Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1cc(F)ccc1C(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1cc(F)ccc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluorobenzoate (1.41 g, 3.12 mmol) obtained from Example 7-(1) was reacted with anisole (2 g, 18.5 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluorobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above was reacted with oxalyl chloride (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 μl), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluorobenzoyl chloride as a crude product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C>[OH:16]/[N:15]=[C:7](\[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1cccnc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=N/O)c1cccnc1
Yield: 50.7 %

Procedure:
A mixture of ethyl 3-pyridylglyoxylate (6.00 g), hydroxylamine hydrochloride (2.79 g), sodium acetate (4.13 g) and ethanol (80 ml) was heated to reflux for 15 hours. The reaction mixture was concentrated, water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate to obtain ethyl E-2-hydroxyimino-2-(3-pyridyl)-acetate (3.30 g, yield 51%) as colorless crystals. m.p. 172-173° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[CH3:38])[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+]>[CH:32]1([C:30]([NH:29][C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]4[CH:35]=[CH:36][C:37]([CH3:38])=[C:16]([NH:15][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][C:4]=5[CH3:10])=[O:9])[CH:17]=4)=[CH:25][N:24]3[N:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: Cc1nc(C(=O)O)c(C)s1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of 2,5-dimethyl-1,3-thiazole-4-carboxylic acid (107 mg, 0.681 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (2 drops) and thionyl chloride (118 μL, 1.36 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (6 mL). N-[6-(3-Amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, the residue was and recrystallized from ethanol to give the title compound (248 mg, 87%) as a white solid.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1.N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C>[Si:5]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL of t-butylchlorodiphenyl silane was added to the mixture of 5 g of 1-(4-hydroxyphenyl)-1-ethanone, 3 g of imidazole, and 70 mL of N,N-dimethylformamide, and stirred overnight at room temperature. The reaction mixture was added with 200 mL of ethyl acetate, washed with water and saturated brine in the subsequent order, and the obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 11.7 g of 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanone [79-1] as a white solid.
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:20]C)(OC)[CH2:16][Br:17])[CH:10]=1)(C)(C)C.C(OC(=O)[NH:30][C:31]1[CH:36]=[C:35]([N:37]([CH3:39])[CH3:38])[C:34]([Cl:40])=[CH:33][C:32]=1[NH2:41])(C)(C)C>C1(C)C=CC=CC=1>[Br:17][CH2:16][C:15]([C:11]1[CH:10]=[C:9]([C:8]2[CH2:7][C:6](=[O:23])[NH:41][C:32]3[CH:33]=[C:34]([Cl:40])[C:35]([N:37]([CH3:38])[CH3:39])=[CH:36][C:31]=3[N:30]=2)[CH:14]=[CH:13][CH:12]=1)=[O:20]
Reactant: COC(CBr)(OC)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: Cc1ccccc1
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-oxo-3-[3-(2-bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (2.34 g) (Example K28) and (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) (1.57 g) in toluene (16 mL) was heated to 100° C. for 5 h. The solvent was evaporated in vacuum and the crude product was purified by chromatography on silica gel using CH2Cl2/AcOEt (1:20) as eluent. A solution of the purified material (2.4 g) in CH2Cl2/TFA (1:1, 30 mL) was stirred at 20° C. for 15 min and then evaporated. The residual oil was dissolved in AcOEt and the solution was washed with 1N HCl and with brine, dried and evaporated. The residue was crystallized from AcOEt/Et2O to give 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one as light-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][CH:10](I)[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH:9]=[CH:10][Sn:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCCC[Sn](C=CC(C)(C)c1ccc(F)cc1)(CCCC)CCCC
