Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3O)=[CH:4][CH:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[N:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reaction time: 23 h

Procedure:
9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-ol I-(4A-7)b (2.49 g, 6.97 mmol) was suspended in 50 ml of toluene. Triethylamine (1.07 ml, 7.68 mmol) was added followed by addition of POCl3 (720 μl, 7.72 mmol) at room temperature. The reaction was warmed to reflux and stirred for 23 hours to give a clear orange solution. After cooling the reaction to room temperature it was concentrated under reduced pressure, diluted with isopropanol (50 ml) and then concentrated further under reduced pressure until copious amount of precipitate came out of solution. The concentrated suspension was cooled in an ice bath and stirred for 2 hours. The precipitate was collected on a sintered glass funnel and rinsed with cold isopropanol to afford, after drying in vacuo, I-(4A-7)c as an off-white solid (2.13 g, 82%): +ESI MS (M+1) 375.1; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.76 (dd, J=7.46, 1.2 Hz, 1H), 7.58–7.40 (m, 7H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CCOCC>[I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N#CCC(=O)c1cccc(I)c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-(3-iodobenzoyl)acetonitrile (36.2 g, 133.5 mmol) and N,N-diphenylformamidine (26.2 g, 133.5 mmol) in toluene (200 ml) was heated at reflux under a nitrogen atmosphere. After 8 h, the reaction mixture was cooled to room temperature and diluted with ether (200 ml) to give 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (31.2 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](O)(=O)[CH3:34].[C:37]([BH3-])#N.[Na+].O>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH:33]([CH3:34])[CH3:37])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1500 mg) in acetone (20 ml) were added acetic acid (0.20 ml) and sodium cyanoborohydride (214 mg) in an ice bath. The mixture was stirred at room temperature overnight and then heated under reflux for 8 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (583 mg, yield 35%) as a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14]>C(O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14]
Reactant: O=Cc1nccs1
Reactant: NCCNCCO
Solvent: CCO
Product: OCCNCCNCc1nccs1
Reaction time: 4 h
Yield: 59.8 %

Procedure:
3 Å molecular sieves (22.5 g) and a solution of 2-thiazole-carboxaldehyde (14.5 g, 128 mmol) in ethanol (90 ml) were sequentially added to a solution of 2-(2-aminoethylamino)ethanol (13.35 g, 128 mmol) in anhydrous ethanol. The reaction mixture was stirred for 4 hours, filtered through a pad of Celite while washing with ethanol (100 ml) and placed in a high-pressure flask. After adding acetic acid (3 ml) and Pd (10% on C, 2 g), the solution was introduced into Parr apparatus and, after several hydrogenation cycles, was stirred for 2 days under a hydrogen atmosphere at 40 psi. The reaction mixture was filtered through a pad of Celite, evaporated under vacuum and purified by flash chromatography (silica, 80/20/10 CH2Cl2/MeOH/NH3 eluent) to give 2-[2-[(2-thiazolylmethyl)amino]ethylamino]ethanol (15.4 g, 60% yield) as a brown oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCCCC2)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 93.7 %

Procedure:
A mixture of 3-fluoronitrobenzene (10.0 g, 70.9 mmol) and piperidine (14 ml, 141 mmol) was stirred at 110° C. for 3 days. After cooling water (200 ml) was added and the mixture was extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate, dried over sodium sulfate and evaporated to dryness to leave 1-(3-nitrophenyl)piperidine (13.7 g, 93%) as an oil. This oil was dissolved in ethanol (150 ml) and was hydrogenated at ambient pressure using palladium on activated carbon as the catalyst to yield 2a (11.7 g, 100%) as an oil.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([OH:18])[CH2:16]Cl.O>CO.CN(C)C=O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([OH:18])[CH2:16][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 40 °C
Yield: 66.3 %

