Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][CH2:19][CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[Cl-:18].[CH:20]([CH:21]([N+:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10](=[O:17])[NH:9][C@@H:2]([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:12]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:19]
Reactant: ClCC=Cc1ccccc1
Reactant: C[C@H](NC(=O)c1cccnc1)c1ccccc1
Solvent: CO
Product: C=CC(c1ccccc1)[n+]1cccc(C(=O)N[C@@H](C)c2ccccc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
A 100 ml methanol solution containing 2.26 g (1.00×10-2 mols) of N-((S)-α-methylbenzyl)nicotinamide was charged into a 250 ml round bottom flask equipped with condenser, addition funnel, drying tube, nitrogen purge and magnetic stirrer. To this stirred reaction mixture was added, dropwise over a 10 minute interval, 50 ml of a methanol solution containing 1.53 g (1.00×10-2 mols) of chloromethylstyrene. The solution was stirred for 24 hours at 25° C., then was concentrated under vacuum to afford solid which was recrystallized from methanol to yield 3.40 g (8.98×10-3 mols) of product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[S:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[OH:25])=[C:11]([C:35]3[CH2:39][CH2:38][CH2:37][CH:36]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:40]I.C(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:26]4[S:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)[O:25][C:35]4([CH2:39][CH2:38][CH2:37][CH:36]4[I:40])[C:11]=3[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)c1nc2c(c(C3=CCCC3)c1[C@H](O)c1ccc(C(F)(F)F)s1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)s1)OC31CCCC1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
To a solution of 67 mg (S)—((S)-5-(tert-butyldimethylsilyloxy)-4-cyclopentenyl-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(5-(trifluoromethyl)thiophen-2-yl)methanol in 1 ml tetrahydrofurane and 1 ml acetonitrile are added under nitrogen 29 mg sodium bicarbonate and a solution of 88 mg of iodine in 200 μl tetrahydrofurane and the reaction is monitored by thin layer chromatography. In the case of low conversion the same amounts of sodium bicarbonate and iodine solution are added up to two times. The mixture is then diluted with diethylether and washed with saturated aqueous sodium sulfite solution and brine. After drying with sodium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 98:2 to 80:20).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]([CH:28]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=3)[O:16][N:15]=2)[CH2:10][CH2:9]1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=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>[Cl:29][C:5]1[CH:4]=[CH:3][C:2]([C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=2)=[CH:28][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=3)[O:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)Cn1nnc(-c2cc(N3CCC(Oc4cc(Br)ccc4Cl)CC3)no2)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: Cc1ccccc1
Product: O=C(O)Cn1nnc(-c2cc(N3CCC(Oc4cc(-c5ccc(OC(F)(F)F)cc5)ccc4Cl)CC3)no2)n1
Temperature: 80 °C

Procedure:
To a suspension of (5-{3-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic acid (130 mg, 0.269 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (98 mg, 0.476 mmol) and Pd(Ph3P)4 (25 mg, 0.022 mmol) in toluene (4 mL) was added aqueous 2 M Na2CO3 (1.5 mL, 3.00 mmol). After the resulting heterogeneous mixture was purged with nitrogen, it was gently heated to 80° C. for 6 h with stirring under a nitrogen atmosphere. After cooling to room temperature, the reaction was poured into aqueous 1 N HCl and extracted with EtOAc. The organic layer was washed with brine and dried (Na2SO4). Solvents were removed under reduced pressure and the crude material was purified by column chromatography on silica gel (gradient from 0% to 3% HOAc/EtOAc). After concentration, the white solid was co-evaporated twice and triturated with Et2O/heptane to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ13.92 (br s, 1H), 7.88-7.83 (m, 2H), 7.57-7.54 (m, 2H), 7.49 (d, 2H), 7.30 (dd, 1H), 7.27 (s, 1H), 5.83 (s, 2H), 5.00-4.93 (m, 1H), 3.68-3.60 (m, 2H), 3.41-3.35 (m, 2H), 2.12-2.02 (s, 2H), 1.87-1.78 (m, 2H). MS: m/z 565 (MH+).
