Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O.CS(O)(=O)=O>C[O-].[Na+]>[O:12]=[C:11]1[O:13][CH:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]1=2
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COP([O-])OC
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl phosphite (11 g, 0.1 mol) then 2-formylbenzoic acid (10.51 g, 0.07 mol) or equivalent were added dropwise at 0° C. under nitrogen to a stirred solution of sodium methoxide [from sodium (2.3 g) in methanol (80 ml)], the mixture was stirred at ambient temperature for 30 minutes, then it was quenched by the addition of methanesulphonic acid (10.6 g, 0.11 mol). The methanol was removed in vacuo, the residue was partitioned between dichloromethane (200 ml) and water (50 ml), then the dichloromethane solution was washed with water (2×50 ml) and dried (MgSO4). The solvent was removed in vacuo to leave dimethyl 3-oxobenzo[c]furan-1-ylphosphonate or equivalent.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:41])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[CH:32]([F:34])[F:33])[N:20]=[C:19]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:18]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].Br[CH2:43][CH:44]([CH3:46])[CH3:45]>CN(C)C=O>[C:3]([O:7][C:8](=[O:41])[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]([C:17]2[CH:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[CH:32]([F:33])[F:34])[N:20]=[C:19]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:18]=2)[CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1cc(-n2c(C(F)F)nc3ccccc32)nc(N2CCOCC2)n1)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (110 mg) was suspended in N,N-dimethylformamide (20 mL), and tert-butyl[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexyl]carbamate (1 g) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a 1-bromo-2-methylpropan (807 mg), followed by stirring at room temperature for 12 hours. After the completion of the reaction, to the reaction solution was added ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified using silica gel chromatography to obtain tert-butyl{trans-4-[{6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}(isobutyl)amino]cyclohexyl}carbamate (163 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:77])[C:69]1[CH:74]=[C:73]([NH2:75])[CH:72]=[CH:71][C:70]=1[F:76])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:77])[C:69]1[CH:74]=[C:73]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])[CH:72]=[CH:71][C:70]=1[F:76])[CH3:66]
Reactant: CCOC(=O)c1cc(N)ccc1F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 5-amino-2-fluoro-benzoic acid ethyl ester (Oakwood, 63 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-20%) to give a white solid. 64 mg.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([Br:12])[CH:11]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[O:13][C:8]1[CH:9]=[C:10]([Br:12])[CH:11]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:7]=1
Reactant: COC(COc1cc(O)cc(Br)c1)OC
Reactant: Cc1ccccc1N=C=O
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(COc1cc(Br)cc(OC(=O)Nc2ccccc2C)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethoxy)-5-bromophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 2-Methylphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-bromophenyl] N-2-methylphenylcarbamate as the residue.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:5]=2[CH:6]=1>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[CH:6][C:5]=2[CH:7]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2cc(N)ccc2o1
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a solution of 2-methyl-5-nitro-benzofuran [19] (125 mg, 0.706 mmol) in methanol (20 mL) was added 5% palladium on carbon (20 mg) and the mixture was stirred under 1 atm H2 for 4 h. The mixture was filtered through celite and the filtrate evaporated. The residue was passed through a silica plug to afford 5-amino-2-methyl benzofuran as a red-brown oil (78 mg, 75%), single spot at Rf 0.45 (1:1 hexane:ethyl acetate). 1H NMR (CDCl3): δ 7.17 (1H, d, J=8.7 Hz), 6.75 (1H, d, J=2.5 Hz), 6.57 (1H, dd, J8.7, 2.5 Hz), 6.20 (1H, s), 3.53 (2H, s, NH2), 2.39 (3 H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13]>CO.[C].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:14]=1
Reactant: COCCCCNc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCCCCNc1cc(F)ccc1N
Temperature: 25 °C
Yield: 104.2 %