Yield: 88.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 17.2 grams (0.030 mole ) of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane and 13.7 grams (0.090 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 100 mL of tetrahydrofuran is heated at reflux for about 18 hours. The reaction mixture is cooled and poured into about 500 mL of water. The mixture is then made acidic with aqueous 2N hydrochloric acid and extracted with three 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5% methylene chloride in petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 12.0 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:34])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][CH2:30][C:31]([OH:33])=O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:68]1([O:72][C:73]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[O:74])[CH2:71][CH2:70][CH2:69]1>CN(C=O)C.ClCCl>[CH:68]1([O:72][C:73]([N:75]2[CH2:80][CH2:79][N:78]([C:31](=[O:33])[CH2:30][NH:29][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:34])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH2:77][CH2:76]2)=[O:74])[CH2:71][CH2:70][CH2:69]1
Reactant: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCN(C(=O)OC2CCC2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
To a solution of 100 mg ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid in 2 ml DMF were added 0.15 ml DIPEA, 81 mg HATU and 0.03 mg 1-cyclobutoxycarbonylpiperazine. After stirring for 1 h it was diluted with dichloromethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH2:49]([O:51][C:52](=[O:61])[C:53](=[O:60])[C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1)[CH3:50].N1C=CC=CC=1>C(Cl)Cl.O>[CH2:49]([O:51][C:52](=[O:61])[C:53]([C:54]1[N:55]=[C:56]([NH:59][C:40](=[O:42])[CH:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[S:57][CH:58]=1)=[O:60])[CH3:50]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-(aminothiazol-4-yl)-oxo-acetic acid ethyl ester (182 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded {2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-oxo-acetic acid ethyl ester (208 mg, 67%) as a clear colorless oil: EI-HRMS m/e calcd for C22H25ClN2O6S2 (M+) 513.0921, found 513.0919.
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[CH:7][N:6]=1.Cl[CH2:14][C:15]#[N:16].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:12][C:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[Se:1][C:14]=1[C:15]#[N:16]
Reactant: N#CCCl
Reactant: [Se-2]
Reactant: N#Cc1cccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1[se]c2ncccc2c1N
Temperature: 65 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a suspension of sodium selenide (0.9 g, 7.2 mmol, prepared from 0.75 g of selenium as described above) in DMF (7 mL) was added a solution of 2-chloropyridine-3-carbonitrile (1 g, 7.2 mmol) in DMF (3 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (0.46 mL, 7.22 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (0.39 g, 7.2 mmol) in methanol (7 mL) was added dropwise and stifling was continued for 1 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (1.3 g, 81%), mp 208-210° C. 1H NMR (400 MHz, DMSO-d6): δ 8.68 (1H, d, J=4.4 Hz, H-6), 8.47 (1H, d, J=8.4 Hz, H-4), 7.55 (1H, dd, J=8.0, 4.8 Hz, H-5), 7.24 (2H, s, —NH2).
Reaction SMILES: [CH2:1]([C:5]1[CH:36]=[CH:35][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=2)=[N:43][CH:44]=1>>[ClH:37].[ClH:37].[ClH:37].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]3[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=3)=[N:43][CH:44]=2)=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Reactant: CCCCc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: CCCCc1ccc(N(Cc2ccc(-c3cc(OC)c(OC)c(OC)c3)nc2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([CH3:17])[C:6](=[O:16])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:9]=1)[CH3:3].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][CH:2]([C:4]2[N:5]([CH3:17])[C:6](=[O:16])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:9]=2)[CH3:3])=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: CC(N)c1nc(-c2ccncn2)cc(=O)n1C
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1C(=O)NC(C)c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 0.112 g (0.48 mmol) of (+/−) 2-(1-amino-ethyl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 5 mL of dimethylformamide was added 0.082 g (0.48 mmol) of 4-fluoro-2-methoxy-benzoic acid and 90 μL (0.58 mmol) of diethyl phosphorocyanidate (DEPC). The resulting mixture was cooled at 0° C., 70 μL (0.53 mmol) of triethylamine was added and stirred at room temperature for 1 h. Water was added and the mixture extracted with diethyl acetate. The extracts were washed with a saturated aqueous solution of ammonium chloride, dried and evaporated. The residue was purified on preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to afford 0.12 g (66%) of the desired compound as a white powder.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:37])[CH:33]([NH2:36])[CH2:34][CH3:35]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:36][CH:33]([CH2:34][CH3:35])[C:32]([O:31][CH3:30])=[O:37])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: CCC(N)C(=O)OC
Agent: Cl
Product: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)OC

