Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:29])[N:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=1)[CH3:14]>CO.CN(C=O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:29])[N:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:16]=2)[CH3:14])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)N(C)c1cc(NC(=O)OC(C)(C)C)ncn1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1NC(=O)N(C)c1cc(NC(=O)OC(C)(C)C)ncn1
Reaction time: 20 h

Procedure:
A solution of tert-butyl {6-[3-(2-methyl-5-nitro-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamate (330 mg, 0.82 mmol) in a mixture of methanol (20 ml) and DMF (50 ml) is hydrogenated in the presence of 10% palladium on charcoal (500 mg) at atmospheric pressure. After 20 h the hydrogenation is complete and the catalyst is filtered off. The filtrate is evaporated to dryness. The residue obtained is triturated with ether, filtered off, and vacuum dried to afford a gray powder: HPLC: tR=5.38 min (purity: 97%, gradient A), ESI-MS: 373.4 [MH]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Product: O=C(N1CCC[C@@H]2c3cc(-c4ccccc4)ccc3C[C@@H]21)C(F)(F)F
Yield: 70 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and phenylboronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 70% of theory; LC (method 1): tR=5.02 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH:23]=[CH2:24]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:39])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH:23]=[CH2:24]
Reactant: C=CCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.3 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 60 ml of dry methylene chloride, under nitrogen, and cooled to 0° C. is added 22.0 ml of triethylamine followed by a solution of 1.2 equivalents of 4'-(2-propenyloxy)-[1,1'-biphenyl]-4-carbonyl chloride in 20 ml of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 4.8 g of the desired product as a solid. M+H 421.2 M+Na 443.2.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14]>C1(C)C=CC=CC=1>[CH3:13][NH:14][C:11]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)=[O:12]
Reactant: CC(C)(C)c1cc(N=C=O)on1
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1cc(C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Into a solution of 3-t-butyl-5-isoxazolyl isocyanate (2.84 g) in toluene (51 ml) is introduced methylamine (1.58 g) at room temperature. The mixture is stirred at room temperature for 2 hours and then at 50° C. for 4 hours. The reaction mixture is evaporated to remove the solvent, and the residue is recrystallized from ethyl acetate to give 1-methyl-3-(3-t-butyl-5-isoxazolyl)urea (2.80 g) as crystals melting at 195.0° to 196.0° C. (decomp.). The yield is 83.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[OH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][N:30]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=2)[CH:31]([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), 4-hydroxy-N′-isopropylbenzohydrazide (202.81 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (40% EtOAc) and dried so that ivory (E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (102.5 mg, 31.8%).
Reaction SMILES: [ClH:1].CO.C(OC([N:14]1[CH2:33][CH2:32][N:17]2[C:18]3[C:23]([N:24]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:25][CH:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=O)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[F:30][C:27]([F:28])([F:29])[C:26]([N:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[CH2:32][CH2:33][NH:14][CH2:15][CH:16]2[CH2:25]1)=[O:31]
Reactant: O=C(OCc1ccccc1)N1CCN2c3ccccc3N(C(=O)C(F)(F)F)CC2C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C(N1CC2CNCCN2c2ccccc21)C(F)(F)F

