg, 0.55 mmol) and 4-biphenylmethyl chloride (240 mg, 1.2 mmol) with K2CO3 (306 mg, 2.2 mmol) as described in Procedure H and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC1CCN(CCO)CC1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(CCOC(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
1.4 Milliliters (0.012 mol) of benzoylchloride were added to a stirred solution of 2.48 grams (0.01 mol) of 4-benzamido-1-(2-hydroxyethyl)piperidine and 2.8 milliliters (0.02 mol) of triethylamine in 10 milliliters of dichloromethane. The solution was stirred at room temperature for 2 hours, then washed with water, dried and evaporated. The residue was crystallised from n-butyl acetate to give 2.5 grams (75% yield) of the title compound m.p. 139°-40° C. Treatment of a solution of the base in ethanol with ethanolic hydrogen chloride precipitated the hydrochloride, m.p. 217°-18° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][C:25](=[O:27])[CH3:26])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:6][CH:5]=1.[CH3:30][Mg]Br>C1COCC1>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][C:25]([OH:27])([CH3:30])[CH3:26])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 10 %

Procedure:
To a solution of (S)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 0.39 mmol) in THF (10 mL) was added methylmagnesium bromide (1 M, 2.5 mL) under nitrogen at −78° C. The mixture was stirred at rt until the reaction was over. The reaction was quenched with satd aq NH4Cl. The organic phase was separated and concentrated to give crude product, which was purified by preparative HPLC to give (S)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (15 mg, 10%). 1H NMR (CDCl3): 1.05 (s, 3H), 1.10 (s, 3H), 1.45 (s, 3H), 2.10 (m, 1H), 2.16 (m, 2H), 2.20 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.60 (m, 1H), 6.16-6.58 (m, 1H), 6.78 (m, 2H), 6.86 (m, 2H), 7.26 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CCOC(=O)C(C)(OC)C(=O)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 50 %

Procedure:
3,5-Dichloroaniline (3.33 grams, 0.02 mole), ethyl 2-(chlorocarbonyl)-2-methoxypropionate (4.0 grams, 0.02 mole), prepared in Example LXII Part C, and triethylamine (2.08 grams, 0.02 mole) were reacted in a manner similar to the procedure described in Example I to give 4.40 grams (0.01 mole) of ethyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-2-methyl-3-oxopropanoate having a melting point of 72° C.-75° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].O.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])S[CH:16]1[CH3:23]>C(O)C>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[S:1](=[O:6])(=[O:2])[CH:16]1[CH3:23]
Reactant: CC1SC(C)(C)C(=O)N1CCCCCl
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1N(CCCCCl)C(=O)C(C)(C)S1(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.4 %

Procedure:
A suspension of potassium peroxymonosulfate (32.0 g) and water (120 mL) was added to a 2° C. solution of 3-(4-chlorobutyl)-2,5,5-trimethyl-4-thiazolidinone (8.0 g) and ethanol (80 mL) over a period of 30 minutes. The cold bath was removed an the resulting mixture was stirred at room temperature for 22 hours, after which ethyl acetate (200 mL) was added. The mixture was filtered, the insolubles washed with ethyl acetate (3×30 mL), and the combined filtrates were diluted with water (200 mL). The organic layer was separated, and the aqueous layer extacted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (200 mL), water (200 mL), and brine (200 mL), dried (Na2 SO4), and concentrated in vacuo to 8.62 g of an off-white solid. The sulfone was recrystallized from ether to give 5.67 g (62.4%) of a white crystalline solid, m.p. 71°-73° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(I)C>>[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:27]1
Reactant: COCC1CCC(=O)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: CCI
Product: COCC1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-methoxymethyl-cyclohexanone (following the procedure described in Example 34, substituting methyl iodide for ethyl iodide) using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][Si:2]([N:5]=[C:6]=[O:7])([CH3:4])[CH3:3].[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]>N12CCCN=C1CCCCC2.ClCCl>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CONCCCCn1c(C)nc2c(N)nc3ccccc3c21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CON(CCCCn1c(C)nc2c(N)nc3ccccc3c21)C(=O)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Trimethylsilyl isocyanate (1.62 mL, 12.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7ene (one drop) were added to a solution of 1-[4-(methoxyamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 10.0 mmol) in dichloromethane (100 mL). The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure to afford 4.1 g of crude N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methoxy-N′-(trimethylsilyl)urea, which was used without purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(O)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)OC(C)(C)C)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(4-(1-(4-hydroxyphenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (300 mg, 0.580 mmol) in DMF (Volume: 4 mL) was added ethyl 2-bromoacetate (0.067 mL, 0.609 mmol) and POTASSIUM CARBONATE (401 mg, 2.90 mmol). The mixture was at rt for 16 h. After cooling to rt, the mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography using 40% EtOAc/Hexanes to give tert-butyl 4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (350 mg). LC-MS (Condition C), MS m/z (M++H) 576.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)O)cc2)S1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)Cl)cc2)S1)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoic acid (0.48 g, 1.29 mmol) in CH2Cl2 (6 mL) was added thionyl chloride (Aldrich, 0.19 ml, 2.58 mmol), and 2 drops of DMF. After stirring the mixture overnight at ambient temp., the crude product was concentrated in vacuo and dried on high vacuum. The product was used in next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1([CH3:24])[CH3:23]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1([CH3:23])[CH3:24]
Reactant: CC1(C)NC(C)(C)N(CCCI)C1=O
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCCN1C(=O)C(C)(C)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Neat diethylene glycol monomethyl ether (1.30 mL, 11.0 mmol, 1.5 equiv.) was added dropwise to a suspension of sodium hydride (400 mg, 60% disp., 10 mmol, 1.35 equiv.) in N,N-dimethylformamide (10 mL) over 5 minutes. The mixture was stirred at room temperature for 15 minutes, before a solution of 3-(3-iodopropyl)-2,2,5,5-tetramethylimidazolidin-4-one (2.29 g, 7.38 mmol) in N,N-dimethylformamide (10 mL) was added via cannula over 15 minutes. The mixture was then stirred overnight at room temperature. After 23 hours, the mixture was concentrated to a yellow oil which was absorbed on silica (5 g). Chromatography on silica (0-6% methanol in dichloromethane) afforded the title compound (190 mg, 8.5%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.68-3.64 (m, 4H), 3.63-3.59 (m, 2H), 3.57-3.54 (m, 2H), 3.53 (t, J=6.1 Hz, 2H), 3.39 (s, 3H), 3.29-3.24 (m, 2H), 1.96-1.89 (m, 2H), 1.82 (br s, 1H), 1.41 (s, 6H), 1.32 (s, 6H); LRMS (ESI/APCI) m/z 303 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(c4ccccn4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(pyridin-2-yl)piperazine (0.030 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(pyridin-2-yl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=1.[F-].[K+].[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])[CH2:27][OH:28].O>O1CCOCC1>[CH2:31]([O:30][C:26]([CH2:27][O:28][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][N:17]=2)=[C:2]([F:1])[CH:7]=1)=[O:29])[CH2:32][CH2:33][CH3:34]
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Reactant: CCCCOC(=O)CO
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)COc1cc(F)c(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Then, 7.61 g of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-16) was dissolved in 10 ml of 1,4-dioxane, to which 5.28 g of potassium fluoride and 9.0 g of butyl glycolate were added, and the mixture was heated under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature. 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 8.37 g (yield, 82%) of 3-[4-(butoxycarbonylmethoxy)-2-fluoro5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound depicted below; m.p., 109.5° C.). ##STR40##
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][OH:7])[CH3:5])[CH3:2].C(O[K])(C)(C)C.[CH2:14]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[N:6][O:7][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:30])=[CH:28][CH:27]=1)[CH3:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)c1ccc(F)cc1
Reactant: CCOC(C)=NO
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)=NOc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 107.3 %

