Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+:5].[Na+].[O:7]([C:14]1[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[O:7]([C:14]1[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([O-:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[Na+:5]
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)[O-])c1cccc(Oc2ccccc2)c1

Procedure:
In a suitable vessel, 32.8 g. of anhydrous sodium carbonate were dissolved in 500 ml. of deionized water. To this solution were added 100 g of 2-(3-phenoxyphenyl)propionic acid. The reaction mixture was agitated vigorously until all of the acid was in solution and reacted to form sodium 2-(3-phenoxyphenyl)propionate. The resulting reaction mixture was diluted to a total volume of 2 l with deionized water. The dilute propionate solution was transferred to a 4 liter beaker.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)[CH:16]=[CH:17][N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1ccccc1
Yield: 19 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude 573 mg, 1.89 mmol) in 20 mL of methanol was added phenylhydrazine (306 mg, 2.84 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-chlorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (125 mg, 19% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([N:16]=[N+]=[N-])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(O)CC1

Procedure:
According to scheme 10, to a stirred solution of 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (XXX) in dichloromethane was added at −60° C. m-chloroperbenzoic acid (MCPBA). The mixture was allowed to slowly warm to room temperature overnight and 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester (XXXI) was obtained. To a solution of 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in ethanol was added water, ammonium chloride and sodium azide. The mixture was stirred at 75° C. over night, to give 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXII). 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in methanol was hydrogenated in the presence of palladium on charcoal (10%) to yield 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXIII). 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1,1′-carbonyl-diimidazole in dimethylformamide are stirred at room temperature for about 16 hours. 4-Amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester was added and stirring was continued for 16 hours at room temperature. It was obtained 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (XXXIV). To a solution of 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in dimethylsulfoxide was added triethylamine, dichloromethane and a solution of sulfur trioxide pyridine complex in dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. After purification 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester (VIII) was obtained.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[N:20][CH:21]=1>ClCCl.[NH4+].[Cl-]>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:24])=[O:23])=[N:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: CCOC(=O)CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C

