Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:1]([C:4]1([C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(C)C1(C(=O)O)CCC(=O)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1(C(=O)OCc2ccccc2)CCC(=O)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A cooled (0° C.) solution of 1-isopropyl-3-oxocyclopentanecarboxylic acid (5.44 g, 32.0 mmol) in DCM (75 mL) was treated with oxalyl chloride (8.36 mL, 95.9 mmol), followed by 3 drops of DMF. The reaction mixture was permitted to warm to rt and stir for 1.75 h. The reaction mixture was then concentrated and stored under vacuum for 30 min. The resulting acid chloride was dissolved in DCM (75 mL), cooled to 0° C., and treated with benzyl alcohol (8.28 mL, 80.0 mmol), followed by triethyl amine (8.92 mL, 64.0 mmol, dropwise). Then approximately 100 mg of DMAP was added and the reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was diluted with DCM and washed with 1N HCl solution, saturated NaHCO3 solution, and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 50% ethyl acetate/hexane) gave benzyl 1-isopropyl-3-oxocyclopentanecarboxylate. 1HNMR (CDCl3, 500 MHz): δ 7.36 (m, 5 H), 5.17 (d, J=2.5 Hz, 2H), 2.85 (d, J=18.5 Hz, 1H), 2.48 (m, 1H), 2.29 (dd, J=10.0, 3.0 Hz, 1H), 1.98-2.23 (m, 3H), 1.93 (m, 1H), 0.95 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][C:10]#[N:11])=[N:7][CH:6]=[N:5]1.Br[CH2:13][CH2:14]Br>CS(C)=O>[CH3:3][N:4]1[C:8]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)=[N:7][CH:6]=[N:5]1
Reactant: BrCCBr
Reactant: Cn1ncnc1CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncnc1C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.06 g, 44.2 mmol) was washed twice with petroleum ether under nitrogen. Then dimethylsulfoxide (10 mL) was added at room temperature. A solution of 2-(1-methyl-1H-1,2,4-triazol-5-yl)acetonitrile (0.9 g, 7.36 mmol) and 1,2-dibromoethane (4.147 g, 22.1 mmol) in dimethylsulfoxide (20 mL) was added dropwise to the sodium hydride suspension over a period of 20 min. The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 5-15% ethyl acetate in petroleum ether) to afford 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbonitrile (0.7 g) as a colorless oil.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[C:4](OCC)=O)=[O:2].[N+:15]([NH:18][C:19]([NH2:21])=[NH:20])([O-:17])=[O:16].C[O-].[Na+]>CO>[N+:15]([NH:18][C:19]1[NH:21][C:1](=[O:2])[C:3]([CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][N:20]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)C(C=O)Cc1ccco1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccco1
Yield: 59.3 %

Procedure:
Ethyl 2-formyl-3-(2-furyl)propionate (24.0 g, 0.122 mol) was added to a mixture of nitroguanidine (12.69 g, 0.122 mol) and sodium methoxide (from 3.09 g, 0.134 mol, sodium) in methanol and the mixture was stirred and heated under reflux for 18 hours and evaporated to dryness. The residue was dissolved in water and the solution was adjusted to pH 4 with acetic acid. The solid which separated was filtered off to give 2-nitroamino-5-(2-furylmethyl)-4-pyrimidone (17.1 g, 59%). A sample recrystallized from methanol-acetic acid and from acetic acid had m.p. 183°-184°.
Reaction SMILES: [O-]CC.[Na+].[Na].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]#[N:14])[CH:7]=1.[N:15](OCCCC)=[O:16]>C(O)C>[OH:16][N:15]=[C:12]([C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)[C:13]#[N:14]
Reactant: N#CCc1cccnc1
Reactant: CCCCON=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1cccnc1