Procedure:
To a stirring solution of ethyl-N-hydroxyacetimidate (3.79 g, 36.8 mmol) in anhydrous DMF (150 mL) under Ar was added tBuOK (4.09 g, 36.4 mmol) all at once. After 40 min benzyl-4-fluorobenzoate 17 (7.63 g, 17.9 mmol) was added and the reaction was stirred at room temperature. After 4 h the reaction was diluted with H2O (500 mL), extracted with EtOAc (4×100 mL), and the combined organics were washed with H2O (2×100 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatographic purification over silica (5-10% gradient EtOAc in hexanes) afforded 19 as a clear syrup (6.02 g, 58%). 1H-NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.0 Hz, 3H), 2.12 (s, 3H), 4.20 (q, J=7.0 Hz, 2H), 5.34 (s, 2H), 7.15-7.19 (m, 2H), 7.31-7.35 (m, 2H), 7.36-7.41 (m, 2H), 7.42-7.36 (m, 2H), 8.00-8.14 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.3, 14.4, 63.1, 66.4, 113.4, 122.9, 128.1, 128.1, 128.6, 131.5, 136.3, 163.5, 166.3, 166.4; GC-MS 228 m/z [M-85]+, benzyl-4-hydroxybenzoate C14H12O3 requires 228.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH2:22]([C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:41]=[CH:42][C:35]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:36][CH:37]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCCCCc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A mixture of 0.82 g of N-methyl-N-phenylsulfonyl-2-chlorobenzohydrazonoyl chloride, 0.70 g of 4-tridecylbenzonitrile, 0.4 g of anhydrous aluminium chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.70 g of the given compound (melting point: 55.0°-57.0° C.).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[N:14][NH:15][C:7]=12>>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[N:14][NH:15][C:7]=12
Reactant: COc1ccccc1-c1n[nH]c2c(Cl)cc(C)nc12
Reactant: NCCO
Product: COc1ccccc1-c1n[nH]c2c(NCCO)cc(C)nc12

Procedure:
The title compound was prepared form ethanolamine and 7-chloro-5-methyl-3-(methoxyphenyl)-1H-pyrazolo[4,3-b]pyridine (D13) in an analogous manner to the preparation of Example 2 giving a pale yellow solid, m.p. 193°-194° C. Ratio of meta and para isomer 1:2
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([S:10][CH3:11])=[CH:5][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: CSc1cccc(C)c1
Solvent: CC(=O)O
Product: CSc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Bromine (2.52 mL, 48.9 mmol) was added dropwise to a solution of 1-methyl-3-(methylthio)benzene (6.14 g, 44.4 mmol) in acetic acid (150 mL) at 0° C. The reaction was then stirred at ambient temperature for 2 h. The reaction was concentrated, and the resulting crude product was purified by chromatography on a silica gel column using 0 to 10% EtOAc/hexane to give 7.94 g (82%) of 1-bromo-2-methyl-4-(methylthio)benzene as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 7.40 (d, 1H, J=8.3 Hz), 7.10 (d, 1H, J=2.1 Hz), 6.92 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 2.45 (s, 3H), 2.35 (s, 3H); LRMS (ESI), m/z 218 (M+H).