Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:38]([O:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44])(=[O:40])[CH3:39]>ClCCl>[C:38]([O:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:4]=1)=[O:44])(=[O:40])[CH3:39]
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirring suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (40.5 g, 87 mmol) in dichloromethane (1000 mL) and triethylamine (36.4 mL, 262 mmol) was cooled down and then 2-chloro-1,1-dimethyl-2-oxoethyl acetate (12.52 mL, 87 mmol) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen for 1 h and 20 min. It was then washed with 2M HCl (300 ml), NaHCO3 solution (300 ml), brine, dried over magnesium sulphate and filtered. The filtrate was evaporated in vacuo to give a white solid. The residue was dissolved in DCM and loaded onto a 1500 g silica column and eluted with 40-100% ethyl acetate in cyclohexane over 8 CV. The required fractions were combined and evaporated in vacuo to give the title compound in two batches (37.87 g, 73%) and (3.39 g) as white foams. HPLC showed that the latter batch was not pure, therefore it was purified again on a 120 g silica column using a gradient of 40-75% ethyl acetate in cyclohexane over 8 CV.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=2[C:25]([O:27]C)=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=2[C:25]([OH:27])=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCCCCC
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
A solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-methoxycarbonyl-5-methylnitrobenzene (4.0 g) in concentrated hydrochloric acid (40 ml) was stirred at 75° C. for 7 hours. The reaction mixture was concentrated in vacuo. To a solution of the residual colorless solid in a mixture of water (20 ml) and acetone (20 ml) were added sodium hydrogencarbonate (1.9 g) and di-t-butyl dicarbonate (2.7 g) in an ice bath. The resulting mixture was stirred at 40° C. for 2 hours. The reaction mixture was extracted with ethyl acetate. The extractant was washed with 0.5M hydrochloric acid, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford a pale yellow solid. To the solid was added hexane and the mixture was filtered to give the desired compound (3.6 g, yield 79%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:19][S:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:24]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.215 g, 3.1 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.7 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-1-ylsulfamoyl)phenyl]-acryloyl chloride (16d) (0.23 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate affording the title compound (0.054 g, 24%). M.p. 180° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.45 (1H, d, J=16.0 Hz); 7.14 (1H, dd, J=7.0 and 1.4 Hz); 7.31–8.14 (11H, m); 9.09 (1H, br s); 10.27 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 4% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.3 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C19H16N2O4S, %: C, 61.94; H, 4.38; N, 7.60. Found, %: C, 61.18; H, 4.32; N, 7.54.
Reaction SMILES: [CH2:1]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl(O)(=O)(=O)=O.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=2)[NH:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Yield: 75.3 %

Procedure:
A mixture of 2-(n-decyl)indole-6-carboxylic acid (62.5 g), perchloric acid (40 ml of strength 70% w/v) and glacial acetic acid (400 ml) were hydrogenated over palladium on charcoal (5% w/w, 8.0 g) at 80°-90° C. and atmospheric pressure. When hydrogen uptake had ceased (after 4 hours) the hot mixture was filtered and the residue was washed with hot (80° C.) glacial acetic acid (500 ml). The combined filtrates were concentrated in vacuo to 450 ml and were poured onto ice (1000 g). The mixture was adjusted to pH 9 by treatment with an aqueous solution of sodium hydroxide (strength 50% w/v) and was then adjusted to pH 4-5 with glacial acetic acid. The solid was collected, was washed with water (3×100 ml) and was dried. The solid was dissolved in boiling ethanol, treated with charcoal, and the solution was filtered. The filtrate was treated with an excess of a solution of hydrogen chloride in ethanol (90 ml of strength 37% w/v) and then the mixture was cooled and diluted with diethyl ether (750 ml). The solid was collected and treated as in Example 56 to give (RS)-2-(n-decyl)indoline-6-carboxylic acid (47.4 g), in the form of a buff solid, m.p. 123°-125° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH3:27]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH3:27])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: CNCCOC
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: COCCN(C)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)methylamine were converted to yield {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine as colorless oil, MS: 374 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:12]([S:19](Cl)(=[O:21])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[OH-].[Na+].O.CCOCC>[CH2:12]([S:19]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:21])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: On1nnc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(Cc1ccccc1)On1nnc2ccc(Cl)cc21
Yield: 56.5 %

