Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][C:19](=[O:54])[NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:53])[C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[CH:32]=[C:31]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([NH2:52])[CH:47]=3)[CH:30]=2)[CH2:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:54])[NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:53])[C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[CH:32]=[C:31]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:47]=3)[CH:30]=2)[CH2:23][CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc(N)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)c1
Yield: 56.7 %

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and {4-[3-(3-amino benzyloxy)-5-(4-cyano phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (0.6 g, 1.09 mmol) and other reagents as described in Example 9(e) were used to afford 0.45 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 2.45 (2H, m), 3.1 (3H, m), 3.7 (2H, m), 5.15 (2H, s), 6.74 (1H, d), 6.88 (1H, m), 6.98 1H, s), 7.12 (3H, d), 7.2 (1H, s), 7.3 (1H, t), 7.42 (1H, s), 7.54 (1H, d), 7.72 (1H, s), 7.86 (2H, d), 8.26 (1H, d).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([O:32]CC)=[O:31])[N:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>[OH-].[K+].CO>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[N:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
100 mg of the ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylate prepared in Example 4A was dissolved in approximately 10 mL of 1 N KOH in methanol. The solution was stirred at 60° C. for 24 hours. The solvent was then removed and the residue dissolved in 5 mL ethyl acetate. The aqueous phase was brought to a pH of 3-4 by addition of 37% HCL. The resulting solid was collected by filtration and washed with water and ether then air dried to provide the product, 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylic acid.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:27])=[N:24][C:25]=1[CH3:26].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:22]2[C:23](=[N:24][C:25]([CH3:26])=[C:20]([CH3:19])[CH:21]=2)[NH:27][CH:5]=1)=[O:17]
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Cc1ccc(N)nc1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3nc(C)c(C)cc3c2=O)cc1C
Yield: 11.2 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (2.01 mmol) 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester, 0.25 g (2.01 mmol) of 5,6-Dimethyl-pyridin-2-ylamine, and 15 mL of diphenyl ether to yield 68.7 mg of 3-(3,4-Dimethyl-benzoyl)-6,7-dimethyl-1H-[1,8]naphthyridin-4-one as a brown solid.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([OH:10])=[N:3][CH:2]=1.[Br:11]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:11][C:8]1[S:7][C:6]2[N:1]=[CH:2][N:3]=[C:4]([OH:10])[C:5]=2[CH:9]=1
Reactant: Oc1ncnc2sccc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncnc2sc(Br)cc12
Temperature: 80 °C

Procedure:
To a solution of thieno[2,3-d]pyrimidin-4-ol (3.0 g, 20 mmol) in glacial acetic acid (40 mL) was added bromine (6.3 g, 39 mmol). After heating to 80° C. for 1.5 hours, the reaction mixture was cooled to room temperature and poured into saturated NaHCO3 and ice. The solid was filtered, washed with water and dried to provide the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(O)[CH:10]([OH:22])[CH2:9]1)=O)(C)(C)C.C(N(S(F)(F)[F:29])CC)C.CO>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([F:29])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:22])=[CH:16][CH:17]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Solvent: CO
Solvent: ClCCl
Product: OC1CNCCC1(F)c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 24 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3,4-dihydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.213 g, 3.34 mmol) in methylene chloride (30 mL) at −78° C. was added diethylaminosulfur trifluoride (DAST, 3 mL). The resulting solution was stirred at −78° C. 4 h. Methanol (20 mL) was added to quench excess DAST and the mixture was allowed to remain at −78° C. 5 min before warming to rt. The mixture was concentrated and purified by silica gel chromatography (80% hexanes/20% ethyl acetate gradient) to afford 4-(4-chloro-phenyl)-4-fluoro-piperidin-3-ol (262 mg, 24%).
Reaction SMILES: [K].[OH:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1COC1C=C(C)C=CC=1C)[C:5]#[N:6].CC1C=CC(C)=CC=1OCC1C=CC=CC=1COC1C=C(C)C=CC=1C>C1(C)C=CC=CC=1>[OH:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Agent: Cc1ccc(C)c(OCc2ccccc2COc2cc(C)ccc2C)c1
Agent: [K]
Solvent: Cc1ccccc1
Product: N#CC(=NO)c1ccccc1

Procedure:
Thus, 1262.7 g of an aqueous solution containing 189.1 g (0.594 mol, 95.8% yield, E/Z=15/85) of the potassium salt of α-hydroxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile was obtained. It was found that 1,2-bis(2,5-dimethylphenoxymethyl)benzene was not found in the aqueous solution, but contained at an amount of 33.7 g (0.097 mol, 96.1% recovery) in 594 g of toluene after washing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=[C:5]2B(O)O.[CH3:21][N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28].O1CCOCC1>[Rh].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=[C:5]2[CH:24]1[CH2:25][C:26](=[O:27])[N:22]([CH3:21])[C:23]1=[O:28]
Reactant: CC(C)(C)[Si](C)(C)n1cc(B(O)O)c2cc(Br)ccc21
Reactant: CN1C(=O)C=CC1=O
Agent: [Rh]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)CC(c2cn([Si](C)(C)C(C)(C)C)c3ccc(Br)cc23)C1=O