Procedure:
To a stirred solution of sodium ethoxide in anhydrous ethanol, prepared from 5 g of sodium and 50 ml of anhydrous ethanol, 24 g of 3-pyridineacetonitrile was added, followed by dropwise addition of 21 g freshly distilled n-butyl nitrite. The reaction mixture was stirred for another hour and the precipitated sodium salt of the oxime was filtered and washed with ether. The free oxime was obtained by acidification of an aqueous solution of the salt and recrystallization from water, yielding 17 g (58%) of the title compound. M.p. 234°-238° C. under decomposition. Usually, the salt was directly used in succeeding reactions.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=3)[S:11][C:10]=2[CH:40]=1)(=O)C.[OH-].[Na+]>CO>[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:29])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:19][CH:20]=3)=[C:12]([C:30]3[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=3)[S:11][C:10]=2[CH:40]=1
Reactant: CC(=O)Oc1ccc(-c2sc3cc(OC(C)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The yellow oil obtained from Example 4 above was dissolved in 700 ml of methanol, and 100 ml. of 5 sodium hydroxide was added. The mixture was stirred for 2 hours at ambient temperature, and then the solvent was removed under vacuum. The residue was dissolved in 500 ml. of water and was washed with two 500 ml portions of diethyl ether. The water layer was acidified to pH 2 with cold methanesulfonic acid, was diluted to about 3 liters, and was washed again with two 1 liter portions of diethyl ether. The aqueous layer was separated, degassed under vacuum, and made basic by addition of sodium bicarbonate. A precipitate developed, and was collected by filtration and washed with water. The solids were vacuum dried at 70° C. to obtain 13 g. of impure product, which was dissolved in 500 ml. of hot acetone, filtered and evaporated down to approximately 100 ml. volume. The solution was cooled and scratched to obtain 11.3 g of product.
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:32]([N:39]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:43])[CH2:41]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.P([O-])([O-])([O-])=O>[CH2:32]([N:39]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:43])[CH2:41][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A) (30.0 g, 108 mmol) in DMF (200 mL) at 0° C. was added NaHMDS (1.0M in THF, 13.6 g, 118 mmol) and N-benzyl-2-bromo-N-isopropyl-acetamide (Preparation 1(C) (35.2, 130 mmol) in DMF (25 mL). The reaction was stirred at room temperature for 24 hours and was diluted with a pH 6.8 phosphate buffer. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (3×), dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 12% acetone in CH2Cl2) provided 13.9 g of N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide. 1H NMR (CDCl3) δ 7.64-7.55 (m, 2H), 7.44-7.08 (m, 11H), 6.89 (m, 1H), 4.96-4.08 (m, 6H), 3.57 (m, 1H), 1.17 (m, 6H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:2]=[O:1]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCC(=O)OC(C)(C)C

Procedure:
Vanillin was alkylated with t-butyl bromoacetate in DMF in the presence of potassium carbonate the usual way to give a waxy solid. (quant.) mp 86.8°-90° C. MS(NH3): 284 (base, M+NH4).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([N:17]1[C:21]([C:22](Cl)=[O:23])=[N:20][N:19]=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([N:17]1[C:21]([C:22]([NH:1][C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][N:9]=2)=[O:23])=[N:20][N:19]=[N:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1cccnc1N
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1cccnc1NC(=O)c1nnnn1Cc1ccccc1

Procedure:
2-Aminonicotinonitrile is reacted with 1-benzyl-1H-tetrazole-5-carbonyl chloride in stoichiometric amounts in the presence of an acid acceptor (pyridine). The product is washed with water, brine, and dried over CaCl2 to yield 1-benzyl-N-(3-cyano-2-pyridyl)-1H-tetrazole-5-carboxamide. The benzyl protecting group is then removed by hydrogenolysis with 10% Pd/C. The product is stirred in water and N NaOH is added to produce the title compound upon lyophilization.
Reaction SMILES: B1(C2CCN(C(OC(C)(C)C)=O)CC=2)OC(C)(C)C(C)(C)O1.BrC1C=CC(C(F)(F)F)=CC=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:45]=1[C:54]1[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH:55]=1.[CH:67]1[C:76]2[C:71](=[C:72](B(O)O)[CH:73]=[CH:74][CH:75]=2)[CH:70]=[CH:69][N:68]=1>O1CCOCC1.O.C(OCC)C>[CH:67]1[C:76]2[C:71](=[C:72]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:45]=3[C:54]3[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH:55]=3)[CH:73]=[CH:74][CH:75]=2)[CH:70]=[CH:69][N:68]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: FC(F)(F)c1ccc(Br)c(I)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cnccc23)CC1
Temperature: 100 °C

Procedure:
A solution of Cl2Pd(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 1.157 g, 1.416 mmol), (n-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Maybridge Chemicals, Cornwall, UK, 8.76 ml, 28.3 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (Combi-Blocks, San Diego, Calif., 9.94 g, 28.3 mmol), and potassium phosphate (36.1 g, 170 mmol) in 100 mL dioxane and 40 mL water was heated to 100° C. for 3 hours. LC/MS showed clean conversion to tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate. To the resulting mixture was added isoquinolin-5-ylboronic acid (Sigma-Aldrich, St. Louis, Mo., 4.90 g, 28.3 mmol) and Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 1.003 g, 1.416 mmol). The reaction mixture was again heated to 100° C. an additional hour before the reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether. The organics were washed with water, then brine, dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.80 g, 21.56 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]2[CH:28]([OH:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=3)[O:21][CH2:20]2)[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C@H:19]2[C@@H:28]([OH:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)[CH:26]=3)[O:21][CH2:20]2)[CH:13]=1
Reactant: Oc1ccc2c(c1)C(O)C(Oc1cccnc1)CO2
Reactant: Clc1ccc2ccccc2n1
Product: O[C@H]1c2cc(Oc3ccc4ccccc4n3)ccc2OC[C@H]1Oc1cccnc1

Procedure:
By the method of Example 1, 2-chloroquinoline and 3-(3-pyridyloxy)-4,6-chromandiol (EP appln. 312,295) were converted to present title product in like yield; mp 112-114° C.; IR (CHCl3) 3563, 1620, 1603 cm-1.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C(OCC)C>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOCC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
To a suspended ethyl ether (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in ethyl ether (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][NH2:6]
Reactant: Cc1ccc(C#N)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CN)cc1Cl
Yield: 84.7 %