Procedure:
In 1 N aqueous sodium hydroxide (13.0 ml) and water is dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (2.23 g) and thereto is added dropwise a solution of benzylsulfonyl chloride (2.5 g) in ether (50 ml) under ice-cooling and stirring, and the mixture is stirred at the same temperature for 1.5 hours and further at room temperature for 1 hour. The reaction mixture is distilled to remove ether. To the resulting residue is added ethyl acetate. The ethyl acetate layer is dried and distilled to remove the solvent. The residue is recrystallized from benzene-n-hexane to give white needles of 1-benzylsulfonyloxy-6-chloro-1,2,3-benzotriazole (2.4 g), melting point: 126.5°-127.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][C:12]1[C:17]2[NH:18][C:19](=[O:21])[S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:14]2[CH:13]=[C:12]([CH3:11])[C:17]3[NH:18][C:19](=[O:21])[S:20][C:16]=3[CH:15]=2)=[O:9])[CH:3]=1
Reactant: Cc1cccc2sc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Temperature: 130 °C

Procedure:
1.93 g (10.0 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 1.80 g (10.9 mmol) 4-methyl-3H-benzothiazol-2-one and 7.33 g (55.0 mmol) aluminium trichloride were combined and heated to 130° C. for 3 h with stirring. The mixture was combined with ice water and EtOAc, the flakes formed were suction filtered and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and the filtrate was evaporated down i. vac. The residue was triturated with DIPE, the precipitate was suction filtered and dried.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:36]([CH:33]2[CH2:35][CH2:34]2)=[O:37])[CH2:14]1)=[O:12])[CH3:9]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
Triethylamine (0.37 mL, 2.7 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (300 mg, 0.87 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. Cyclopropanecarbonyl chloride (0.08 mL, 0.87 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate in hexane to afford the title compound as a pale yellow solid (305 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[C:19][CH2:20][OH:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1.[H][H]>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][CH2:20][OH:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1
Reactant: OCC#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: OCCCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12

Procedure:
A suspension of 11.07 g (34.8 mmol) of 5-chloro-2-(2-chlorophenyl)-7-(3-hydroxy-1-propynyl)-benzoxazole in 120 ml of ethyl acetate was treated with 3.70 g of neutral Raney-nickel. After the hydrogen uptake ceased, the nickel was filtered off and washed, and the solution evaporated in vacuo. Crystallization from dichloromethane/di-isopropyl ether gave the title compound in two crops (6.12 g (54.6%) and 1.61 g (14.4%)), mp 82-4° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH:12]=[CH:11][C:10]=1[N+:26]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+]>Cl>[CH2:1]([NH:8][C:9]1[C:10]([NH2:26])=[CH:11][CH:12]=[C:13]([S:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Sc2cccc3cnccc23)cc1NCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: Nc1ccc(Sc2cccc3cnccc23)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
N1-Benzyl-5-(5-isoquinolylsulfanyl)-2-nitroaniline 840 mg (2.2 mmol) was dissolved in concentrated hydrochloric acid 25 ml, stannous chloride dihydrate 2.45 g (10.8 mmol) was added, and the mixture was stirred overnight at room temperature. 50% sodium chloride was added to obtain an alkaline solution, and the solution was extracted with ethyl acetate. The organic layer was washed with water and with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and N2-benzyl-4-(5-isoquinolylsulfanyl)-1,2-benzene diamine 730 mg (94.1%) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:16]=[CH:17][C:12]([CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 6.5 °C
Reaction time: 14 h
Yield: 86.9 %