Procedure:
To an oven dried, argon purged flask fitted with magnetic stir-bar is charged 5-bromo-1-(tert-butyldimethylsilyl)-1H-indol-3-ylboronic acid 15 (141.6 mg, 0.400 mmol), N-Methyl maleimide 16 (22.2 mg, 0.200 mmol), Rhodium catalyst (0.05 equiv.), anhydrous dioxane (1 mL) and stirring begun. H2O (0.05 mL) added, and mixture heated in an oil bath as per the conditions outlined in Table 9 below. The reaction mixture was filtered through silica gel bed, and the solvent was evaporated to obtain crude product. The crude product was purified via chromatography on silica gel (20% Ethylacetate/80% Hexanes) to yield 3-(5-bromo-1-(tert-butyldimethylsilyl)-1H-indol-3-yl)-1-methylpyrrolidine-2,5-dione 17. The enantiomeric excess was determined with chiral HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:21][CH:20]=[CH2:19])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:15])[CH3:18]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Temperature: 0 °C
Yield: 103 %

Procedure:
A mixture of 10.0 g of 4'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester is dissolved in 100 ml of acetone and 8.02 g of allyl bromide added under a nitrogen atmosphere. While stirring 15.0 g of potassium carbonate is added and the reaction mixture refluxed for 16 hours. The reaction mixture is cooled to 0° C. and poured into 200 ml of ice-water and extracted with chloroform (3×150 ml). The combined extracts are washed with 1N HCl and water, dried (Na2SO4) and evaporated in vacuo to give 12.0 g of the desired product m.p. 89°-92° C. M+H=283.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:13]C1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1.Cl>CN(C=O)C>[ClH:13].[CH3:8][C:7]1[C:2]([NH2:1])=[CH:3][C:4]([NH:9][C:10]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1
Reactant: Clc1nccc(-c2cccnc2)n1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Temperature: 100 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)acetamide (5 g, 25 mmol, commercially available) in DMF (5 mL) was added 2-chloro-4-(pyridin-3-yl)-pyrimidine (4 g, 35 mmol, commercially available) and KI (0.5 g, 3 mmol). After stirring at 100° C. overnight, the reaction mixture was cooled to 10° C., quenched with H2O, (100 mL), extracted with CH2Cl2 (2×100 mL) and the combined organic layers were dried (Na2SO4) and concentrated. The residue was dissolved in conc. HCl (10 mL), stirred at 80° C. for 2 h, and then concentrated to yield 6-methyl-N′-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine hydrochloride (4.5 g, 65% yield) as the HCl salt. 1H NMR (300 MHz, CDCl3): δ 7.93-7.96 (m, 2H), 7.50-7.47 (m, 1H), 7.47-7.41 (m, 5H), 7.25-7.27 (m, 2H), 2.21 (s, 3H); MS (ESI) m/e: 277 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][NH2:38])([CH3:32])[CH3:31].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][C:34]([O:33][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:39])[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)CCCN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Temperature: 130 °C
Yield: 73.3 %

