Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)OCCCCC1CCCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 123.5 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9H-purine-2,6-diamine (250 mg) in dry N,N-dimethylformamide (4.46 ml) at room temperature was added potassium carbonate (395 mg). The reaction mixture was stirred at 60° C. for 90 min. The reaction was cooled to room temperature and 4-(tetrahydro-2H-pyran-3-yl)butyl methanesulfonate (186 mg) was added and the reaction stirred at 90° C. for 2 hours. The reaction mixture was taken up in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil (366 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (30-70%) to afford the title compound as an orange gum (172 mg).
Reaction SMILES: CN(C(O[N:9]1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23]CN(C(C)C)C(C)C.C([O:34][C:35](=[O:50])[C:36]1[CH:41]=[CH:40][C:39]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:38]([NH2:49])[CH:37]=1)C.O>CN(C=O)C.CCO>[CH:43]1([N:42]2[C:39]3[CH:40]=[CH:41][C:36]([C:35]([OH:34])=[O:50])=[CH:37][C:38]=3[N:49]=[C:23]2[C:14]2[CH:13]=[CH:12][C:11]([NH2:16])=[C:10]([NH2:9])[CH:15]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nc3cc(C(=O)O)ccc3n2C2CCCCC2)cc1N
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
A solution of 1 g (2.84 mmol) of the product of the previous step, 0.91 g (2.84 mmol) of TBTU and 0.73 g (5.68 mmol) of DIEA in 10 mL anhydrous DMF was allowed to stand at room temperature for 15 min. To this solution was added 0.90 g (3.41 mmol) of Compound 11, and the solution was allowed to stand at room temperature overnight. The solution was then poured into 100 mL H2O, stirred for 30 min, filtered and dried. The solution of the solids thus obtained, in 50 mL 1M HCl and 25 mL EtOH, was refluxed at 110° C. overnight. The solvents were removed and the residue was treated with 14 mL 2 M NaOH in 70 mL of MeOH at 60° C. overnight. The MeOH was evaporated, the residue was diluted with 70 mL H2O and acidified to pH 6. The precipitate was filtered, washed with H2O and dried yielding 0.95 g brown solid. MS: 351.20 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH:12]2[CH2:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([O:18][C:16]1[CH2:17][CH:12]([CH2:11][CH2:10][S:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:8][CH:7]=2)[CH2:13][C:14](=[O:19])[CH:15]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C1CC(=O)CC(CCSc2ccc(C(F)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC1=CC(=O)CC(CCSc2ccc(C(F)(F)F)cc2)C1

Procedure:
6.32 Grams of 5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 50 ml of tetrahydrofuran, and 2.12 g of triethylamine was added. Thereafter, 1.73 g of acetyl chloride was added dropwise with thorough stirring under ice-cooling. After continuing stirring for further 2 hours at room temperature, the precipitated solid was filtered off. The solvent was removed from the filtrate, and the residue was dissolved in ether. The ether layer was successively washed with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate. Ether was removed to obtain 7.13 g of 1-acetoxy-5-[2-(4-trifluoromethylphenylthio)ethyl]-1-cyclohexene-3-one.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([CH3:17])([CH3:16])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH3:18][C:19]([CH3:32])([CH3:31])[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[N:23]=[N:22]1>C(O)(=O)C>[Br:1][C:11]1[C:10]2[N:6]([CH2:5][C:4]([CH3:17])([CH3:16])[CH3:3])[N:7]=[N:8][C:9]=2[CH:14]=[CH:13][C:12]=1[OH:15].[Br:1][C:29]1[C:24]2[N:23]=[N:22][N:21]([CH2:20][C:19]([CH3:32])([CH3:31])[CH3:18])[C:25]=2[CH:26]=[CH:27][C:28]=1[OH:30]
Reactant: CC(C)(C)Cn1nnc2cc(O)ccc21
Reactant: CC(C)(C)Cn1nnc2ccc(O)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Product: CC(C)(C)Cn1nnc2ccc(O)c(Br)c21
Reaction time: 1 h

Procedure:
Bromine (60 μL, 1.2 mmol) was added to a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-6-ol & 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (0.22 g, 1.1 mmol), prepared as a 1.3:1.0 mixture according to example 6, and acetic acid (10 mL) at rt. After 1 h, the reaction was concentrated and purified by silica gel chromatography to give 7-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-6-ol and 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol. MS (ESI): 284/286 (M+H). Similar procedures as outlined in example 1 were followed using 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol. 1H NMR (500 MHz, DMSO) δ 7.96 (d, 2H), 7.92 (d, 1H), 7.52 (d, 1H), 7.16 (d, 2H), 4.50 (s, 2H), 4.26 (t, 2H), 4.18 (t, 2H), 2.02-1.91 (m, 4H), 0.96 (s, 9H). MS (ESI): 500/502 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:26])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccc(Br)cc2)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude benzhydryl alcohol (53.2 g, 135 mmol) was dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloride was added dropwise. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 500 mL of toluene and the solvent again was removed under vacuum to eliminate excess thionyl chloride, providing crude α-(4-bromophenyl)-3-(tert-butyldimethyl-silyloxy)benzyl chloride as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:3]=12
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)cc1
Temperature: 80 °C
Yield: 24.7 %

Procedure:
To a suspension of (E)-N-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide (32) (174 mg, 0.36 mmol), 4-chlorophenylboronic acid (68 mg. 0.44 mmol) and K3PO4.3H2O (292 mg, 1.1 mmol) in DME (3 mL) and water (0.5 mL) was added Pd(dppf)Cl2.DCM (15 mg, 0.02 mmol). The resulting mixture was purged with N2 (3×) before heated to 80° C. overnight under N2 atmosphere. The mixture was cooled down to room temperature. The solvents were evaporated and the residue was pre-purified by column chromatography (silica gel, methanol in methylene chloride (1% Et3N)) followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(4-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide (33) (41 mg, yield 25%) as a white solid. LC-MS (ESI): m/z (M/M+2) 463/465. 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.29 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.69-6.60 (m, 1H), 5.94 (s, 1H), 3.27 (s, 2H), 2.88 (d, J=5.8 Hz, 1H), 2.03 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:21])[NH:7]1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(OCC)(=O)C>C1COCC1.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[O:9][C:8](=[O:21])[NH:7]1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3ccccc3CN2)O1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step A(7), 320 mg, 0.93 mmol) in THF (20 mL) was added 4-methoxybenzaldehyde (253 mg, 1.86 mmol) and acetic acid (2 drops). This mixture was stirred at rt overnight. NaBH(OAc)3 (588 mg, 2.78 mmol) was added and the reaction mixture was stirred at rt for 2 days. Ethyl acetate (300 mL) was added and the mixture was washed with aqueous sodium carbonate, H2O, dried (Na2SO4), and concentrated in vacuo. Crude mixture was purified by silica gel Flash Chromatography to give 420 mg of the title compound (80% yield): 1H NMR (CDCl3, 500 MHz) δ 2.57 (1H, t, J=10 Hz), 2.96 (1H, dd, J=5, 20 Hz), 3.17 (1H, dd, J=5, 15 Hz), 3.44-3.50 (2H, m), 3.68 (2H, dd, J=10, 45 Hz), 3.80 (3H, s), 3.84-3.88 (3H, m), 4.66 (1H, dd, J=5, 10 Hz), 5.29 (1H, s), 6.71-6.74 (3H, m), 6.88 (2H, d, J=10 Hz), 6.98 (1H, d, J=5 Hz), 7.15-7.21 (5H, m). MS (ESI) (M+H)+ 465.12.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@@H:12]2[F:19])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>O>[F:19][C@H:12]1[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:23])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3F)c2n1
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Reaction time: 24 h

Procedure:
2,6-Diamino-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine (0.1 g, 0.35 mmoles) prepared as in Example 1, was dissolved in 10 ml of water. Calf intestine adenosine deaminase (10 I.U., Boehringer Mannheim) was added and the solution incubated at 37° C. for one day. The solvent was removed under vacuum. The residue was dissolved in acetonitrile/water (85/15) and chromatographed on silica gel with acetonitrile/water (85/15) as the solvent. Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilization yielded 0.14 g of the title compound that analysed as a 1.1 hydrate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16][NH2:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:28]=O)[C:22]=2[CH:21]=[CH:20][N:19]=1.CC(O)=O>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16]/[N:17]=[CH:28]/[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][N:19]=[CH:18]3)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C2CC2C(=O)N/N=C/c2cccc3cnccc23)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a room temperature solution of 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86 mmol) in ethanol (10 mL) were added isoquinoline-5-carbaldehyde (162 mg, 1.0 mmol) and a catalytic amount of glacial AcOH (0.4 mL) under an inert atmosphere. The reaction mixture was then stirred at 90° C. for 4 h, concentrated in vacuo, and the residue was then dissolved in DCM (50 mL). The organic layer was washed with saturated NaHCO3 solution (15 mL) and brine (15 mL). The organic layer was then separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 1% MeOH in dichloromethane to afford (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene) cyclopropanecarbohydrazide (160 mg, 50%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 11.60 (s, 1H), 9.38 (s, 1H), 8.71-8.56 (m, 2H), 8.25-8.12 (m, 2H), 8.11-7.99 (m, 2H), 7.39-7.29 (m, 2H), 7.19-7.06 (m, 2H), 2.41-2.33 (m, 1H), 1.95-1.90 (m, 1H), 1.42-1.34 (m, 2H), 1.25 (s, 9H). MS: M m/z=372.2 HPLC: 96%, (Condition-A).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.CN.[CH2:12]([N:14](CC)CC)C>>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:14][CH3:12])[C:2]=1[NH2:1]
Reactant: CCN(CC)CC
Reactant: Nc1c(Cl)ncnc1Cl
Agent: CN
Product: CNc1ncnc(Cl)c1N

Procedure:
5-Amino-4,6-dichloropyrimidine (15.0 g, 91.4 mmol) and methylamine (2M solution in THF, 5 eq) were initially charged, and triethylamine (27.76 g, 274 mmol) was added. The mixture was stirred under reflux until the conversion was complete (about 3 hours). The reaction mixture was then concentrated, and water was added to the residue. The pH was adjusted to 7-8 using saturated Na—HCO3 solution. The mixture was extracted 3× with methylene chloride, the combined organic phases were dried over sodium sulphate and filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>ClCCl>[CH3:23][S:20]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(OS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To a stirred solution of ethyl 3-hydroxybenzoate (3.32 g, 20 mmol) in dichloromethane (20 mL) cooled to 0° C. was added triethylamine (4.17 mL, 30 mmol). To this was added mesyl chloride (1.94 mL, 25 mmol) dropwise over 15 min. The reaction was stirred at 0° C. for 15 min then quenched with water and the phases separated. The aqueous layer was extracted with dichloromethane and the combined organics were dried over MgSO4 and concentrated in vacuo. The crude material was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a white solid (2.698 g, 55%). 1H NMR (300 MHz, CDCl3) δ: 7.98 (m, 1H), 7.89 (s, 1H), 7.47 (m, 2H), 4.35 (q, J=7.0 Hz, 2H), 3.16 (s, 3H), 1.37 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 165.3, 149.3, 132.9, 130.3, 128.7, 126.9, 123.2, 61.8, 37.8, 14.5 ppm. IR (neat, cm−1): 1721, 1384, 1369, 1268, 1194, 1168, 1098, 936, 840, 798.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2[NH:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Solvent: O
Product: CNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Methylamine (available as a 40% solution in water, 21 mL, 0.25 mol) was added to a suspension of 6-benzyloxy-4-chloro-3-nitroquinoline (13.74 g, 43.65 mmol) in distilled water (300 mL), and the reaction was stirred at 100° C. for 1.5 hours. The reaction was allowed to cool to ambient temperature and stirred for three hours. A precipitate formed, which was isolated by filtration, washed with distilled water (3×), and recrystallized from 2-propanol (44.2 mL/g). The crystals were isolated by filtration and washed with cold hexanes (2×100 mL) to provide 11.36 g of N-(6-benzyloxy-3-nitroquinolin-4-yl)-N-methylamine as orange crystals.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH:14](=O)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]([NH:27][NH2:28])(=[O:26])[CH3:25]>C(Cl)(Cl)Cl.CO>[C:24]([N:27]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH:14]=[N:28]1)(=[O:26])[CH3:25]
Reactant: CC(=O)NN
Reactant: O=CC=Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)N1N=CCC1c1ccccc1