Procedure:
5-Fluoro-N-(4-methoxybutyl)-2-nitroaniline (494 mg) was dissolved in methanol (20 ml), 10% palladium carbon (50% in water, 100 mg) was added, and the mixture was stirred under a hydrogen stream at ambient temperature and normal pressure for hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (451 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])C)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23].[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:17][CH2:18][O:19][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (7, 0.94 g, 2.59 mmol) in THF (anhydrous, 100 mL) were added tert-butyl chloro-dimethyl silane (0.86 g, 5.7 mmol), Et3N (0.8 mL, 5.7 mmol) and cat. amount of DMAP. The solution was stirred at room temperature overnight. The solution was filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-50% EtOAc/hexanes gradient, to afford 1.1 g (89% yield) of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([Cl:8])Cl)#[N:2].C[Si](C)(C)[CH:11]1[CH2:15][NH:14][CH2:13][CH2:12]1>C(Cl)Cl>[Cl:8][P:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[N:14]1[CH2:15][CH2:11][CH2:12][CH2:13]1
Reactant: N#CCCOP(Cl)Cl
Reactant: C[Si](C)(C)C1CCNC1
Solvent: ClCCl
Product: N#CCCOP(Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To a solution of 2-Cyanoethyldichlorophosphite (2.0 g, 11.6 mmol, 1.5 mL) in CH2Cl2 (30 mL) was added dropwise 4-(trimethylsilyl)pyrrolidine (2.0 mL, 1.7 g, 11.6 mmol) at 0° C. The resulting mixture was stirred overnight at room temperature. The solvent was removed under the reduced pressure to give a colorless oil (2.48 g, 88%) as a product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-])=O.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:22])[CH:18]=[N:19][C:20]=1[CH3:21].Cl[Sn]Cl>N1C=CC=CC=1.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:22][C:17]1[CH:18]=[N:19][C:20]([CH3:21])=[C:15]([CH3:14])[CH:16]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(N)cnc1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2N)cnc1C
Yield: 105.7 %

Procedure:
The title compound (2.7 g, 13.0 mmol) was prepared in two steps from 2-nitrobenzenesulfonyl chloride (3.20 g, 14.4 mmol) and 5,6-dimethylpyridin-3-amine (1.5 g, 12.3 mmol) in pyridine (20 mL) at rt; followed by SnCl2 (8.88 g, 46.8 mmol) in ethanol at reflux for 2 h using the methods of (IntA1), steps 1 and 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:31].[O:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:38][CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:31]
Reactant: CS(=O)(=O)c1nccc(-c2ccn(C(c3ccc(Cl)c(F)c3)c3cnco3)c(=O)c2)n1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1C(c1ccc(Cl)c(F)c1)c1cnco1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A microwave tube was charged with a solution of 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (53 mg, 0.12 mmol) in DMA (1.2 mL). Tetrahydro-2H-pyran-4-amine (35 mg, 0.35 mmol) was added neat by syringe. The reaction was put into a microwave apparatus and heated to 120° C. After 1 hour, the solution was diluted to 30 mL with ethyl acetate and washed with a water/brine mixture (4×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. TLC in ethyl acetate showed complete loss of starting material and a new spot of nearly the same rf. The crude product was loaded onto a Biotage 12M column with ethyl acetate and eluted. Product containing fractions were pooled and concentrated to an oil, 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.43 (dd, 1H), 7.31 (d, 1H), 7.22 (br s, 1H), 7.08 (s, 1H), 7.00 (m, 2H), 6.90 (s, 1H), 6.83 (dd, 1H), 5.20 (br d, 1H), 4.11 (m, 1H), 4.01 (m 2H), 3.55 (m, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=483.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[C:4]([CH3:20])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:22](OC)(OC)(OC)[CH2:23][CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH2:23]([C:24]1[O:21][C:3]2[C:2]([N:1]=1)=[CH:19][C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:10][CH2:11][C:5]=1[C:4]=2[CH3:20])[CH3:22]
Reactant: Cc1c(O)c(N)cc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCc1nc2cc3c(c(C)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Yield: 95 %