Procedure:
To a stirred solution of N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg), potassium carbonate (410 mg) and tetrabutylammonium bromide (2 mg) in N-methylpyrrolidinone (5 mL) was added 4-amino-butanoic acid 1,1-dimethylethyl ester (1 g). The mixture was heated at 130° C. for 72 hours after which it was cooled and poured into water. The mixture was extracted with dichloromethane (3×20 mL) and the combined extracts dried, filtered and evaporated. Purification (SiO2, ethyl acetate:isohexane 3:7 as eluant) gave the sub-title compound (200 mg).
Reaction SMILES: ClC1C(OCC#C)=CC(N2C(C#N)=C(C#N)N(CCC)C2=O)=C(F)C=1.[Cl:26][C:27]1[C:32]([N+:33]([O-])=O)=[CH:31][C:30]([N:36]2[C:40]([C:41]#[N:42])=[C:39]([C:43]#[N:44])[N:38]([CH:45]([F:47])[F:46])[C:37]2=[O:48])=[C:29]([F:49])[CH:28]=1.C(N(CC)CC)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59].Cl>ClCCl>[Cl:26][C:27]1[C:32]([N:33]([S:58]([CH3:57])(=[O:60])=[O:59])[S:58]([CH3:57])(=[O:60])=[O:59])=[CH:31][C:30]([N:36]2[C:40]([C:41]#[N:42])=[C:39]([C:43]#[N:44])[N:38]([CH:45]([F:47])[F:46])[C:37]2=[O:48])=[C:29]([F:49])[CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1c(C#N)n(C(F)F)c(=O)n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(-n2c(C#N)c(C#N)n(C(F)F)c2=O)c(F)cc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
The product of Example 77, 1-(4-chloro-2-fluoro-5-nitrophenyl)-4,5-dicyano-3-difluoromethyl-1,3-dihydro-2H-imidazol-2-one, (0.7 g, 2.1 mmol) was dissolved in dichloromethane and treated sequentially at 0° C. with triethylamine (0.56 g, 5.5 mmol) and methanesulphonyl chloride (0.56 g, 5 mmol). The solution was allowed to stir 16 hours at ambient temperature, then poured onto 10 mL of 1N hydrochloric acid solution. The organic layer was separated, washed with brine, and dried and concentrated via standard techniques to furnish 1 g of 1-(4-chloro-2-fluoro-5-bis(methanesulphonyl) amino-phenyl)-4,5-dicyano-3-difluoromethyl-1,3 -dihydro-2H-imidazol-2-one (VI) (M.S. M+ 483).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.C[Si]([N:29]=[N+:30]=[N-:31])(C)C.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[C:3]([C:17]2[N:29]=[N:30][NH:31][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(C#Cc3ccccc3)c2nc1OC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(-c3nn[nH]c3-c3ccccc3)c2nc1OC
Temperature: 170 °C
Yield: 58 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-(2-phenylethynyl)quinoxaline (2.0 g, 5.57 mmol) and trimethylsilyl azide (20 mL) was heated at 170° C. in a sealed vessel for 18 hours. After cooling, water (20 mL) was added followed by saturated aqueous sodium hydrogen carbonate solution (50 mL) and the mixture extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 98:2, by volume) to afford the title compound (1.3 g, 58%) as a brown foam.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[C:13]([C:14](OCC)=[O:15])[C:9]=3[C:8](=[O:30])[N:7]([CH3:31])[C:6]2=[O:32])[CH2:3][CH2:2]1.O>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])=[C:13]([CH2:14][OH:15])[C:9]=3[C:8](=[O:30])[N:7]([CH3:31])[C:6]2=[O:32])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC1CC1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(CO)c(Cc3ccccc3C(F)(F)F)sc2n(CC2CC2)c1=O
Temperature: 60 °C

Procedure:
The product of step b) (6.65 g) was dissolved in tetrahydrofuran (200 mls) and LiA1H(OtBu)3 (43 mls, 1M in tetrahydrofuran) was added. The reaction mixture was heated at 60° C. for 18 hrs. Water was then added and the reaction mixture was concentrated to dryness in vacuo. The residue was extracted into ethyl acetate and the solution was dried over magnesium sulphate, filtered, and concentrated in vacuo to a greenish solid which was ultrasonicated in isohexanes for 3 hrs before being collected via filtration to yield 2.76 g of the subtitle compound as a green solid.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([O:19][CH2:20][CH:21]([O:42][CH2:43][N:44]1[CH:52]=[N:51][C:50]2[C:49](=[O:53])[NH:48][C:47]([NH2:54])=[N:46][C:45]1=2)[CH2:22][O:23][C:24](=[O:41])[C@H:25]([C@H:37]([CH2:39][CH3:40])[CH3:38])[NH:26]C(OCC1C=CC=CC=1)=O)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)C1C=CC=CC=1.C(Cl)Cl.CO.C(O)(C(F)(F)F)=O>[Pd].C(O)(=O)C.O>[NH2:26][C@H:25]([C:24]([O:23][CH2:22][CH:21]([O:42][CH2:43][N:44]1[CH:52]=[N:51][C:50]2[C:49](=[O:53])[NH:48][C:47]([NH2:54])=[N:46][C:45]1=2)[CH2:20][O:19][C:17](=[O:18])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:11])=[O:41])[C@H:37]([CH2:39][CH3:40])[CH3:38]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC)OCn1cnc2c(=O)[nH]c(N)nc21
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)OCC(COC(=O)[C@@H](N)[C@@H](C)CC)OCn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 14 h