Temperature: 220 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To 10 ml of diphenyl ether were added 1.3 g of cinnamaldehyde and 0.8 g of acetylhydrazine, followed by gradual heating to 220° C. over 30 minutes. Stirring was continued for 3 hours at that temperature. After cooling, the reaction liquid as such was subjected to silica gel chromatography (chloroform/methanol=100/1). Thus there was obtained 1.2 g of 1-acetyl-5-phenyl-2-pyrazoline in the form of light yellowish oil as the desired product. The yield was 64.8%.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)[CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].[ClH:30].C(OCC)C>CO>[ClH:30].[ClH:30].[N:16]1([CH2:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][NH:5][CH2:14][CH2:13]3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(N1CCc2cc(CN3CCCCC3)ccc2C1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: c1cc2c(cc1CN1CCCCC1)CCNC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,2,2-Trifluoro-1-(6-(piperidin-1-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (1.88 g, 5.76 mmol) was dissolved in methanol (23 ml); potassium carbonate (1.99 g, 14.4 mmol) was added and the reaction mixture was stirred for 15 h at RT. The solvent was then removed under vacuum, and the residue was taken up in dichloromethane and washed with water (15 ml). The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in an acetone/diethyl ether mixture, and the hydrochloride was precipitated with 2 M hydrogen chloride in diethyl ether (3 equiv.) and, after being filtered out with suction, was dried under vacuum. Yield: 1.62 g (93%)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[C:24](C(O)=O)[CH:23]=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([CH2:41][CH2:42][NH2:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:32]2[CH:31]=[CH:30][C:29]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:34][CH:33]=2)=[O:7])[C@H:9]([C:16]([NH:43][CH2:42][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:18])[CH2:10]1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCc1ccccc1
Product: CON=C1C[C@@H](C(=O)NCCc2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-phenylethanamine, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=456.
Reaction SMILES: [CH:1]12[CH2:13][CH:4]([C:5]3[C:6]([OH:12])=[CH:7][CH:8]=[C:9]([OH:11])[C:10]=31)[CH2:3][CH2:2]2.B(F)(F)F.CCOCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:31])(O)[CH:28]=[CH2:29].O>O1CCOCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]1([CH3:31])[CH2:28][CH2:29][C:7]2[C:6](=[C:5]3[CH:4]4[CH2:13][CH:1]([CH2:2][CH2:3]4)[C:10]3=[C:9]([OH:11])[CH:8]=2)[O:12]1
Reactant: Oc1ccc(O)c2c1C1CCC2C1
Reactant: C=CC(C)(O)CCCCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CC1(CCCCl)CCc2cc(O)c3c(c2O1)C1CCC3C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-5,8-diol (1.34 g, 794 mmol), 1.0 mL (3.97 mmol) of BF3.Et2O and 25 ml of dioxane was heated up to 110° C. under a N2 atmosphere. A solution of 6-chloro-3-methyl-hex-1-en-3-ol (1.12 g, 8.6 mmol) in 24 ml of dioxane was added slowly to the mixture. The addition was completed after two hours and the mixture was continued to reflux for an additional 3 hours. After cooling down to room temperature, the mixture was poured to water, extracted with ethyl acetate, washed with water and dried over MgSO4. After removal of the solvents, the residue was mixed with methanol/HCl and let stand overnight at room temperature. After the removal of the solvents the residue was purified via flash column chromatography on silica gel (1:3 EtOAc/Hex) twice to give 1.30 g of 2-(3-chloro-propyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-6-ol. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.39 (s, 1H), 4.27 (s, 1H), 3.63-3.47 (m, 4H), 2.73-2.70 (m, 2H), 2.00-1.47 (m, 8H), 1.43-1.15 (m, 4H); MS: 307 (M+H+, 100%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35])(=[O:46])=[O:45]
Reactant: Cc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 85.3 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-methyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.5 mg, 0.170 mmol) was dissolved in dichloromethane (3 mL), and the solution was treated with triethylamine (0.095 mL, 0.68 mmol) and methanesulfonyl chloride (0.026 mL, 0.34 mmol), followed by purification by slurry using hexane to obtain 4-methanesulfonyloxy-5-methyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.3 mg, yield 85%).