Procedure:
Slurry aluminum chloride (140.9 g, 1.075 mol) and 4-chlorobutyryl chloride (148 g, 1.5 mol) in methylene chloride (1.0L) add, by dropwise addition, cumene (125 g, 1.04 mol) over a thirty minute period under a nitrogen atmosphere while maintaining the internal temperature between 5-8° C. with an ice bath. Allow the stirred solution to come to room temperature and continue stirring under nitrogen for 14 hours. Cautiously add the methylene chloride solution to 1L of crushed ice with stirring and add additional methylene chloride (400 mL). Separate the organic phase and wash with 10% hydrochloric acid (3×300 mL), water (3×300 mL), 10% sodium bicarbonate (3×300 mL) and water (3×300 mL). Dry (MgSO4), filter and wash with methylene chloride (150 mL). Evaporate the solvent to give the title compound (203 g, 86%) as a clear oil which crystallizes on standing; mp 35-37° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH:22]1[CH2:24][CH2:23]1)[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([C:45]2[C:46]([CH2:51]OS(C)(=O)=O)=[N:47][CH:48]=[CH:49][CH:50]=2)([CH3:44])[CH3:43])=[CH:38][CH:37]=1>CC#N>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:51][C:46]1[C:45]([C:42]([C:39]2[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=2)([CH3:44])[CH3:43])=[CH:50][CH:49]=[CH:48][N:47]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1)[CH:22]1[CH2:23][CH2:24]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(CNCCCCN(C(=O)OC(C)(C)C)C2CC2)c(C)c1
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1COS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCN(C(=O)OC(C)(C)C)C2CC2)Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)c(C)c1

Procedure:
Using General Procedure A: Reaction of cyclopropyl-{4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester and DIPEA in CH3CN with methanesulfonic acid 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl ester gave {4-[{3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-cyclopropyl-carbamic acid tert-butyl ester as an oil. 1H.NMR (CDCl3) δ 0.51-0.54 (m, 2H), 0.64-0.70 (m, 2H), 1.21-1.28 (m, 4H), 1.42 (s, 9H), 1.63 (s, 6H), 2.14 (s, 3H), 2.28 (s, 3H), 2.33-2.40 (m, 3H), 3.00-3.04 (m, 2H), 3.27 (s, 2H), 2.62 (s, 2H), 6.90 (d, 2H, J=8.6 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.20-7.22 (m, 2H), 7.84 (d, 1H, J=7.4 Hz), 8.12 (s, 1H), 8.53 (d, 1H, J=3.3 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:24]([NH:27][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)NC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 72.6 %

Procedure:
A solution of compound 119 (0.75 g, 2.926 mmol) in 1,2-dichloroethane (20 mL) was treated with AcOH (0.16 mL, 2.926 mmol), isopropyl amine (0.25 mL, 2.926 mmol), NaBH(OAc)3 (0.93 g, 4.390 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 139 (0.636 g, 73%) as a semi-solid. 1H NMR (DMSO-d6) δ 0.99 (d, 6H, J=6.0 Hz), 1.36-1.47 (m, 1H), 1.89-1.97 (m, 2H), 2.45-2.56 (m, 2H), 2.81-2.89 (m, 1H), 2.91-2.99 (m, 1H), 3.16 (brs, 1H), 6.14 (brs, 1H), 7.80 (s, 1H), 7.88 (dd, 1H, J=2.1, 9.0 Hz), 7.95 (d, 1H, J=9.0 Hz), 8.30 (d, 1H, J=2.1 Hz), 11.83 (brs, 1H); ESI-MS (m/z, %) 300 (MH+, 100), 241 (35).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][C:25]#[N:26])[O:12][C@H:11]1[N:27]1[C:49]2[N:48]=[C:47]([Cl:50])[N:46]=[C:31]([NH:32][N:33]3[CH2:38][CH2:37][CH:36]([S:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:35][CH2:34]3)[C:30]=2[N:29]=[CH:28]1)(=O)C1C=CC=CC=1.N.C(OCC)(=O)C>CO>[Cl:50][C:47]1[N:46]=[C:31]([NH:32][N:33]2[CH2:34][CH2:35][CH:36]([S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:37][CH2:38]2)[C:30]2[N:29]=[CH:28][N:27]([C:49]=2[N:48]=1)[C@@H:11]1[O:12][C@H:13]([CH2:24][C:25]#[N:26])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: N#CC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 8.8 %