Procedure:
15 ml solution of 2.0 g 3-chloro-4-methylbenzonitrile in tetrahydrofuran was added dropwise into 40 ml solution of 453 mg lithium aluminum hydride in tetrahydrofuran in a nitrogen atmosphere. The mixture was heated under reflux for 2 hr and 10 min. The mixture was ice-cooled, and 0.45 ml water, 0.45 ml of 15% aqueous sodium hydroxide, and 1.35 ml water were added dropwise thereinto such that the solution was kept at 10° C. or less. The solution was filtered through Celite, and the resulting filtrate was dried by adding anhydrous sodium sulfate. It was filtered through a NH-form silica gel, and the filtrate was evaporated to give 1.74 g of 3-chloro-4-methylbenzylamine.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>CO.ClCCl>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccncc1

Procedure:
2-(5-Benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-[2-(4-pyridyl)ethyl)carbamoyl]propyl]acetamide. The compound described in part a. was subjected to conditions similar to those described in Example 1. Multiple use of chromatography (first column) with chloroform:methanol (gradient, 97:3, 94:6), (second column) chloroform:methanol (98:2), (chromatotron-2 mm plate: flow 6 mL/min) dichloromethane:methanol (gradient, 98:2, 96:4) yielded the title compound; TLC: Rf =0.21, dichloromethane:methanol (97:3); MS: m/z=661(M+1). Analysis for C34H34F2N6O6.0.7 H2O: Calculated: C, 60.65; H, 5.30; N, 12.48; Found: C, 60.62; H, 5.24; N, 12.39. This product is also a Compound of the invention.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc(-c2nc3cc(N)ccc3s2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc2sc(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
To a solution of 2-p-tolylbenzo[d]thiazol-5-amine (110 mg, 0.46 mmol) in pyridine (3 mL) at room temperature was added butyryl chloride (53 μL, 0.50 mmol). The resulting mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate, followed by aqueous sodium bicarbonate and finally with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 25 mg (18%) of the title compound (LCMS RT=7.10 min, MH+ 311.0)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19].O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[N:13]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=3)[N:14]=[CH:15][C:7]=12
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2cnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (603 mg, 3 mmol) in DMF (3 mL) at 0° C. was treated with NaH (120 mg, 60%, 3 mmol), stirred for 20 min, treated with 3-nitrobenzyl bromide (648 mg, 3 mmol), stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (EtOAc:Heptane, 1:1) to give the title compound as a cream solid (472 mg, 47%). A portion of the solid (70 mg) was suspended in MeOH, treated with HCl in dioxan (4-M, 1 mL), diluted with diethyl ether and filtered to give the hydrochloride salt of the title compound (79 mg, 100%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:31]1(OB(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccccc1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A mixture of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), phenylboric acid (0.15 g, 1.2 mmol), sodium carbonate (0.26 g, 2.5 mmol), toluene (10 ml), ethanol (2 ml) and water (2 ml) was stirred at room temperature under an argon atmosphere for 30 min. To the resulting mixture was added tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), and then the mixture was refluxed under an argon atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-2-isobutyl-1-oxo-6-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.42 g, 89.4%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>O1CCCC1>[Br:9][C:5]1[CH:6]=[C:7]([Br:8])[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=1
Reactant: Nc1ncc(Br)cc1Br
Reactant: CC(=O)C(C)Br
Solvent: C1CCOC1
Product: Cc1nc2c(Br)cc(Br)cn2c1C
Yield: 73 %

Procedure:
A mixture of 31.8 g of 2-amino-3,5-dibromopyridine, 22 g of 3-bromo-2-butanone and 350 ml of tetrahydrofuran is heated to reflux for 9 days, and the precipitate formed is filtered off and dried in vacuo. It is then suspended in 1 l of water and adjusted to pH 8 using 6 molar aqueous sodium hydroxide solution. The precipitate formed here is filtered off and washed with water. 28 g of the title compound of melting point above 90° C. (sintering) are obtained.
Reaction SMILES: [B-]C#N.[Na+].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1.C(O)(=O)C.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>CO>[CH:24]1([CH2:30][N:8]2[CH2:7][C:6]([CH3:19])([CH3:5])[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=3)[CH2:9]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Reactant: O=CC1CCCCC1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CN(CC2CCCCC2)Cc2cc([N+](=O)[O-])ccc21
Temperature: 35 °C
Reaction time: 16 h

Procedure:
Sodium cyanotrihydroborate (0.600 g, 9.55 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.600 g, 2.91 mmol), acetic acid (0.210 mL, 3.66 mmol) and cyclohexanecarbaldehyde (0.4 g, 3.57 mmol) in methanol (40 mL). The reaction mixture was stirred at 35° C. for 16 hours. The reaction was neutralized with saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified with silica gel column chromatography (3% ethyl acetate/petroleum ether) to provide the title compound.