Reaction SMILES: [C:1]1([CH2:7]C[Mg][Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]([CH3:25])[C:13]1([C:23]#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+].Cl[Si](C)(C)C>C1COCC1.O>[ClH:10].[CH3:11][N:12]([CH3:25])[C:13]1([CH2:23][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]CCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(CCc2ccccc2)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1M 2-phenylethylmagnesium chloride solution in THF (550 ml, 550 mmole) was added within 15 minutes under argon and while cooling with ice to a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (39 g, 186 mmole) in THF (300 ml) and the mixture was then stirred for 16 hours at room temperature. The reaction mixture was worked up by adding saturated ammonium chloride solution (295 ml) and water (120 ml) while cooling with ice, and was extracted with diethyl ether (3×150 ml). The organic phase was washed with water (100 ml) and saturated NaCl solution (100 ml) and then concentrated by evaporation. A brown oil remained (60.4 g). The crude product was dissolved in ethyl methyl ketone (310 ml) and ClSiMe3 (35.6 ml, 282 mmole) was added while cooling with ice. After 16 hours at RT the resultant solid product was suction filtered and washed with ethyl methyl ketone.
Reaction SMILES: [Br-].[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH3:4].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[Na+]>CCO.O>[Br-:13].[CH2:14]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCBr
Reactant: CCCNCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCN(CCC)CCC[N+](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of propylamine (5.5 mL, 0.067 mol) in EtOH (100 mL) is added 3-bromo-N,N,N-trimethylpropan-1-aminium bromide (5.0 g, 0.0191 mol) portionwise at 0° C. over 20 minutes. The solution is warmed to room temperature and then refluxed for 4 hours. The solution is cooled to room temperature, and the solvent is removed via rotary evaporator to provide the crude di-bromo salt (5.69 g, 0.0179 mol). The salt is dissolved in MeOH (200 mL) and NaOH is added portionwise (0.717 g, 0.0179 mol) in MeOH (50 mL) over 30 minutes at room temperature. The solution is stirred an additional 2 hours at room temperature after addition is complete and then the solvent is removed via rotary evaporator. The residue is stirred with CH3CN (150 mL) for 30 minutes and the solids filtered off. The filtrate is concentrated via rotary evaporation and the residue is pumped on 24 h under vacuum to provide the 3-(propylamino)-N,N,N-trimethylpropan-1-aminium bromide (4.07 g, 0.017 mol), which is used without further purification. The 3-(propylamino)-N,N,N-trimethylpropan-1-aminium bromide (4.07 g, 0.017 mol) is dissolved in EtOH (100 mL) and 1-bromododecane (4.55 mL, 0.019 mol) is added dropwise over 15 minutes. The reaction is refluxed 24 hours, cooled to room temperature, and solid NaOH (0.68 g, 0.017 mol) is added. The reaction is stirred 2 hours at room temperature, and then the solids are filtered off. The filtrate is concentrated to give a white solid. The solid is dissolved in water (200 mL) and extracted with EtOAc (3×150 mL). The organic layers are combined and discarded, and the aqueous layer is frozen and lyophilized under vacuum for 48 hours to provide 3-(dodecyl(propyl)amino)-N,N,N-trimethylpropan-1-aminium bromide as a white solid (5.29 g, 0.013 mol).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][NH:8][C:9]([C:11]1[C:25](=[O:26])[C:24]2[C:19](=[C:20]([Cl:27])[CH:21]=[CH:22][CH:23]=2)[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:12]=1[OH:28])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.O>[Cl:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[C:13]1([CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:12]([OH:28])=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:29])=[O:5])=[O:10])[C:25]2=[O:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(Cl)cccc2C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(Cl)cccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A mixture of t-butyl-N-((8-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.13 g, 0.31 mmol) in 1.5 mL TFA was stirred at room temperature for 30 minutes. The mixture was diluted with 20 mL water, and a white solid precipitate formed. The solid was collected by filtration and washed with 20 mL water. The solid was dried under high vacuum to give 0.11 g off-white solid. MS m/e: (M+H)+ 366.