Procedure:
A 80 μl portion of hydrochloric acid-methanol and 0.1 g of 10% Pd-C were added to 3 ml of ethanol solution containing 93 mg (0.22 mmol) of 3-benzyloxycarbonyl-2,3,4,4a,5,6-hexahydro-6-trifluoroacetyl-1H-pyrazino[1,2-a]quinoxaline, and 3 hours of catalytic hydrogenation was carried out at room temperature. The catalyst was filtered, the solvent was removed by evaporation under a reduced pressure and then the resulting residue was recrystallized from methanol-isopropyl ether to obtain 43 mg (61% in yield) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]1([P:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:9]1([P:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[N:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[N:8]=[CH:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[P:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: ClCCl
Product: C(=N[C@@H]1CCCC[C@H]1N=Cc1ccccc1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
7.5 g of granulated molecular sieves (4A) are baked in a Schlenk tube. After addition of 50 ml of dichloromethane, 1.75 g (15 mmol) of trans-1,2-diaminocyclohexane and 8.7 g (30 mmol) of o-diphenylphosphinobenzaldehyde, the reaction mixture is stirred for 24 hours. After filtration through Celite, the solvent is removed and the residue is recrystallized with 50 ml of ethanol, giving the product in the form of a light-yellow powder in a yield of 8.6 g (13 mmol, 87%). 1H-NMR (400 MHz, CDCl3): δ=8.71 (d, J=4 Hz, 2H, N═C—H), 7.78–6.64 (m, 28 H, aromat. H), 3.16 (m, 2H, C—H), 1.66–1.31 (m, 8H, (CH2)4) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][O:50]1.CCOC(/N=N/C(OCC)=O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:55][CH:52]([CH2:53][OH:54])[CH2:51][OH:50])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.6 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (80 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution. Triphenylphosphine (112 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (38 mg), and diethylazodicarboxylate (0.078 ml) were added to the solution, and the mixture was stirred at room temperature for 6 hr. Further, 1 N sulfuric acid (4 ml) was added thereto, the mixture was stirred at room temperature overnight, and the reaction solution was brought to 0° C. and was stirred. The reaction solution was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (50 mg, yield 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:33]=[CH:34][C:35]([N:38]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:36][CH:37]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.45 g of 4-nitrobenzenesulfonyl chloride in 20 ml of methylene chloride are added dropwise to a solution of 2.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine in 50 ml of methylene chloride and 1.0 ml of triethylamine. The solution is stirred overnight at RT, extracted with water, and the organic phase is dried and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 3:2. After concentration of the corresponding eluate fractions, the title compound of m.p. 234.5° C. is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CO.[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[CH:12][CH:13]=[CH2:14]>C(O)C>[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21]1[C:22]([NH2:23])=[N:4][C:3]([NH2:5])=[N:2][CH:24]=1)=[CH:12][CH:13]=[CH2:14]
Reactant: C=CC=Cc1cc(OC(C#N)=CNc2ccccc2)c(I)cc1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C=CC=Cc1cc(Oc2cnc(N)nc2N)c(I)cc1C

Procedure:
To a suspension of guanidine hydrochloride (3.10 g, 32.5 mmol) in 10 mL ethanol was added a solution of 25% NaOMe in methanol (7.0 mL, 32.5 mmol). The resulting solution was added to the crude 2-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-3-phenylamino-acrylonitrile of step 4, and the mixture was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water, and extracted with methylene chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (10% MeOH/methylene chloride+0.1% NH4OH), and recrystallized from EtOAc to give 2.1 g of 5-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-pyrimidine-2,4-diamine, MP=195-197° C.
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)C>[Cl:1][C:2]([Cl:11])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C=C(Cl)Cl
Solvent: CC(Cl)(Cl)Cl
Product: ClC(Cl)=Cc1ccccc1CBr

Procedure:
211 g (1.13 moles) of 2-(2,2-dichlorovinyl)-toluene, 251 g (1.41 moles) of N-bromosuccinimide and 2 g of azoisobutyronitrile in 1300 ml of dry 1,1,1-trichloroethane are refluxed, an additional 1 g of azoisobutyronitrile is added to the reaction mixture after one hour, and heating is continued for a further hour.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][C:17]([NH:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:18][CH:19]=3)[N:14](COCC[Si](C)(C)C)[N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][C:17]([NH:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:18][CH:19]=3)[NH:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3Cl)c2)c2cnc(NCCN3CCOCC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1CNc1cccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1
Reaction time: 3 h

Procedure:
To a stirred solution of [3-[3-(2-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (120 mg, 0.202 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another three hours at this temperature. The solvent was evaporated under reduced pressure and the pH of the residue was adjusted to 8 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (10 mL), dried and concentrated. It was purified by prep-HPLC to give {3-[3-(2-chloro-benzylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-morpholin-4-yl-ethyl)-amine. (Yield 15 mg, 61%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](C#N)=[CH:4][N:3]=1.[Cl-].[NH4+].[N-]=[N+]=[N-].[Na+].Cl.[OH2:21]>CN(C)C=O>[OH2:21].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cnc(Cl)c2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2cnccc2c1
Temperature: 120 °C