Procedure:
A solution of the product of stage (a) (2.0 g, 2.66 mmol) and 10% palladium on carbon (250 mg, Aldrich) in glacial acetic acid (250 ml) was shaken on a Parr Hydrogenator under 30 to 35 psi H2 for 5 hours. Reaction progress was monitored by TLC (silica gel, CH2Cl2 :MeOH/9:1). The catalyst was removed by filtration (Millipore Prefilter). Dilution of the filtrate with ether caused the product to separate as an oil. After 14 hours at 5° C., the supernatant was decanted from a colourless gum, which was dried under high vacuum to a white foam. The foam was dissolved in water (20 ml), filtered, and freeze-dried to a white foam; yield, 1.3 g (79%). H-NMR (DMSO-d6) 7.79(3,1H), 6.49(br s,2H), 5.41(s,2H), 3.9-4.2(m,4H), 3.10(d,1H), 3.06(d,1H), 1.9 (HOAc), 1.5(m,1H), 1.34(m,4H), 1.1(m,4H); 0.73-0.78(m,12H), 13C-NMR (DMSO-d6) 156.80, 153.96, 151.30, 137.47, 116.30, 73.41, 70.78, 62.88, 62.57, 58.15, 24.18, 21.28, 15.33, 15.28, 11.33; HPLC (Versapack C-18; 30% MeOH (aq.)/0.1% TFA) 1 peak, k'=1.22; UV max (H2O) 251 nm (12,000). MS (positive ion/Cl) m/z 482. Anal. Calcd. for C21H 35 N7O6.2HOAc:1H2O: C,48.46; H,7.32; N,15.82. Found: C,48.52; H,7.3; N,15.75.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[NH:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16]>ClCCl.C(O)(C(F)(F)F)=O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[NH:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CNc1cnnc2ccc(C(F)(F)F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNc1cnnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl 2-(6-(trifluoromethyl)cinnolin-4-ylamino)acetate (as prepared in the previous step, 200 mg, 0.61 mmol, 1.00 equiv) in dichloromethane (5 mL) and CF3COOH (0.2 mL). The reaction mixture was stirred overnight at room temperature, and then was concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:10]1([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.[ClH:21]>O1CCOCC1.CCOCC>[ClH:21].[CH3:1][NH:2][C:10]1([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1(COc2cccnc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC1(COc2cccnc2)CC1
Temperature: 25 °C

Procedure:
A solution containing 0.32 g of the compound obtained in Step 1 in 3 ml of dioxane and 3 ml of 4N hydrochloric acid in dioxane is stirred at ambient temperature and under an inert atmosphere, and is then diluted with ether. The liquid phase is then separated off and the residue is taken up in 25 ml of ethanol. The solution is concentrated to 2 ml and is then diluted with 20 ml of ether and stirred; the precipitate formed is filtered off, rinsed and dried, allowing the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-methoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:23])[CH:14]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH3:32]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:23])[CH:14]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:31][CH3:32])[CH:12]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3cn[nH]c3)cnc2N)cc1F
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)OC)c(F)c3)n2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
To methyl 4-(3-amino-6-(1H-pyrazol-4-yl) pyrazin-2-yl)-2-fluorobenzoate (45 mg, 0.115 mmol) in DMF (2 mL) was added potassium carbonate (47.6 mg, 0.345 mmol), followed by bromoethane (0.017 mL, 0.230 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixtures was partitioned between ethylacetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, evaporated and purified by flash chromatography eluting with 0-60% of EtOAc (contains 10% of MeOH)/heptane to yield the desired product (25 mg, 64%, 80% purity). LCMS (m/z): 342.0 (MH+), 0.73 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:17]4[N:16]=[C:15]([C:14]([F:29])([F:13])[F:30])[O:19][N:18]=4)[CH:21]=3)=[O:24])[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Cc1csc(N2CCNCC2)n1
Product: Cc1csc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)n1
Yield: 39 %

Procedure:
This compound was synthesized from 4-methyl-2-(piperazin-1-yl)thiazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (90 mg, yield 39%) as yellow viscous liquid. 1H NMR (400 MHz, CDCl3) δ 8.23-8.19 (m, 2H), 7.67-7.61 (m, 2H), 6.20 (m, 1H), 3.94 (m, 2H), 3.57 (m, 6H), 2.26 (m, 3H). MS (ESI) m/z: Calculated for C18H16F3N5O2S: 423.10. found: 424.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[NH:3]1.[ClH:21]>C(O)C>[ClH:21].[CH3:7][N:6]1[C:5](=[O:8])[C:4]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[NH:3][C:2]1=[O:1]
Reactant: CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: CCO
Product: CN1C(=O)NC2(CCNCC2)C1=O
Yield: 116.1 %

Procedure:
A mixture of tert-butyl 2,4-dioxo-3-methyl-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (4.7 g, 16.6 mmol), hydrogen chloride (5 g, 13.7 mmol) and ethanol (90 mL) was heated approximately 10 minutes at reflux. The mixture was cooled in an ice-bath and the solids were collected, washed with ethanol and dried at 70° C. to give 3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (3.5 g, 15.9 mmol).