Procedure:
Triethylamine (543 μL, 3.90 mmol) followed by ethyl glycinate (161 mg, 1.56 mmol) were added to a solution of 5-bromopyridine-2-sulfonyl chloride (200 mg, 0.780 mmol) in dichloromethane (2.6 mL) was added. The reaction mixture was stirred at room temperature and was monitored by LCMS. Upon completion, the reaction was diluted with saturated aqueous NH4Cl and the organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH in DCM:hexanes) to yield ethyl N-[(5-bromopyridin-2-yl)sulfonyl]glycinate. MS APCI calc'd for C9H12BrN2O4S [M+H]+ 323 and 325. found 323 and 325.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:11]1[N:15]2[C:16]3[C:21]([NH:22][C:23](=[O:24])[C:14]2=[N:13][N:12]=1)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=3)[CH3:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:29]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:29][C:18]1[CH:17]=[C:16]2[C:21]([NH:22][C:23](=[O:24])[C:14]3[N:15]2[C:11]([CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH3:10])=[N:12][N:13]=3)=[CH:20][C:19]=1[C:25]([F:27])([F:26])[F:28]
Reactant: BrBr
Reactant: CCOP(=O)(OCC)C(C)c1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CCOP(=O)(OCC)C(C)c1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(Br)cc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of 1-[1-(diethoxyphosphoryl)ethyl]-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (811 mg, 1.94 mmol), silver sulfate (605 mg, 1.94 mmol) and bromine (100 μl, 1.94 mmol) in 5 ml of conc. sulfuric acid was stirred overnight at room temperature. The mixture was filtered and the filtrate was added dropwise to 100 ml of ice/water. The resulting precipitate was isolated by filtration, washed with water and dried to give 514 mg (53%) of the title compound; m.p.>200° C., decomp. 1H-NMR (DMSO-d6): δ 1.12 (t, 3H), 1.18 (t, 3H), 1.74 (dd, 3H), 3.95 (quint, 2H), 4.07 (quint, 2H), 4.78 (dq, 1H), 7.81 (s, 1H), 8.59 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: CN1CCNCC1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with 1-methylpiperazine (CAS Reg. No. 109-01-3) to give the title compound as colorless foam. MS (ESI): m/z=586.1 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:15](CC)CC)C.[C:20]1([S:26](Cl)=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]1[CH:24]=[CH:25][C:20]([S:26]([NH2:15])=[O:27])=[CH:21][CH:22]=1
Reactant: O=S(Cl)c1ccccc1
Reactant: CCN(CC)CC
Agent: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: NS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.87 g of N-phenylpiperazine in 150 ml of dichloromethane containing 4.59 ml of triethylamine is added dropwise with stirring under nitrogen a solution of 4.82 g of benzenesulfinyl chloride in 50 ml of dichloromethane. The reaction mixture is stirred for 3 hours at room temperature, diluted with 100 ml of dichloromethane and washed with 150 ml of water and 100 ml of 5% potassium carbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated in vacuo to a nearly colorless crystalline solid. Recrystallization from ethanol affords 6.37 g of 1-phenylpiperazine-4-benzenesulfinamide as a nearly colorless crystalline solid, mp, 101°-104° (softens 98°).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[CH3:25][S:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:31][C:30]1[CH:32]=[CH:33][C:27]([S:26][CH3:25])=[CH:28][CH:29]=1
Reactant: CSc1ccc(N)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(SC)cc3)c2cc1OC
Yield: 95.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 181.0 mg (1.3 mmol) of 4-(methylmercapto)-aniline to give 334.1 mg (95.2%) of the product as a yellow solid, m.p. 235-237° C., mass (electrospray, m/e): M+H 351.9, 352.9, 353.8, 354.9.
Reaction SMILES: [Mg].II.Br[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH3:14][O:15][B:16](OC)[O:17][CH3:18]>C1COCC1.CCOCC>[CH3:14][O:15][B:16]([O:17][CH3:18])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: COB(OC)OC
Reactant: Cc1cc(C)c(Br)c(C)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COB(OC)c1c(C)cc(C)cc1C
Temperature: -15 °C
Reaction time: 3 h