Procedure:
30 g of sodium were added to a solution of 88.5 g of imidazole in 600 ml of methanol; the solvent was then evaporated off. The residue was dissolved in 300 ml of dimethylformamide and heated to 115°-120° C. To the solution so obtained was added, dropwise and under stirring, a solution of 225 g of 1-(2',4'-dichlorophenyl)-2-chloro-ethanol in 400 ml of dimethylformamide. The mixture was heated to 115°-120° C. and maintained at that temperature for 20 minutes and, after subsequent cooling to 40° C., 2500 ml of iced water were added under vigorous stirring. The product precipitated under stirring over a period of about two hours, the upper liquid was then decanted off, a further 2500 ml of water were added and, after standing, the whole was filtered. The precipitate thus obtained was dried and crystallized from toluene. 170 g of the desired product, melting at 134°-135° C., was obtained.
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].[S:11]([C:15]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=O)([OH:14])(=[O:13])=[O:12].[OH2:27].[Cl-].[Na+]>CS(O)(=O)=O>[C:24]([C:22]1[CH:21]=[CH:20][C:16]([C:17]2[C:5]3[C:3]([O:4][C:3]4[C:5]=2[CH:6]=[C:7]([F:10])[C:8](=[O:9])[C:2]=4[F:1])=[C:2]([F:1])[C:8]([OH:27])=[C:7]([F:10])[CH:6]=3)=[C:15]([S:11]([OH:14])(=[O:13])=[O:12])[CH:23]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1ccc(C(=O)O)c(S(=O)(=O)O)c1
Reactant: O
Reactant: Oc1ccc(F)c(O)c1F
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)c1ccc(-c2c3cc(F)c(=O)c(F)c-3oc3c(F)c(O)c(F)cc23)c(S(=O)(=O)O)c1

Procedure:
2,4-Difluororesorcinol (13, 0.200 g, 1.37 mmol) and 2-sulfoterephthalic acid (0.184 g, 0.68 mmol) are heated together in methanesulfonic acid (2 mL) at 100° C. overnight with stirring. After cooling, the reaction mixture is poured into cold water (30 mL). Sodium chloride is added portionwise with stirring until a precipitate forms, which is collected on a Buichner finnel and dried in vacuo to give Compound 83 as 40 mg of a red-orange powder: Rf =0.65 (CH3CN:H2O:acetic acid 8:1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=1.[Li]CCCC.CON(C)[C:27](=[O:29])[CH3:28]>C(OC)(C)(C)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][CH2:8][C:6]2[CH:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[N:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(COCc2cncc(Br)c2)cc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccc(COCc2cncc(C(C)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a solution of 3-bromo-5-{[(4-methoxybenzyl)oxy]methyl}pyridine (4.4 mmol) in methyl t-butyl ether (20 mL) was added n-BuLi (2.5M in hexane, 1.96 mL) dropwise at −78° C. The reaction mixture was allowed to stir for 15 min and then N-methoxy-N-methylacetamide (6.7 mmol) in methyl t-butyl ether (3 mL) was added dropwise. The reaction mixture was allowed to stir for 30 min at −78° C. and then diluted with water and allowed to warm to rt. After stirring for 30 min, the phases were separated and the aqueous solution was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 1-(5-{[(4-methoxybenzyl)oxy]methyl}pyridin-3-yl)ethanone (3.1 mmol, 70%) as a white solid. LCMS: (FA) ES+ 272.1.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:12]([N+](CCCC)(CCCC)CCCC)CCC.CI>C(Cl)Cl.[OH-].[Na+]>[CH3:12][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: ClCCl
Product: Cn1ccc2c(C=O)cccc21
Yield: 98.7 %

Procedure:
34 g of indol 4-carboxaldehyde in 800 ml of methylen chloride were mixed for 4 hours at ambient temperature with 79.5 g of tetrabutyl ammonium hydrogeno sulfate and 16.04 ml of methyl iodide in 400 ml of 5N sodium hydroxide and 300 ml of methylene chloride were added, followed by decanting and extraction was effected with methylene chloride. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 36.8 g of the expected product melting at <40° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:14].S(Cl)(Cl)=O.[C:28]([OH:36])(=[O:35])/[C:29](=[C:31](\[CH:33]=O)/[Cl:32])/[Cl:30].N1C=CC=CC=1>C(Cl)CCl>[Cl:30][C:29]1[C:28](=[O:35])[O:36][CH:33]([O:14][C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:18]2)[C:31]=1[Cl:32]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCN(CC)c1ccc(C2(OC3OC(=O)C(Cl)=C3Cl)OC(=O)c3ccccc32)c(C)c1
Yield: 84.2 %