Procedure:
This compound was prepared by general method A, described in more detail in Example 22. 2',3'-Di-O-benzoyl-2-chloro-5'-cyano-5'-deoxy-N-(4-phenylthio-1-piperidinyl)adenosine [prepared from 1-amino-6-phenylthiopiperidine (Knutsen, L. J. S., Lau, J., Sheardown, M. J., Thomsen, C.; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) and 9-(2',3'-di-O-benzoyl-5'-cyano-5'-deoxy-β-D-ribofuranosyl)-2,6-dichloro-9H-purine as described in Example 24] (1.5 g, 2.5 mmol) in methanol (20 ml) was treated with methanolic ammonia (5 ml). The reaction mixture was stirred at ambient temperature for 0.75 h. Ethyl acetate (5 ml) was added to the residue on evaporation to provide 2-chloro-5'-cyano-5'-deoxy-N-(4-phenylthio-1-piperidinyl)adenosine (0.11 g, 46%) as a solid, m.p. 159°-161° C., 1H-NMR (400 MHz, DMSO-d6) δ1.68 (2H, br q, piperidine C--H), 1.98 (2H, m, piperidine C--H), 2.78 (2H, br, piperidine C--H), 3.04 (2H, br d, H-5'a and H-5'b), 4.11 (2H, m, H-4' and H-3'), 4.63 (1H, m, H-2'), 5.54, 5.68 (2H, 2d, 2'-and 3'-OH), 5.88 (1H, d, H-1'), 7.22-7.45 (5H, 3m, Ar--H), 8.38 (1H, s, H-8), 9.49 (1H, s, N--H). HPLC retention time 20.34 min. (gradient elution over 30 min; 25-45% acetonitrile/0.1% ammonium sulfate in water), purity 96% at 250 nm). C16H20ClN7O3. 0.7 H2O. 0.1 EtOAc requires C, 51.4; H, 5.1; N, 18.7. Found C, 51.4; H, 4.9; N, 18.3%.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].[N-]=C=O>CC(C)=O>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH:28][C:29]([C:3]1[C:4](=[O:12])[O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:2]=1[OH:1])=[O:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: [N-]=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1c(O)c2ccccc2oc1=O

Procedure:
To 8.1 g (0.05 mole) of 4-hydroxy-2-oxo-2H-1-benzopyran dissolved in 200 ml acetone is added 5.6 g (0.05 mole) of triethylamine, followed by the addition of 3,4-dichlorophenyl isocyanate. The mixture is heated to reflux, and in 1/2 hour none of the isocyanate is left as determined by infra-red. The acetone solution is concentrated and the yellow viscous liquid is taken up in chloroform and washed with dilute hydrochloric acid. A white solid precipitates from the chloroform-acid mixture and is collected by filtration. The insoluble white solid is slurried in boiling acetone to yield 11.0 g of pure white powder, the product, m.p. 227°C to 228°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:24]([C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=4)=[O:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.1 eq, 0.13 mmol) was added to a solution 1-methyl-1H-imidazole-2-carboxylic acid (15 mg, 1.0 eq, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 1.1 eq, 0.13 mmol), 1-hydroxybenzotriazole (16 mg, 1.0 eq, 0.12 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a yellow solid (14 mg, 0.04 mmol, 35%). LCMS: [M+H]+=335, Rt=1.44 min, 100% purity.