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[C:26]([CH3:30])=[N:27][NH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[C:26]([CH3:30])=[N:27][NH:28][CH:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1n[nH]cc1-c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1n[nH]cc1-c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:16][O:17]C1CCCCO1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=S)[CH:29]=[CH:30][CH:31]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:44][NH2:45].C(O)(=O)C>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[C:9]2=[N:44][NH:45][C:33]=3[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=2)=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: COc1cc2c(cc1OCCCOC1CCCCO1)CCC2=O
Reactant: NN
Reactant: COc1cccc(N=C=S)c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(Nc2[nH]nc3c2Cc2cc(OCCCO)c(OC)cc2-3)c1

Procedure:
A mixture of 6-methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one (Intermediate L) (0.16 g, 0.0005 mole), 3-methoxy-phenyl isothiocyanate (Compound 19a) (0.08 mL, 0.0006 mole) and THF (1.5 mL) was added to lithium hexamethyldisilane (0.7 mL, 0.0007 mole) dropwise at room temperature with stirring. The reaction mixture was stirred for 4 hrs. Hydrazine (0.035 mL, 0.0011 mole) and acetic acid (0.66 mL, 0.0011 mole) were added to the reaction mixture, which was then heated at the reflux temperature for 18 hrs. To the resulting mixture was first added water (10 mL) and then the reaction mixture was extracted with CH2Cl2. The organic layers were combined and washed with aqueous NaHCO3 solution, then washed with water and brine solution, dried (Na2SO4), and solvent was removed in vacuo. The crude material was purified on the reverse phase HPLC and converted to the desired product upon standing in the 1% TFA in CH3CN: water solution. Lyophilization yielded the title compound, 3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol as a white powder. MS m/z 382 (M+H)+; 1HNMR (DMSO-d6): 1.88(m, 2H), 3.40(s, 2H), 3.57(t, 2H), 3.72(s, 3H), 3.78(s, 3H), 4.05(t, 2H), 6.38(d, 1H), 6.68(d, 1H), 6.77(s, 1H), 7.10(m, 2H), 7.25(s, 1H), 8.75(br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([O:1][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(OS(C)(=O)=O)cc4C(F)(F)F)c3)S2)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (10 mg, 0.02 mmol) in 1 mL CH2Cl2 was added DIEA (7.7 mg, 0.06 mmol) and methanesulfonyl chloride (4 mg, 0.03 mmol). The mixture was stirred for 1 h and loaded onto a silica gel-packed column. The desired product was eluted with 0-100% gradient of CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc (8.6 mg, 74%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=O)[NH:24][CH:23]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:25]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:24][CH:23]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1-c1ccc(OC)cc1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: CCOC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c1-c1ccc(OC)cc1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 5-formyl-4-(4-methoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (60 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OC[C@@H]1CCCN1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OC[C@@H]1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 41 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-2-pyrrolidinemethanol to give the title compound in 41% yield; NMR Spectrum: 1.49-1.53 (m, 1H), 1.60-1.66 (m, 2H), 1.77-1.82 (m, 1H), 2.33-2.36 (m, 1H), 2.58 (br s, 1H), 2.77-2.79 (m, 1H), 3.13-3.15 (m, 1H), 3.26-3.29 (m, 2H), 3.37-3.41 (m, 1H), 4.39 (t, 2H), 4.44 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.87 (t, 1H), 7.93 (d, 1H), 8.29 (s, 1H), 8.40 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: C([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][CH2:15][CH:9]([NH2:8])[CH2:10][C:11]=2[CH:19]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CC(N)CCC2