Procedure:
In a manner similar to that described in Example 1 above, 2.0 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid, 0.77 g of thionyl chloride and 1.1 g of mucochloric acid were interacted in 20.0 ml of ethylene dichloride in the presence of 0.8 ml of pyridine to obtain 2.5 g of 3-[3,4-dichloro-2(5H)-furanon-5-yl]oxy-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula II: R0 =R=R1 =R2 =H; R4 =R4' =R5 =CH3 ; X=O; Y=3,4-dichloro-2-(5H)-furanon-5-yl), an orange-colored oil. A significant infrared maximum appeared at 1758 cm-1 (C=O;s). A toluene solution of the product spotted on an acidic clay-coated paper developed a yellow-colored image.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH2:20][CH2:21][S:22][CH3:23])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH2:20][CH2:21][S:22][CH3:23])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2CCSC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCCC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Yield: 108.9 %

Procedure:
To a stirred solution of intermediate 21, ethyl 3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (97 mg, 0.2mmol) in 3 mL tetrahydrofuran was added lithium hydroxide (1 5 mg, 0.6 mmol) in 3 mL water. After 20 min the reaction mixture was acidified with 1N HCl and extracted with CH2Cl2. The extract was dried over MgSO4, filtered and concentrated to give 82 mg of the title compound (88% yield). LC/MS m/e 377.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]([CH2:19][CH2:20][CH3:21])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)(Cl)Cl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:29]([NH:28][CH3:27])=[O:30])[CH:10]=2)[C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CCCc1c(C(=O)C(C)C)c2ccc(NC(=O)NC)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (100 mg) in chloroform (2 ml) was added methylisocyanate (0.5 ml) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour, then evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:1) to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzyl)-3-isobutyryl-6-(3-methylureido)-2-propylindole (75 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:18]2[NH:26][C:25]3[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=3[CH:19]=2)[N:3]=1.[CH3:28][C:29](OC(C)=O)=[O:30]>C(Cl)Cl>[C:29]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:30])[CH3:28]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC[C@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.5 %

Procedure:
Prepared according to Example 50, using TEA (57.6 μl, 0.414 mmol), (S)-2-(2-methyl-3-(pyrrolidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 55, 125 mg, 0.345 mmol), Ac2O (65.1 μl, 0.690 mmol), and DCM (3.5 mL) stirring at 25° C. for 1.5 h. Purification by trituration with Et2O and elution through a Si-carbonate cartridge (Silicycle) provided (S)-2-(3-((1-acetylpyrrolidin-3-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (23 mg, 16.5%). 1H NMR (DMSO-d6) δ: 7.84-7.90 (m, 1H), 7.53-7.59 (m, 1H), 7.32-7.40 (m, 1H), 7.13-7.21 (m, 2H), 6.89-6.97 (m, 1H), 4.61-4.75 (m, 1H), 3.45-3.98 (m, 3H), 3.38-3.45 (m, 1H), 2.82-2.90 (m, 2H), 2.57 (s, 3H), 2.04-2.44 (m, 2H), 1.98 (s, 3H), 1.12-1.21 (m, 2H). m/z (ESI, +ve) 405.1 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.[H][H]>[Pd]>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC(N)=O)C4CCCC4)c3)ncnc21
Reaction time: 17 h
Yield: 99.7 %