Procedure:
To a stirred solution of activated magnesium flakes (3.11 g, 0.128 mol) and a crystal of iodine, 2-bromomesitylene (23.40 g, 0.118 mol) in THF (80 cm3) was added dropwise at room temperature. The reaction was allowed to reflux for 3 hours. After the reaction mixture was cooled, it was added dropwise to an ether solution (80 cm3) of trimethoxyborane (26 cm3, 0.229 mol) at −15° C. The reaction stirred at −15° C. for 3 hours and then was warmed up to room temperature and left to stir overnight. The solution was then filtered under argon and the precipitated salts were washed with dry pentane (20 cm3). The filtrates were combined, concentrated and distilled under vacuum to give the desired dimethoxymesitylborane. 1H NMR (200 MHz, CDCl3) δ 2.28 (s, 6H), 2.30 (s, 3H), 3.58 (s, 6H), 6.84 (s, 2H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:23])[N:14]=[C:13]4[N:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=5)[CH:25]=[CH:26][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:5]([O:22][CH:17]([C:16]1[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[O:1][CH2:2][CH2:3][CH2:4]3)=[C:12]2[CH:26]=[CH:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]2=[N:14][C:15]=1[CH3:23])[C:18]([O:20][CH3:21])=[O:19])([CH3:10])([CH3:6])[CH3:4]
Reactant: COC(=O)C(O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCCO2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 2-(4-(chroman-6-yl)-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (784 mg, 1.638 mmol) in t-Butyl acetate (36 mL) was treated with perchloric acid (0.394 mL, 6.55 mmol) and then stirred at ambient temperature for 40 minutes. The mixture was quenched by adding 15% NaOH and then stirred for 10 minutes. The mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford a pale yellow residue: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30 (dd, J=2.0, 8.4 Hz, 1 H), 7.23-7.06 (m, 3 H), 7.06-6.95 (m, 2 H), 6.90 (dd, J=5.3, 8.4 Hz, 1 H), 6.20 (dd, J=3.5, 10.0 Hz, 1 H), 5.52-5.34 (m, 3 H), 4.28 (t, J=5.2 Hz, 2 H), 3.76 (d, J=5.5 Hz, 3 H), 2.93-2.74 (m, 2 H), 2.71 (d, J=2.7 Hz, 3 H), 2.15-1.96 (m, 2 H), 0.94 (d, J=2.1 Hz, 9 H); LC/MS (m/z) ES+=535 (M+1).
Reaction SMILES: C([O:5][P:6]([O:37]C(C)(C)C)([O:8][CH2:9][O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[C@@:15]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([F:26])[C:14]1=[O:36])=[O:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[P:6]([O:8][CH2:9][O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=2)[C@@:15]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([F:26])[C:14]1=[O:36])=[O:12])([OH:7])([OH:37])=[O:5]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCOP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a 25 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid di-tert-butoxy-phosphoryloxymethyl ester ((S)-XV) (0.110 g, 0.176 mmol) was added 2 mL anhydrous dichloromethane, and trifluoroacetic acid (0.060 g, 0.527 mmol). The reaction was allowed to stir at room temperature for 4 hours. The dichloromethane was evaporated in vacuo, and the crude foam was purified by reverse phase chromatography (C18 2:1CH3CN:H2O) producing the title compound (0.070 g, 78%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=8.26 (s, 1H), 7.68 (s, 1H), 7.45 (d, 1H, J=7 Hz), 7.28-7.24 (m, 2H), 6.72 (d, 1H, J=7 Hz), 5.90-5.81 (m, 2H), 3.48 (s, 3H); 31P NMR (CDCl3 162 MHz) δ=−0.233; 19F NMR (CDCl3 376 MHz) δ=−63.3, −153.8; LRMS [M−H]−511.4, [M+NH4]+530.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)=O.[NH3:14]>C(Cl)(Cl)Cl>[Cl:11][C:9]1[N:8]=[C:7]([S:12][CH3:13])[N:6]=[C:5]([C:3]([NH2:14])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Cl)nc(SC)n1
Reactant: N
Solvent: ClC(Cl)Cl
Product: CSc1nc(Cl)cc(C(N)=O)n1
Reaction time: 0.33 h
Yield: 103.4 %

Procedure:
A 500 mL flask was charged with the 6-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester (4.37 g, 20 mmol), and chloroform (30 mL). Ammonia (57 mL, 7 M in methanol, 0.4 mol, 20 eq.) was added with stirring. HPLC analysis after 20 minutes indicated no starting methyl ester remained. The mixture was sparged with nitrogen for 30 min, then concentrated in vacuo, and dried under high vacuum to afford the 6-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid amide (4.21 g, quant.) in sufficient purity for use in the next step. 1H NMR (500 MHz, CDCl3) □ 7.76 (s, 1H), 7.60 (br s, 1H), 5.97 (br s, 1H), 2.61 (s, 3H); ESI-MS m/z 204.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18]O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl.CN(C=O)C>[Cl:33][CH2:18][C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]methanol (200 mg, 0.51 mmol) in DCM (6 mL) and DMF (100 μL) was added oxalyl chloride (129 μL, 1.52 mmol) and the resulting solution was stirred at room temperature for 19 h. The reaction mixture was concentrated in vacuo to an oil which was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 8-Chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine as an impure mixture which was used directly in subsequent reactions.
Reaction SMILES: [C:1]([C:3]1[N:4]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1)#[N:2].O1CCOCC1.[ClH:22].O1CCOCC1.CCOC(C)=O.CCCCCC>C(OCC)C>[ClH:22].[NH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)Nn1cccc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1cccn1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 3L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple/JKEM thermocontroller, addition funnel and ice water cooling bath. (2-Cyano-pyrrol-1-yl)-carbamic acid, tert-butyl ester (85 g, 0.41 mol) was added and dissolved with 1,4-dioxane (400 mL), then the stirred orange solution was cooled to 0° C. and HCl/dioxane (4N, 820 mL, 8 eq.) was slowly added from the addition funnel, maintaining an internal temperature below 5° C. After ˜30 minutes the solution became cloudy and stirring@ room temperature was continued for 5 hours; the reaction was monitored for completion by TLC (silica gel, GHLF, 1:3 EtOAc/hexane, UV; Note: the free base may be observed as a high-Rf spot and can be misinterpreted as incomplete reaction). The reaction mixture was diluted with diethyl ether (2 L) and the precipitated solids were collected by suction filtration and washed with ether (1 L). Drying (vacuum oven@50° C.) afforded the desired product as 50.5 g (85%) of a tan solid. 1H-NMR (CD3OD): 7.05 (dd, 1H, J=2.8, 1.9 Hz), 6.75 (dd, 1H, J=1.8, 4.2 Hz), 6.13 (dd, 1H, J=2.8, 4.4 Hz), 5.08 (s, 3H, NH3+); MS: GC/MS, m/z=108.2 [M+H].
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:17][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH3:6]
Reactant: Cc1ccc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc2ccccc2c1OP(=O)(Cl)Cl
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.176 mL, 1 equiv) and 2-methylnaphthalen-1-ol (Aldrich, 0.3 g, 1 equiv) were stirred in anhydrous diethyl ether (10 mL). Anhydrous triethylamine was added (0.264 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate was very unstable at room temperature. The progress of the reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([C:11]([O:13]CC)=[O:12])[CH:9]2[CH:5]1[CH2:6][CH2:7][C:8]2=[O:10].Cl>>[F:3][C:4]1([C:11]([OH:13])=[O:12])[CH:9]2[CH:5]1[CH2:6][CH2:7][C:8]2=[O:10]
Reactant: CCOC(=O)C1(F)C2CCC(=O)C21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC2C1C2(F)C(=O)O
Reaction time: 2.5 h
Yield: 103.9 %