Procedure:
A mixture of 7.0 g of 1-chloro-4-cyanoisoquinoline, 4.3 g of ammonium chloride, 5.3 g of sodium azide and 100 ml of dimethylformamide was heated at 120° C. for 16 hours. The mixture was poured into 600 ml of water and acidified to a pH of 2 with hydrochloric acid. The cream colored precipitate which formed was separated by filtration and dried and then recrystallized from dimethylsulfoxide to give 5-(1H-tetrazol-5-yl)tetrazolo[5,1-a[isoquinoline hemihydrate melting at about 235°-250° C. decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1C
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 321.6 mg.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:24])=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:23][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([F:24])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-86, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (10 mL) to afford 0.083 g of the desired product. 1H NMR (300 MHz, DMSO): δ 1.13 (s, 9H), 4.30 (d, J=6.4 Hz, 2H), 7.53-7.66 (s, 3H), 7.91-8.15 (s, 3H), 12.67 (s, 1H); MS (adz): 455.19 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CCOCC.CCCCCC>[CH2:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCBr
Reactant: Cc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCCCCCCc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of 25 g of 2-methylquinoline in 40 ml of ether was added slowly to a mixture of 70 ml of a 1.6M solution of n-butyllithium in hexane and 40 ml of diethyl ether. The reaction mixture was stirred at room temperature, then it was cooled to about 5° C. and a solution of 28.9 g of n-hexyl bromide in 10 ml of ether was slowly added. The reaction mixture was then warmed to room temperature and stirred at room temperature for 2 hours. For working-up, the reaction mixture was added to 500 ml of water and extracted with ether. The organic phase was washed with slightly acidified water, dried and evaporated. The crude product obtained was purified by chromatography on a silica gel column using dichloromethane as the eluent. 31 g of oily crude 2-n-heptylquinoline were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: COCCN
Product: COCCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
0.3 mol (56.2 g) of 3,4-dichloronitrobenzene in 170 ml of 2-methoxyethylamine is heated to reflux for 3 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:23][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([Cl:22])=[CH:21][C:12]=2[C:10](=[O:11])[NH:9][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH3:8])[CH2:6][CH3:7])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 0.95 g of 2-[(4-chloro-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-butyric acid ethyl ester, 0.76 g 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 1.43 g triphenylphosphine in 30 mL of dry THF, 1.10 g of diisopropylazodicarboxylate were added. After 18 h at room temperature 1.43 g of triphenylphosphine and 1.10 g of diisopropylazodicarboxylate were added, and after 3 h again 1.43 g of triphenylphosphine and 1.10 g of diisopropylazodicarboxylate were added. After an additional 24 h the reaction was concentrated. After chromatography on silica (ethyl acetate/heptane) 1.17 g of 4-[4-chloro-2-(1-ethoxycarbonyl-1-methyl-propylcarbamoyl)-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester was obtained.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[O:9][C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N=C=NCCCN(C)C)C.[CH:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31]>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH:30]([NH:32][CH2:33][C:34]([O:17][C@H:12]([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C@H:10]1[C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:18])[O:9]1)=[O:35])=[O:31]
Reactant: O=CNCC(=O)O
Reactant: C=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: C=CCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CNC=O
Yield: 53.9 %

Procedure:
Prepared according to representative procedure described in Example 48 above (i.e., acylation) using hydroxy β-lactone 13j (15.0 mg, 0.059 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (14.8 mg, 0.077 mmol), 4-dimethylaminopyridine (8.71 mg, 0.071 mmol), 0.5 mL of xylene were azeotroped in vacuo for 1.0 h. After twelve hours the residue was then dissolved in CH2Cl2 (1.5 mL) and N-formyl glycine (9.12 mg, 0.089 mmol) was added. The resulting mixture was purified twice by chromatography (SiO2, gradient 10-40% EtOAc:hexanes) to afford β-lactone 17f (10.8 mg, 55%).