Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)=[O:5].[H-].[Na+].[CH3:14]I>CN(C=O)C>[CH3:14][N:8]1[CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][N:10]=[CH:9]1
Reactant: CI
Reactant: COC(=O)C1CN=CNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN=CN(C)C1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
1,4,5,6-Tetrahydro-5-methoxycarbonylpyrimidine hydrochloride (300 mg, 1.35 mmol) and NaH (60% in mineral oil 107 mg, 1.35 mmol) were suspended in anhydrous DMF (5 ml) in an oven dried round bottom flask with stirring under nitrogen. After stirring 15 minutes CH3I 84 μl, 1.35 mmol) was added via syringe and stirring continued 3 hours at room temperature. The solvents were evaporated in vacuo and the residue triturated with chloroform. The resulting suspension was filtered and evaporated in vacuo. Chromatography (silica, chloroform/methanol, 9:1) gave 160 mg (76%) crystals mp 93°-95° C. identified by 300 MHz nmr; ms m/z=156.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([CH:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)O)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[H][H]>C(O)C.[Pd]>[CH2:27]([C:19]1[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10]3)[N:17]=2)=[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: [H][H]
Reactant: OC(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: c1ccc(Cc2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 65.9 %

Procedure:
To a solution of concentrated sulfuric acid (9 mL, 169 mmol) in ethanol (25 mL) was added 10% palladium on carbon (200 mg) and a solution of {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (350 mg, 0.908 mmol) in ethanol (5 mL). The reaction mixture was stirred under 55 PSI of hydrogen for 3 days. The reaction mixture was filtered through a pad of celite. Saturated aqueous sodium bicarbonate solution was added to the filtrate until basic. The resulting mixture was concentrated on rotovap to remove the excess ethanol, then extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (29:1 dichloromethane:methanol) provided 4-(2-benzylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (221 mg, 66%) as an off-white solid. 1H NMR (CDCl3) δ 8.45 (d, 1H), 8.25 (d, 1H), 8.19 (d, 1H), 7.30–7.13 (m, 6H), 6.82 (m, 1H), 6.63 (d, 1H), 5.12 (d, 1H), 4.52 (s, 2H), 4.35 (m, 1H), 2.03 (m, 2H), 1.78–1.50 (m, 6H); MS m/z 370 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:24]CCC.C[Si](C)(C)[O:30][C@@H:31]1[C@@H:36]([O:37][Si](C)(C)C)[C@H:35]([O:42][Si](C)(C)C)[C@@H:34]([CH2:47][O:48][Si](C)(C)C)[O:33][C:32]1=[O:53]>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:32]2([O:53][CH3:24])[C@H:31]([OH:30])[C@@H:36]([OH:37])[C@H:35]([OH:42])[C@@H:34]([CH2:47][OH:48])[O:33]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene (213 g) in anhydrous THF/toluene (1:2 v/v, 1.7 L) under argon was added n-BuLi (2.5 M in hexane, 245.9 mL) dropwise at −60±5° C. The mixture was stirred for 30 min, and then transferred to a stirred solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (310.5 g) in toluene (1.6 L) at −60±5° C. The reaction mixture was continuously stirred at −60±5° C. for 1 h before quenching with an aqueous solution of saturated ammonium chloride (1.5 L). The mixture was allowed to warm to room temperature and stirred for 1 h. The organic layer was separated and the water layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (1 L), dried over Na2SO4, and concentrated. The residue was dissolved in methanol (450 mL), and methanesulfonic acid (9.2 mL) was added at 0° C. The solution was allowed to warm to room temperature and stirred for 20 h. The reaction was quenched with an aqueous solution of sodium bicarbonate (50 g) in water (500 mL) and then additional water (900 mL) was added. The mixture was extracted with ethyl acetate (3×1.0 L). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:18](O)[C:19]#[CH:20]>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:20][C:19]#[CH:18])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reactant: C#CCO
Product: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Using the procedure of Step A of Example 13, 3.6 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxy-ethenyl]cyclopropane-carboxylate and 1 ml of propargyl alcohol were reacted and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with 0.1N hydrochloric acid, with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in a 9-1 cyclohexane-ethyl acetate mixture and the mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate yielded 2.1 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-(propargyloxy-carbonyl)-ethenyl]cyclopropane-carboxylate.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[OH-:31].[K+].Cl>C(O)(C)(C)C.O>[OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:14])=[O:31])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(N)=O)ccc32)cc1

Procedure:
0.18 g (0.44 mmol) 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile (Example 15A) is dissolved in 15 ml tert-butanol, mixed with 0.23 g (3.6 mmol) pulverized, 88% potassium hydroxide and heated under reflux for 11 h. Having cooled down, the mixture is hydrolyzed in water and acidified with 1N hydrochloric acid. Three extractions with diethyl ether, concentration to half the volume on the rotary evaporator, washing with water and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 1:1) and yields the product as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=O.[NH2:18]/[C:19](/[CH3:23])=[CH:20]\[C:21]#[N:22]>CC(O)=O.CCOC(C)=O>[C:21]([C:20]1[CH:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][N:7]=[C:6]3[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:3])[NH:18][C:19]=1[CH3:23])#[N:22]
Reactant: C/C(N)=C/C#N
Reactant: CON(C)C(=O)c1n[nH]c2ccc(C=O)cc12
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.4 %