Procedure:
A 1M aqueous solution of sodium hydroxide in an amount of 1.0 mL was added dropwise to 0.17 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate while being ice-cooled. The mixture was stirred for 2.5 hours at the same temperature. The pH of the reaction mixture was adjusted to 1 with concentrated hydrochloric acid, followed by extractions with chloroform three times. The organic layers were combined, and the combined organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, thereby yielding 0.15 g of (1RS,5RS,6RS)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:6]=1)=[N+]=[N-]>CO.[Pd]>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:7]1[N:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCc1cccc(OCC(F)(F)F)n1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
A mixture of 2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine (Step-5, 0.44 g, 1.90 mmol) and palladium 10% on carbon (0.070 g) in methanol (12 mL) is vigorously stirred at room temperature under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure to give 0.27 g (68% yield) of the title compound as dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16][C:17](O)([CH3:19])[CH3:18].CCN(CC)CC>C1(C)C=CC=CC=1.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)O
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1

Procedure:
A suspension of 0.2 g (1.17 mmol) 2-chloro-6-methyl-isonicotinic acid in 5 ml toluene is treated with 2 drops of DMF and 0.17 ml (2.33 mmol) SOCl2 and refluxed for 4 h. The mixture is concentrated under reduced pressure and the residue is taken up in 1.5 ml DCM, 0.22 ml tBuOH and 0.24 ml Et3N and stirred in the presence of 7 mg (0.06 mmol) DMAP for 18 h. The mixture is diluted with DCM, washed with 10% aqueous citric acid, water and 10% aqueous NaHCO3, dried with sodium sulfate and evaporated. Chromatography of the product on silica gel (hexane/EtOAc 4:1 and 3:1) yields the title compound as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[C:5]#[N:6].CO>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(N)cc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 3-amino-5-chlorobenzonitrile in THF at RT was added slowly borane methyl sulfide complex (2.5 eq.). The resulting reaction mixture was stirred at RT for 1 h and heated at reflux for 2 hrs. The reaction mixture was cooled to −30° C. and MeOH was added slowly to quench the reaction. Solvent was evaporated in vacuo after the reaction mixture was stirred at RT for 30 min. to give 3-amino-5-chlorobenzylamine, which was used without purification. LCMS (Method A) RT 0.16 min., MH30 157.