Yield: 105.9 %

Procedure:
A mixture of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (1.0 g) and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5.5 hours. After filtration, the filtrate was evaporated in vacuo to give 3-methoxy-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (720 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH:17]2[CH2:19][N:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]([O:30]CC)=[O:29])=[CH:24][N:23]=3)[CH2:21][CH:16]2[CH2:15]1)(=[O:13])=[O:12].[OH-].[Na+].Cl>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:15][CH:16]2[CH2:21][N:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]=3)[CH2:19][CH:17]2[CH2:18]1)(=[O:13])=[O:12]
Reactant: CCOC(=O)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a suspension of ethyl 2-[5-(naphthalene-2-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-pyrimidine-5-carboxylate (0.201 g, 0.44 mmol) in ethanol (2 ml) was added 6M NaOH solution (2 ml, 12 mmol). The reaction was heated at 80° C. for 2 h, then cooled to r.t. The pH was adjusted to ˜5 by addition of 2M HCl. The solution was allowed to stand overnight, and the product was collected by filtration to give the title compound (0.154 g, 82%). 1H NMR (300 MHz, d6-DMSO) δ: 2.80-2.95 (2H, m), 3.17 (2H, dd, J=3.6, 10.2 Hz), 3.20-3.30 (2H, m), 3.46 (2H, dd J=7.2, 10.5 Hz), 3.61 (2H, dd, J=6.9, 11.7 Hz), 7.60-7.78 (2H, m), 7.82 (1H, dd, J=1.8, 8.7 Hz), 8.06 (1H, d, J=8.1 Hz), 8.13 (1H, d, J=8.7 Hz), 8.18 (1H, d, J=7.8 Hz), 8.47 (1H, s), 8.59 (2H, s).
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:7][C:6]([C:19]23[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[C:23](=[O:29])[NH:22][C:20]3=[O:21])=[C:5]([F:30])[CH:4]=1.C(OCC)C>C(O)(=O)C.[Fe]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[C:3]([Cl:2])=[CH:4][C:5]([F:30])=[C:6]([C:19]34[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[C:23](=[O:29])[NH:22][C:20]4=[O:21])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=C1NC(=O)C2(c3cc(Oc4ccc([N+](=O)[O-])cc4)c(Cl)cc3F)CCCCC12
Agent: [Fe]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1ccc(Oc2cc(C34CCCCC3C(=O)NC4=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a stirred solution of 20 mL of water in 200 mL of glacial acetic acid was added 6.0 g (0.014 mole) of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-3,4,5,6-tetrahydrophthalimide. This mixture was stirred at room temperature while 6.0 g (0.11 mole) of iron filings were slowly added. After complete addition the mixture was stirred at room temperature for one hour. Diethyl ether was added and the resultant mixture was filtered through a pad of celite. The filtrate was washed with 200 mL of water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a solid. This solid was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 4.0 g of 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-3,4,5,6-tetrahydrophthalimide as a solid, m.p. 213°-215° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:7]=12.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[C:12]3[CH:13]=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:17]=3[C:18](=[O:19])[C:7]=12
Reactant: O=[N+]([O-])O
Reactant: Cc1ccnc2c1C(=O)c1ccccc1-2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccnc2c1C(=O)c1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
A mixture of 35.2 ml of 98.9% strength sulfuric acid with 35.2 ml of 99% strength nitric acid was added dropwise at from +5° to 10° C. to a solution of 15.6 g (0.08 mol) of 4-methyl-5H-indeno[3,2-b]-pyridin-5-one in 35.2 ml of conc. sulfuric acid in the course of 1 hour. After stirring at 25° C. for 14 hours and additionally stirring at 70° C. for 4 hours, the mixture was cooled to 20° C., stirred into 500 g of ice and brought to pH 10 with a 50% strength aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, the combined extracts were concentrated under reduced pressure and the residue was crystallized at +10° C. using 30 ml of ether. 13 g (67% of theory) of 4-methyl-7-nitro-5H- indeno[3,2-b]pyridin-5-one were obtained as yellow crystals of m.p. 225°-227° C.