Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.ClC(OCC(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Na+]>CN(C)C=O.C(OCC)C.C(N(CC)CC)C>[CH2:23]([N:30]1[CH2:35][CH2:34][N:33]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a solution of 50 ml of dimethylformamide with 5.0 g of 6-carboxy-3,4-dihydrocarbostyril and 4 ml of triethylamine, 3.87 g of isobutyl chloroformate in 2 ml of dimethylformamide solution was added dropwise. After stirring at a room temperature for 30 minutes, 5.5 g of benzylpiperazine in 3 ml of dimethylformamide solution was added to the former solution and stirred at a room temperature for 30 minutes, then stirred continuously at 50°-60° C. for 1 hour. The reaction mixture was poured into a voluminous amount of a saturated sodium chloride aqueous solution and extracted with chloroform and the chloroform extract was washed with water and dried. After removal of the solvent, to the residue thus obtained was added diethyl ether to crystallize the residue and recrystallized from ethanol to obtain 3.4 g of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: NC1N=CN=C2C=1N=CN2CC1N(C2C=CC=CC=2C)C(=O)C2C(=CC=CC=2C)N=1.[NH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34]([OH:36])=[O:35].[Cl:42][CH2:43][C:44](Cl)=[O:45]>>[Cl:42][CH2:43][C:44]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34]([OH:36])=[O:35])=[O:45]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)CCl
Agent: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(C)c2c1=O
Product: Cc1cccc(NC(=O)CCl)c1C(=O)O

Procedure:
The synthetic scheme for the preparation of 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one, 1, is shown in FIG. 1. 2-amino-6-methylbenzoic acid, 1″, is reacted with 2-chloroacetyl chloride to produce the 2-(−2-chloroacetamido)-6-methylbenzoic acid, 2″. Reaction with o-toluidine and phosphoryl trichloride yields the cyclized intermediate, 3″. Further reaction with diBOC-protected adenine give the BOC protected product, 4″, which is deprotected resulting in 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one, 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][CH2:8][CH:9]1[CH2:11][CH2:10]1)[C:3](O)=[O:4].[H][H]>[H-].[Al+3].[Li+].[H-].[H-].[H-]>[NH2:1][C@@H:2]([CH2:6][S:7][CH2:8][CH:9]1[CH2:11][CH2:10]1)[CH2:3][OH:4]
Reactant: N[C@@H](CSCC1CC1)C(=O)O
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: N[C@H](CO)CSCC1CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice water cooled solution of lithium aluminum hydride (200 mL of 1.0 M) was added solid 2(R)-amino-3-cyclopropylmethylsulfanylpropionic acid. The addition was done by tapping in portions through a funnel in such a manner as to control hydrogen gas evolution. The ice bath was removed, and the reaction mixture was heated at reflux for 16 h. The reaction mixture was removed from heat and cooled in an ice water bath. Diethyl ether (110 mL) was added, followed by dropwise addition of water (5 mL), 15% aqueous sodium hydroxide (5 mL), and water (15 mL). After stirring in the ice water bath for 1.5 h, the reaction mixture was filtered. The filtrate was dried over anhydrous sodium sulfate, and concentrated to give 2(R)-amino-3-cyclopropylmethylsulfanyl-propan-1-ol (14.9 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH:8]([CH2:11][CH3:12])[CH2:9][OH:10])=[N:3][CH:2]=1.[Br:13]Br.[OH-].[Na+]>C(O)(=O)C>[Br:13][C:5]1[C:4]([NH:7][CH:8]([CH2:11][CH3:12])[CH2:9][OH:10])=[N:3][CH:2]=[N:1][CH:6]=1
Reactant: BrBr
Reactant: CCC(CO)Nc1ccncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(CO)Nc1ncncc1Br
Reaction time: 24 h

Procedure:
2-(4-Pyrimidinylamino)-1-butanol (4.2 g) was dissolved in acetic acid (42 mL), and bromine (1.5 mL) was added dropwise at a normal temperature. After stirred for 1 day at the same temperature, the solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1.1) to give the title compound (4.4 g) as white crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([N:28]([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:30][N:28]([CH3:29])[C:25]([C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:27])[CH3:26]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN(C)C(C)(C)c1nnc2ccc(F)cn12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(C)(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 112 mg, 2.80 mmol) in DMF (2.50 mL) was added Intermediate A (114 mg, 0.70 mmol) and the reaction stirred for 20 min. Intermediate 76b (153 mg, 0.70 mmol) was added in DMF (2.50 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (120 mg, 47%). LCMS (Method 4): Rt 0.31, m/z 366 [MH+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:31][C:17]([F:16])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[N:8]3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CCCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-(5-chloropentyl)-1H-benzotriazole (8.0 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.7 g compound (I-42) with a yield of 61.5%. ESI-MS [M+H]+: m/z 417.2.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[S:7].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)(C)C.C1C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][C:6]([NH:16][CH2:15][CH2:13][OH:14])=[S:7]
Reactant: NCCO
Reactant: Cc1ccc(CN=C=S)c(C)c1
Solvent: CC(C)O
Solvent: c1ccccc1
Product: Cc1ccc(CNC(=S)NCCO)c(C)c1
Yield: 58 %