Procedure:
1,1-Dimethylethyl 8-amino-7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.1 g) was treated with trimethyl orthopropionate (0.802 ml) and pyridinium p-toluenesulfonate (0.1 eq) in dry DMF (19 ml) at 60° C. for 1.5 hours. Volatiles were evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 1/4) providing the title compound as white solid (1.18 g, 95% yield).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][CH3:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][CH3:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC=CC=CCOc1ccc(C(O)(c2ccccc2)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Compound 35 (2.0 grams) was dissolved in THF (45 mL) and phenylmagnesium bromide (1.0M solution in THF; 10.6 mL, 10.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours, and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo and purified column chromatography (silica gel; hexane/CH2Cl2, 1/9) to afford 1.84 grams (77%) of compound 36 as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ1.73 (d, J=6.9 Hz, 6H), 4.54 (d, J=6.0 Hz, 4H), 5.68-5.80 (m, 4H), 6.02, 6.11 (m, 2H), 6.20-6.37 (m, 2H), 6.85 (d, J=6.9 Hz, 4H), 7.05 (d, J=7.0 Hz, 4H), 7.14-7.32 (m, 5H); Anal. Calcd for C31H32O3 (452.5920): C, 82.27; H, 7.13; Found: C, 82.30; H, 7.11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:17]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH:23]=[CH:24][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)#[N:20]
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Product: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Oc1cc(CC(=O)O)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 44 step (i).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[C:8]([NH2:10])=[O:9].[H-].[Na+].[CH3:15]I>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[C:8]([NH:10][CH3:15])=[O:9]
Reactant: COc1cccc(N)c1C(N)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N)cccc1OC
Temperature: 3 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
Slow addition of 4.98 g. (0.03 mole) of 6-amino-o-anisamide to a mixture of 57% NaH (1.32 g., 0.0315 mole) in 50 ml. dimethylformamide was carried out at room temperature. After the evolution of H2 ceased, the mixture was cooled to 3° C. and 2.06 ml. (0.033 mole) of methyliodide was slowly added at 3°-5° C. The temperature was allowed to go up to room temperature and stir for 2 hours. The mixture was concentrated, the residue extracted into ethyl acetate-water, the mixture was basified, and the ethyl acetate layer was washed with water, brine and dried. Concentration gave a tan solid that was crystallized (ethanol), giving 0.45 g (8%) Of 6-amino-N-methyl-o-anisamide m.p. 186°-189° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:34])C(=O)C1>CC#N>[Br:34][C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (4.40 g, 11.9 mmol) in CH3CN (25 mL), was added NBS (3.60 g, 20.2 mmol). The resulting solution was stirred for 30 minutes at 80° C. before being concentrated in vacuo. The reaction was diluted with ethyl acetate (200 mL), washed with water (×3), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 2-6% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 5-bromo-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil. LRMS (ESI) calc'd for C18H22N4O3SiBr [M+H]+: 449, found 449.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([C:17]#[C:18][C:19]3[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)=[C:15]([CH3:26])[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>O.C1COCC1>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([C:18]#[C:17][C:16]2[C:11]([N:8]3[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:27])=[O:2])[CH2:6][CH2:7]3)=[N:12][CH:13]=[N:14][C:15]=2[CH3:26])=[CH:24][CH:23]=1
Reactant: COC(=O)CC1CCN(c2ncnc(C)c2C#Cc2ccc(N)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnc(N2CCC(CC(=O)O)CC2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.87 g (7.85 mmol) {1-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-4-yl}-acetic acid methyl ester using 0.82 g (19.6 mmoL) LiOH in 10 mL water and 40 mL THF. The reaction mixture is stirred over night at 50° C. The THF is removed under reduced pressure and the residue is taken up DCM and MeOH and separated from insoluble material. The filtrate is dried over MgSO4 and the solvent is removed under reduced pressure. After drying 2.9 g (95%) of crude product is obtained which is used for the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(Cc2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(Cc2ccccc2)n1

Procedure:
86 mg (84.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-benzyl-3-propyl-1H-pyrazol-5-yl)propanal (62mg, 0.242 mmol), 1-(2-fluorophenyl)piperazine (76 mL, 0.484 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl>CN(C)C=O>[CH3:1][O:2][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(C(F)(F)F)nc1NS(=O)(=O)C=Cc1ccccc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(C(F)(F)F)nc1OC
Reaction time: 8 h
Yield: 66.2 %

Procedure:
Sodium methoxide (336 mg) was added to a solution of 320 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamide in 10 ml of N,N-dimethylformamide followed by stirring overnight. The reaction mixture was poured into a mixture of ice and 1N hydrochloric acid and the solid separated out therefrom was collected by filtration. This solid was purified by a silica gel column chromatography (chloroform) and the resulting oil was crystallized from ether to give 210 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1.[OH-].[K+].Cl>C(O)C.O.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 3.0 g of ethyl p-{[2-(2-naphthyloxy)-ethyl]amino}benzoate, and 3.0 g of potassium hydroxide in 200 ml of ethanol-water (95:5) is refluxed for 3 hours. The mixture is diluted with 100 ml of water and brought to pH 6.0 with concentrated hydrochloric acid. The mixture is filtered and the solid washed with 50 ml of water and 20 ml of cold ethanol-water (4:1) to give the product, mp 208°-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nccn1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nccn1Cc1ccc(Cl)cc1

Procedure:
Ethyl 1-(4-chlorobenzyl)-1H-imidazole-2-carboxylate (7.28 g, 27.5 mmol), was dissolved in EtOH (10 mL) and 10% aq. NaOH (20 mL) and stirred at rt for 15 h. The solvent was then stripped off, water was added, and the solution acidified with HCl. The resulting precipitate was collected over a filter and washed with 1M HCl and dried to afford the title compound as a white powder without further characterization. (Yield: 6.506 g, 27.5 mmol, 100%)