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24; 80.00 mg; 0.18 mmol) and 2-amino-butyric acid methyl ester hydrochloride (Sigma, 55 mg; 0.36 mmol), the title compound was obtained as a colorless oil after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(Cl)Cl.CCO>N1C=CC=CC=1>[C:23]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.07 h

Procedure:
A mixture of 2'-deoxyuridine (100 g, 0.44 mol) and triphenylmethyl choride (147 g, 0.53 mol) in 250 mL of pyridine was heated at 100° C. for 30 minutes. One-third of the cooled solution was added at a slow flow rate to a mixture of ice water (2:3) in a commercial blender blending for 3-5 minutes after adding the solution. The resulting white precipitate was filtered and washed twice, stirring in 2 L of water. Recrystallization was accomplished by refluxing the product in a benzene-acetone solution (1:1) for 15 minutes, yielding 128 g (62%). The compound softened at 76° C., began to melt at 152-155° C., and darkened in color at 155-159° C. Rf =0.71 (CHCl3 --EtOH, 4:1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:11]([CH:12]=O)=[CH:10][N:9]=2)[S:5][CH:6]=1.[CH3:23][O:24][C:25](=[O:46])[CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:9]=[CH:10][C:11](/[CH:12]=[CH:26]/[C:25]([O:24][CH3:23])=[O:46])=[CH:14][C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncc(C=O)cc2Oc2ccccc2)n1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of mL 6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyde (311 mg, 1.00 mmol) and THF (10 mL) was added methyl(triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol) and the reaction mixture was stirred at room temperature. After 4 hours, additional methyl(triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol) was added and the reaction mixture was stirred overnight. Filtered, concentrated the filtrate, and purified by silica gel chromatography (1:1 EtOAc in hexanes) to afford (E)-methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)acrylate.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.Cl.Cl.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CN=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>CO>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1cccnc1

Procedure:
Free base of the titled compound was prepared from 2-methyl-1-(2-pyridyl)-1H-benzimidazole and pyridine-3-carboxaldehyde according to the preparation of (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole dihydrochloride (Example 44). The free base and oxalic acid were dissolved into MeOH. Concentration and recrystallization from ethyl MeOH/EtOH yielded the titled compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:13])([CH3:12])[S:9][C:8]=2[CH:14]=1)([OH:3])=O.C(Cl)(=O)[C:16]([Cl:18])=O.Cl>CCOCC>[Cl:18][CH2:16][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:13])([CH3:12])[S:9][C:8]=2[CH:14]=1)=[O:3]
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2S1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Product: CC1(C)Oc2ccc(C(=O)CCl)cc2S1
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture consisting of 10 g of 5-carboxy-2,2-dimethyl-1,3-benzoxathiole (IV), 10 g of oxalyl chloride and 20 ml of ether was boiled gently for 2 hours. The solution was cooled and evaporated and the residue (V) was added to an ether solution of diazomethane prepared from 25 g of N-nitroso-N-methyl urea. After stirring the mixture for 18 hours at room temperature the solution (VI) was acidified with methanolic hydrogen chloride and then evaporated to leave a solid residue which was recrystallized from ether/hexane to yield 6 g of 5-chloroacetyl-2,2-dimethyl-1,3-benzoxathiole (VII), m.p. 84°-86° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1(c2ccncc2)CCCC1
Solvent: CC#N
Product: CCOC(=O)C1(C2CCN(Cc3ccccc3)CC2)CCCC1

Procedure:
Ethyl 1-pyridin-4-ylcyclopentanecarboxylate and benzyl bromide were reacted in acetonitrile under heating. The residue obtained by subjecting the reaction solution to evaporation under reduced pressure, triethylamine and platinum oxide were reacted in ethanol under a hydrogen atmosphere to obtain ethyl 1-(1-benzylpiperidin-4-yl)cyclopentanecarboxylate.