Procedure:
2,4-Dimethylbenzyl isothiocyanate (15.7 grams; 0.08 mole) was mixed with 23 milliliters (ml) of isopropyl alcohol and a solution of ethanolamine (5.8 grams; 0.08 mole) in 23 ml of isopropyl alcohol added dropwise thereto with stirring. The temperature of the reaction mixture was maintained below about 50°C during the ethanolamine addition and then stirred at ambient temperatures for a period of about 16 hours. The reaction mixture was then concentrated to dryness and the residue obtained taken up in benzene. The resulting benzene solution was cooled to give crystals which were filtered off. The title product was thus obtained in about a 58% yield as a crystalline solid having a melting point of 101-103°C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10](=[O:12])[CH3:11])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.[BrH:13].[Br:14]Br>C(O)(=O)C>[Br:13][CH:11]([Br:14])[C:10]([C:3]1[N:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]2=[N:1][CH:2]=1)=[O:12]
Reactant: CC(=O)c1cnc2cccnn12
Reactant: Br
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1cnc2cccnn12)C(Br)Br
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
1-(Imidazo[1,2-b]pyridazin-3-yl)ethanone (502 mg, 3.11 mmol) was dissolved in acetic acid (7.8 mL) and 33% HBr in acetic acid (0.564 mL, 3.11 mmol) was added. Bromine (0.177 mL, 3.43 mmol) was added and the solution stirred at 60° C. for 1.5 h. After stirring for 1.5 h, added more bromine (0.08 mL, 1.56 mmol) and 33% HBr in acetic acid (0.282 mL, 1.56 mmol). The solution was stirred at 60° C. for 3 h. The solution was then cooled to room temperature and quenched with 10% aqueous sodium thiosulfate. The aqueous layer was extracted with dichloromethane (×3). The organic layers were combined and washed with aqueous saturated sodium bicarbonate. The organic layer was collected and dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was taken on to the next step without further purification. 1H NMR (500 MHz, CD3SOCD3) δ 8.88 (d, 1H); 8.83 (s, 1H); 8.40 (d, 1H); 7.66 (s, 1H); 7.61 (dd, 1H). LRMS (APCI) calc'd for (C8H5Br2N3O) [M+H]+, 317.9. found 317.9.
Reaction SMILES: [C:1]([CH2:3][C:4](Cl)=[O:5])#[N:2].[CH3:7][Si:8]([CH2:19][CH2:20][CH2:21][NH2:22])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>ClCCl>[C:1]([CH2:3][C:4]([NH:22][CH2:21][CH2:20][CH2:19][Si:8]([CH3:7])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[O:5])#[N:2]
Reactant: N#CCC(=O)Cl
Reactant: C[Si](C)(C)O[Si](C)(CCCN)O[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)O[Si](C)(CCCNC(=O)CC#N)O[Si](C)(C)C
Yield: 70.4 %

Procedure:
Cyanoacetyl chloride (5.2 g, 0.05 mol) is added dropwise over 20 minutes to a mixture of 3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propylamine (13.93 g, 0.05 mol) and of triethylamine (5 g, 0.05 mol) in 40 ml of dichloromethane. The temperature rises to 32° C. The mixture is refluxed for two hours. The reaction mixture is poured into 150 ml of water and is extracted with dichloromethane. The organic phases are washed with water and dried over sodium sulfate, and the solvent is then evaporated off. After purification by passing through a column of silica (eluent: 70/30 heptane/ethyl acetate), 12.2 g (70% yield) of cyano-N-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl]acetamide are obtained in the form of a colorless oil, which is used without further purification in the following step.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@:19]12(O)[N:26](C)[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[Na].O>C(#N)C>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][C@@:11]23[N:26]([CH3:19])[C@@H:23]([CH2:24][CH2:25]2)[CH2:22][CH:21]=[CH:20]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(C)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(C)(c1ccccc1)c1ccccc1)CC2