Procedure:
To a 25 ml round bottom flask equipped with a stir bar was charged (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxoprop-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10, 1.15 g, 2.63 mmol), tetrahydrofuran (THF, 20.0 ml, 246 mmol) and 10% palladium on carbon (50% wet, 130 mg) at room temperature. The resulting reaction mixture was degassed three times back filling with hydrogen gas each time before the hydrogenation reaction was conducted under a steady stream of hydrogen gas released by a hydrogen balloon. The reaction was checked after 17 h and was found to be complete. The reaction mixture was then filtered through a Celite bed to remove the catalyst and the Celite bed was rinsed with a small volume of tetrahydrofuran (THF). The combined filtrates were concentrated under reduced pressure to afford the crude (4-(1-(3-amino-1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (11, 1.15 g, 1.153 g theoretical, 99% yield) as a yellow to brown oil, which solidified upon standing in vacuum at room temperature. This crude product (11) was found to be pure enough (>98% by HPLC) to do the following reaction without further purification. For 11: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.73 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.70 (d, 1H, J=3.8 Hz), 7.32 (bs, 1H), 7.09 (d, 1H, J=3.8 Hz), 6.75 (bs, 1H), 6.21 (s, 2H), 4.56 (td, 1H, J=4.0, 9.8 Hz), 2.86 (dd, 1H, J=10.5, 5.6 Hz), 2.63 (dd, 1H, J=4.0, 15.3 Hz), 2.32 (m, 1H), 1.77 (m, 1H), 1.56-1.19 (m, 7H), 1.06 (s, 9H); LCMS (EI) m/e 439 (M++H); C23H30N6O3 (MW, 438.52), LCMS (EI) m/e 439 (M++H).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: c1ccc(COc2nsnc2-c2cccnc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[CH2:14][C:15]([CH3:17])=[CH2:16].O>CN(C=O)C>[I:1][C:2]1[C:3]([O:10][CH2:16][C:15]([CH3:17])=[CH2:14])=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C=C(C)CCl
Reactant: COc1cccc(O)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cccc(OC)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2-iodo-3-(methyloxy)phenol (Intermediate 3, 10.3 g) in DMF (100 ml, SCRC) was added NaH (60%, wt., 1.977 g, 49.4 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour and 3-chloro-2-methyl-1-propene (3.73 g, 41.2 mmol, Aldrich) was added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (3 times 200 ml, SCRC) and the combined organic layer were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc/PE (1/30) to afford the title compound as a yellow liquid (11.6 g)
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[NH:8].[C:10]([O:16][CH3:17])(=[O:15])[CH2:11][C:12]([CH3:14])=O.[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O.C([O-])(=O)C.[K+]>C(O)C(F)(F)F>[CH3:17][O:16][C:10]([C:11]1[CH:21]([C:20]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=2[Cl:18])[N:8]=[C:7]([C:3]2[S:2][CH:6]=[CH:5][N:4]=2)[NH:9][C:12]=1[CH3:14])=[O:15]
Reactant: N=C(N)c1nccs1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: OCC(F)(F)F
Product: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-4-fluorobenzaldehyde (0.16 g, 1.0 mmol) in trifluoroethanol (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from 1/4 to 1/2) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22])=O.[NH2:27][C:28]([NH2:30])=[O:29]>CC(O)=O>[OH:26][C:19]1[C:18]([CH:16]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:30][C:28](=[O:29])[NH:27]2)=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1cccc(C=O)c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: N#Cc1cccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)c1O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 1,2-diphenylethanone (1.6 g, 8.16 mmol), and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) (1.0 g, 6.80 mmol) in AcOH (5 mL) was added urea (1.2 g, 20.4 mmol). The mixture was stirred at 120° C. under microwave for 3 h. The volatiles were removed under reduced pressure and standard aqueous workup procedure was followed. The crude was recrystallized by EA (10 mL) to afford Compound 94 as a white power (436 mg, 26%). 1H NMR (DMSO-d6500 MHz): δ 8.10 (s, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.58 (d, J=7.5 Hz, 3H), 7.30-7.36 (m, 3H), 7.18 (s, 1H), 7.02 (d, J=6.0 Hz, 3H), 6.78 (d, J=6.0 Hz, 2H), 4.44 (d, J=2.0 Hz, 1H), 4.14 (s, 1H); MS (ESI): m/z 368.1 [M+1]+.