Procedure:
A mixture of 5-formyl-N-methoxy-N-methyl-1H-indazole-3-carboxamide (400 mg, 1.72 mmol) from Synthetic Preparation 6, and 3-aminocrotononitrile (299 mg, 2.12 mmol) in HOAc (5 mL) was kept at 110° C. for 2 hr. After cooling to rt, the reaction mixture was diluted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by flash chromatography to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-methoxy-N-methyl-1H-indazole-3-carboxamide (500 mg, 80.5%) (Cpd. No. 143, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=9.65 (s, 1H), 7.85 (s, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 4.58 (s, 1H), 3.78 (s, 3H), 3.44 (s, 3H), 2.03 (s, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.CN(C)C(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:60](Br)([F:62])[F:61]>C1COCC1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][CH:10]=[C:60]([F:62])[F:61])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=C(F)F)c4cccc(Br)c4)c3)ncnc21
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (0.05 g, 0.00009 mol) in N,N-dimethylacetamide (2 mL, 0.02 mol) was added triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50 uL, 0.0006 mol) and 0.76 M zinc in THF (0.7 mL). The reaction was stirred at room temperature for 18 hs. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc, Hexane (1:2) to give 4-{1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (20 mg, 40%) as a clear oil. m/z=560, 562 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[C:5]([NH:10][CH3:11])[C:4]=1[N+:12]([O-:14])=[O:13].N[CH2:16][CH:17]([OH:20])[CH2:18][OH:19].C[N:22]1CCCC1=O>O1CCOCC1>[CH3:1][NH:2][C:3]1[C:8]([NH2:22])=[C:7]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:6]=[C:5]([NH:10][CH3:11])[C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: CN1CCCC1=O
Reactant: NCC(O)CO
Reactant: CNc1cc(F)cc(NC)c1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CNc1cc(CC(O)CO)c(N)c(NC)c1[N+](=O)[O-]

Procedure:
A mixture of 0.01 mole (2 g) of 2-methylamino-6-methylamino-4-fluoronitrobenzene and 38 g of 3-amino propane 1,2-diol in 7 ml of dioxan diluted with 1 ml of N-methylpyrrolidone was refluxed for 15 hours.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=1>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:24]1[CH:25]=[CH:26][C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:23]1)[CH3:32]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: CCOC(=O)Cn1ccc(N)n1
Product: CCOC(=O)Cn1ccc(NC(=O)c2cc(-c3cc(F)cc(F)c3)cc(C)n2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using Ethyl (3-Amino-1-pyrazolyl)acetate instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=401.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][C@@H:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][CH:5]=2.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:19]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])[CH2:20][CH2:19]1)[CH:7]=[CH:6][CH:5]=2
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: Cc1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Product: Cc1cc2c(OC[C@@H](O)CNCC3CCN(CCC(F)(F)F)CC3)cccc2[nH]1
Yield: 36 %