Procedure:
4.80 g (0.02 mol) of methyl 2,2-diphenylpropionate 3b, 2.78 g (0.02 mol) of tropenol, and 0.046 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. From the residue, 4c is precipitated as the hydrochloride and this is recrystallized from acetone. Yield: 5.13 g (67% of theory); TLC: Rf value: 0.28 (eluent: sec-butanol/formic acid/water 75:15:10); melting point: 134° C.-135° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][Mg]Br.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>O1CCCC1.[Cu](Cl)Cl.[Li]>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: CC(C)CC[Mg]Br
Reactant: BrCCCCCCCCCCCBr
Agent: Cl[Cu]Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCCCBr
Temperature: -10 °C
Reaction time: 1 h

Procedure:
By a procedure analogous to that described above, 3-methylbutyl magnesium bromide in tetrahydrofuran is reacted with 34.5 g. (0.11 moles) of 1,11-dibromoundecane and 0.2 g. of lithium copper chloride in 75 ml. of tetrahydrofuran. After 1 hour stirring at -10° C., the solution is evaporated, and the resultant oil is distilled in vacuo to yield the colorless 1-bromo-14-methylpentadecane.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][NH2:17]>O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:17][N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: NN
Solvent: O
Product: c1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 170 °C
Yield: 67 %

Procedure:
To 2-fluorobenzophenone (1.0 g, 5.0 mmol) was added hydrazine (5 mL) and the reaction was heated to reflux for 3 hours. The reaction was then added to water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried with sodium sulfate (Na2SO4) and concentrated to an oil. The subsequent hydrazine adduct was heated with pyridine (20 mL) to 170° C. for 4 days. Pyridine was then removed under vacuum and the resulting oil taken up in water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers were dried (Na2SO4) and concentrated to give the final compound (650 mg, 67% yield). 1H NMR (CDCl3) δ 10.6 (br s, 1H), 8.04–7.99 (m, 2H), 7.56–7.50 (m, 2H), 7.47–7.33 (m, 2H), 7.29–7.19 (m, 3H); ES-MS (m/z) 195 [M+1]+.
Reaction SMILES: ClC1C=CC([C:8]2[C:9]([F:20])=[C:10]([S:16]([O-:19])(=[O:18])=O)[CH:11]=[C:12]([F:15])[C:13]=2F)=CC=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35]2[N:40]3[CH:41]=[CH:42][N:43]=[C:39]3[CH:38]=[CH:37][CH:36]=2)[CH:29]=1>CS(C)=O.C(OCC)(=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:13]2[C:12]([F:15])=[CH:11][C:10]([S:16]([O:24][C:21]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)(=[O:18])=[O:19])=[C:9]([F:20])[CH:8]=2)=[C:30]([C:35]2[N:40]3[CH:41]=[CH:42][N:43]=[C:39]3[CH:38]=[CH:37][CH:36]=2)[CH:29]=1
Reactant: O=S(=O)([O-])c1cc(F)c(F)c(-c2ccc(Cl)cc2)c1F
Reactant: Oc1ccc(Cl)cc1-c1cccc2nccn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=S(=O)(Oc1ccc(Cl)cc1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred mixture of 4-chlorophenyl-2,4,5-trifluorobenzenesulfonate (1.64 g, 5.10 mmol) and potassium carbonate (2.11 g, 15.3 mmol) in dimethylsulfoxide (15 mL) at ambient temperature was added 4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenol (1.25 g, 5.10 mmol). The mixture was stirred at ambient temperature for 3 h and diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 20-50% gradient of ethyl acetate in dichloromethane to afford 4-chlorophenyl 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluorobenzenesulfonate as a colorless foam in 66% yield (1.84 g): 1H NMR (300 MHz, DMSO-d6) δ7.92-7.40 (m, 10 H), 7.27 (dd, J=7.5, 7.5 Hz, 1H), 7.11-6.90 (m, 3H); MS (ES+) m/z 546.8 (M+1), 548.8 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:45])([F:44])[C:10]1[CH:11]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[O:28])[N:21]=2)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl.CO>[F:19][C:16]([F:17])([F:18])[C:14]1[CH:13]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:28])[N:21]=2)[CH:11]=[C:10]([C:9]([F:8])([F:44])[F:45])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCC1CCCNC1
Yield: 146.9 %