Procedure:
Prepared from 2-methyl-4-[(2S)-oxiranylmethoxy]-indole (0.150 g, 0.74 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0. 250 g, 1.2 mmol) of according to the procedure used for Example 2 to give 0.110 g of the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:62])[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[C:45]3[C:40](=[C:41]4[CH:53]=[CH:52][CH:51]=[CH:50][C:42]4=[C:43]4[CH:49]=[CH:48][CH:47]=[CH:46][C:44]4=3)[C:39]3[C:34]2=[C:35]2[CH:61]=[CH:60][CH:59]=[CH:58][C:36]2=[C:37]2[CH:57]=[CH:56][CH:55]=[CH:54][C:38]2=3)=[CH:18][CH:17]=1)=[O:13].[CH:63]1([NH2:66])[CH2:65][CH2:64]1.[CH2:67]1COCC1>>[CH:63]1([NH:66][CH:67]=[C:11]([C:10](=[O:62])[C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]3[C:45]4[C:40](=[C:41]5[CH:53]=[CH:52][CH:51]=[CH:50][C:42]5=[C:43]5[CH:49]=[CH:48][CH:47]=[CH:46][C:44]5=4)[C:39]4[C:34]3=[C:35]3[CH:61]=[CH:60][CH:59]=[CH:58][C:36]3=[C:37]3[CH:57]=[CH:56][CH:55]=[CH:54][C:38]3=4)=[CH:18][CH:17]=2)=[O:13])[CH2:65][CH2:64]1
Reactant: O=C(CC(=O)c1cc(F)c(F)cc1F)OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Reactant: C1CCOC1
Reactant: NC1CC1
Product: O=C(OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
To an oven-dried flask was added 4-[[10-(17H-tetrabenzo[a,c,g,i]fluoren-17-yl)-decyl]oxy]phenyl]-methyl 2,4,5-trifluoro-β-oxobenzenepropanoate (6) (122.5 mg, 0.148 mmol) and dissolved in freshly distilled THF (10 mL). The flask was purged with nitrogen and N,N-dimethylformamide diethyl acetal was added as a solution in THF (1 mL) via syringe. Glassware was washed with THF (2 mL). The solution was stirred at room temperature under an atmosphere of nitrogen for 24 hours. Cyclopropylamine (120.2 mg, 0.818 mmol) was added as a solution in THF (1 mL) and the resultant solution stirred at room temperature under nitrogen for 72 hours. The solution was quenched by the addition of saturated ammonium chloride solution (20 mL) and organic products extracted faith DCM (2×20 mL), dried over MgSO4 and solvent removed in vacuo to yield a dark yellow oil. This was purified by flash column chromatography using DCM as eluent to yield [4-[[10-(17H-tetrabenzo[a,c,g,i]fluoren-17-yl)-decyl]oxy]phenyl]methyl α-[(cyclopropylamino)-methylene]-2,4,5-trifluoro-β-oxobenzenepropanoate as a pale yellow solid (45.1 mg, 0.051 mmol, 34%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[C:12]1([O:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:19](=[O:20])[O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([O:10][CH3:11])=[N:4][C:5]=1[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1nc(C)c(C)cc1N
Solvent: ClCCl
Product: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3-Amino-5,6-dimethyl-2-methoxypyridine(1.52 g, 0.01 mol) and phenylchloroformate(1.56 g, 0.01 mol) were dissolved in dichloromethane and was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:6) to obtain the titled compound.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[C:9]([C:12]1[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:11])[CH3:10].O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:18][C:17]1[C:12]([C:9](=[O:11])[CH2:10][C:1]([O:4][CH3:5])=[O:6])=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: CC(=O)c1nccnc1C
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)c1nccnc1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
21.4 g of dimethyl carbonate was added dropwise to a stirred mixture of 5.7 g of sodium hydride and 100 ml of toluene at room temperature. Then the mixture was heated to 80° C. and a solution of 16.1 g of 2-acetyl-3-methylpyrazine in 75 ml of toluene was added dropwise and the mixture was stirred at 75° C. for one hour. The mixture was cooled, 100 ml of water was added and the mixture was acidified with glacial acetic acid. The organic phase was separated, dried (Na2SO4) and stripped of volatiles. The residue was flash chromatographed on silica gel, with a 9:1 v:v mixture of methyl chloride and ethyl acetate as eluent. The second set of fractions was stripped of solvent to give methyl 3-(3-methyl-2-pyrazinyl)-3-oxopropionate (31A), as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: CC#N
Product: N#CCC(O)c1cc(F)cc(Br)c1

Procedure:
Alkylation of 3-bromo-5-fluorobenzaldehyde with acetonitrile following the method used in Example 50 except KOBu-t was used instead of LDA gave 3-(3-bromo-5-fluorophenyl)-3-hydroxypropanenitrile as a light color oil. Yield (2.5 g, 86%): 1H NMR (400 MHz, CDCl3) δ 7.34 (bs, 1H), 7.21-7.24 (m, 1H), 7.08-7.11 (m, 1H), 5.02 (t, J=6.4 Hz, 1H), 2.75 (d, J=6.4 Hz, 2H).
Reaction SMILES: CCl.[OH-].[K+].[C:5]1(C)C=CC=CC=1.[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25]>CCOCC.O>[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:5])=[O:25]
Reactant: Cc1ccccc1
Reactant: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Agent: CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Methyl chloride (0.45 g, 9.0 mmol), 85% potassium hydroxide (0.30D g, 4.5 mmol) and toluene (9 ml ) were added to (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (0.94 g, 3.0 mmol). The mixture was stirred at 100° C. for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extrcted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.88 g, Yield: 90.2%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 11.0 g. of 3-[p-(benzyloxy)phenyl]propanol and 10.4 ml. of triethylamine in 175 ml. of dichloromethane chilled to -10° C. is added dropwise, over 10 minutes, a solution of 3.89 ml. of methanesulfonyl chloride in 10 ml. of dichloromethane. The solution is stirred at -10° C. for 30 minutes, washed with 150 ml. of cold water, 75 ml. of cold 10% HCl, 75 ml. of cold saturated sodium bicarbonate, 75 ml. of cold saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo to give off-white crystals, m.p. 65°-69° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[O:24])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 46.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-methylpiperazine (54 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 5a (80 mg, yield 49%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][NH2:26]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[N:3]=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1ccc(NNc2nc(Cl)nc3c2ncn3C2CCCC2)c(Cl)c1

Procedure:
2-Chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.