Procedure:
In a 25 mL single neck round-bottomed flask (Z)-tert-butyl 3-((3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamido)methyl)piperidine-1-carboxylate (1) (0.1 g) was dissolved in dichloromethane (5 mL) and TFA (1.0 mL) dissolved in dichloromethane added dropwise. The progress of the reaction was followed by TLC on silica gel in 10% methanol in dichloromethane as a mobile phase in UV visualization. Reaction mixture was concentrated by rotary evaporation (40° C., 20 mmHg) to afford 0.12 g of compound. The resulting crude compound was purified by ‘SAEx’ column chromatography. Fraction collected together to obtain compound (40 mg) yield 49%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.[Cl-].ClC1N(C)CC[NH+]1C>ClCCl.O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: COc1cccc(N)c1C(=O)O
Reactant: NCc1ccccc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cccc(N)c1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a solution of 2-amino-6-methoxybenzoic acid (0.841 g, 5.0 mmol, 1.0 equiv), benzylamine (0.643 g, 6.0 mmol, 1.2 equiv), and diisopropylethylamine (1.935 g, 15.0 mmol, 3.0 equiv) in 50 mL of dichloromethane was added 2-chloro-1,3-dimethylimidazolinium chloride (1.099 g, 6.5 mmol, 1.3 equiv) at room temperature. The mixture was stirred at room temperature for 6 hours, poured into water, and extracted with dichloromethane. The organic solution was successively washed with aqueous saturated NaHCO3 and water. The organic layer was dried over MgSO4 and the solvent was removed by rotary evaporator. The residue was purified by column chromatography (silica gel, 2% 2.0 M ammonia MeOH solution in CH2Cl2) to give 2-Amino-N-benzyl-6-methoxybenzamide (0.593 g, 46%) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.81 (s, 3H), 4.62 (s, 1H), 4.63 (s, 1H), 6.07 (vb.s., 2H), 6.19 (d, J=8.2 Hz, 1H), 6.32 (d, J=8.2 Hz, 1H), 7.07 (t, J=8.2 Hz, 1H), 7.14-7.54 (m, 5H), 8.05 (br. s., 1H); HPLC: tR=4.72 min, UV254=99%; HRMS (ESI): m/z calcd for C15H16N2O2 [M+1]+257.1296. Found 257.1294.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][O:16]C(=O)C)[C:4]=2[N:5]=[CH:6][N:7]=1.N>CO>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OCCOCn1cc(Cl)c2c(Cl)ncnc21
Agent: N
Solvent: CO
Product: OCCOCn1cc(Cl)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-Chlorosuccinimide was added to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3) (0.35 g) in dry methylene chloride (15 mL). The reaction mixture was stirred at room temperature for 8 days. At that time, TLC established a complete disappearance of starting material. Water (50 mL) was added to the mixture and the product was extracted with CHCl3 (3×30 mL). The chloroform extracts were combined and washed with water, then dried over anhydrous Na2SO4. The solvent was removed at 40° C. in vacuo and the resulting thick syrup was subjected to column chromatography. Elution of the silica gel column (15×2 cm) with benzene; chloroform (1:1), yielded a colorless oil (single spot on TLC) after evaporation of all the UV absorbing fractions at a reduced temperature and pressure, which was crystallized from ethyl alcohol to afford colorless needles of the acetylated intermediate, (7a, 0.23 g) (59.95%). 4,5-Dichloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (7a, 0.31 g) was then dissolved in dry methanol (15 mL) and to this solution was added methanol which had previously been saturated with ammonia at 0° C. (25 mL). The reaction mixture was stirred in a pressure bottle at room temperature for 20 hours. The solvent was evaporated at 30° C. in vacuo and the semi-solid mass was subjected to column chromatography. Elution of the product from a silica gel column (15×2 cm) with 2% MeOH in CHCl3 yielded a colorless compound, after evaporation of all the appropriate UV absorbing fractions.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:41](Cl)(=O)[O:42]C1C=CC=CC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C1COCC1>[CH3:25][N:22]1[C:23]([CH3:24])=[C:19]([C:17]([NH:16][C:12]2[C:11]([F:33])=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:42])[CH:7]=3)=[C:14]([F:15])[CH:13]=2)=[O:18])[C:20](=[O:32])[N:21]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: C1COCCN1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(NC(=O)N4CCOCC4)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (250 mg, 0.56 mmol) and Et3N (0.25 mL, 1.68 mmol) in THF (10.0 mL) was added phenyl carbonochloridate (0.25 mL, 1.68 mmol). The mixture was stirred at rt for 2 hours, then morpholine (0.35 mL, 3.46 mmol) was added. The reaction mixture was stirred rt for 24 hours and partitioned between aq NH4Cl (40 mL) and DCM (40 mL). The organic phase was separated and the aqueous phase was extracted with DCM (40 mL×3). The combined organic phases was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=4/1) to give the title compound as a white solid (70 mg, 21%).