Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:42])[CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g, 1.6 mmol) in pyridine (11 mL) at 0° C. was treated with hydrocinnamoyl chloride (0.324 g, 1.92 mmol). The reaction mixture was stirred at 0° C. for 20 min and the ice bath was removed to stir at room temperature. The reaction was complete after 5.5 hours. Sodium hydroxide solution (1 N, 20 mL) was added and stirred for 30 minutes. The organic layer was removed under reduced pressure. Dichloromethane (20 mL) was added, and the layers were partitioned. The aqueous layer was extracted with dichloromethane (80 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 5% methanol in dichloromethane to 50% methanol in dichloromethane on a 35 g ISCO silica gel column to give 0.569 g (63%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.569 g, 1 mmol) in warmed ethyl acetate was treated with a warmed solution of maleic acid (0.384 g, 3 mmol) in ethyl acetate. The formed precipitate was filtered under a nitrogen atmosphere and dried under high vacuum to give the tri maleate salt. 1H NMR (d6-DMSO) δ 9.238 (s, 1H), 8.2216 (s, 1H), 8.1991-8.1786 (d, 1H, J=8.2 Hz), 7.3147-7.2664 (m, 4H), 7.2366-7.2330 (m, 1H), 7.2026-7.1732 (dd, 2H), 6.171 (s, 6H), 4.6649-4.6083 (m, 1H), 4.0948-4.0697 (m, 1H), 3.8916 (s, 3H), 3.1750-3.1632 (d, 2H, J=4.72 Hz), 2.9364-2.8984 (m, 2H), 2.7885-2.7506 (m, 2H), 2.5290 (s, 2H), 2.3905-2.3231 (m, 4H), 2.1489 (s, 3H), 2.0549-1.9243 (m, 6H), 1.4821-1.4457 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 1.75 min (100%), MH+ 569.4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1
Reactant: O=C1CN(c2ccc(-c3cncs3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C1CN(c2ccc(-c3cncs3)cc2O)S(=O)(=O)N1
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2-benzyloxy-4-thiazol-5-yl-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (87 mg, 0.217 mmol) in EtOH (2.5 mL) and water (22.5 mL) is added 10% Pd/C (100 mg) and the mixture is stirred under an atmosphere of H2 for 2.5 h. The mixture is filtered through Celite and the filtrate evaporated. The residue is purified by reverse phase HPLC (CH3CN/water/0.1% TFA) to afford the title compound as a light yellow solid: 1H NMR (CD3O4.37 (s, 1H), 7.04 (d, J=8 Hz, 1H), 7.08 (s, 1H), 7.35 (d, J=8 Hz, 1H), 7.97 (s, 1H), 8.79 (s, 1H); (M−1)−=310.
Reaction SMILES: O.[SH2:2].[Na].Br[CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CCOCC>O>[SH:2][CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(Br)C(C)=O
Reactant: S
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(S)C(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
A round bottom flask was charged with sodium hydrogensulfide hydrate (1.23 g, 16.9 mmol) in water (14.2 mL). The solution was cooled to about 0° C. followed by the addition of ethyl 3-bromo-4-oxopentanoate (3.79 g, 16.9 mmol) dropwise over about 30 min. The mixture was stirred at about 0° C. for about 3 h. To the reaction mixture was added Et2O (40 mL) and the reaction was warmed to ambient temperature. The crude product was partitioned between Et2O (15 mL) and water (15 mL). The layers were separated and the aqueous layer was back extracted with Et2O (10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford ethyl 3-mercapto-4-oxopentanoate (1.74 g, 9.87 mmol, 58%, which was used without further purification). LC-MS (Table 1, Method g) Rt=2.24 min, m/z 177 (M+H)+.
Reaction SMILES: [S:1](=[O:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][C:6]=1[C:12]([F:15])([F:14])[CH3:13].N([O-])=O.[Na+].[ClH:20]>C(O)(=O)C.O.[Cu]Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:1]([Cl:20])(=[O:3])=[O:2])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[CH3:13]
Reactant: CC(F)(F)c1cc(N)ccc1Cl
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(F)(F)c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
Amounts used: 2 mL of acetic acid was saturated with sulfur dioxide, 47 mg of copper(I) chloride, 365 mg (1.91 mmol) of 4-chloro-3-(1,1-difluoro-ethyl)-phenylamine dissolved in a mixture of 1.2 mL of acetic acid and 0.6 mL of concentrated hydrochloric acid, 145 mg of sodium nitrite in 1 mL of water. Flash chromatography on silica using 0-15% ethyl acetate in hexanes afforded 377 mg of the product as a white solid. LC-MSD spectrum not observed;
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)C(O)=O)=[CH:14][C:12]=2[CH:13]=1.C(Cl)(=O)[C:28](Cl)=[O:29].[CH3:33][N:34](C)[CH:35]=[O:36].Cl.CNOC>C(Cl)Cl.N1C=CC=CC=1>[CH3:28][O:29][N:34]([CH3:33])[C:35](=[O:36])[C:25]1[CH:24]=[CH:20][CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:11]3[O:10][C:9]([CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C@H:2]4[CH3:1])=[CH:13][C:12]=3[CH:14]=2)[CH:26]=1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)O)c3)ccc2o1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Agent: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
The product from Example 144 was suspended in CH2Cl2 (25 mL) and treated with 2 M oxalyl chloride in CH2Cl2 (3.0 mL, 6.0 mmol). After the bubbling had subsided, N,N-dimethylformamide (300 μL) was added slowly over 15 minutes. After an additional hour, more N,N-dimethylformamide (100 μL) was added. After another 30 minutes, the mixture was concentrated and dissolved into CH2Cl2 (5 mL). N,O-Dimethylhydroxylamine hydrochloride (488 mg, 5.0 mmol) and pyridine (1 mL) were added, the reaction flask was placed in a water bath, and the mixture was stirred overnight, concentrated, diluted with 1,2-dichloroethane (5 mL), heated at 85□C for four hours, concentrated, and partitioned between CH2Cl2 and water. Saturated aqueous NaHCO3 was added until the pH of the aqueous phase exceeded seven. Then the aqueous phase was separated and extracted with CH2Cl2. The combined organic phases were washed consecutively with water and brine, dried (Na2SO4), and chromatographed on silica with a gradient of 0 to 4% MeOH/CH2Cl2 to provide the title compound as a viscous brown syrup (60% yield from ester). 1HNMR (300 MHz, CD3OD) δ 1.19 (s, 3 H), 1.37-1.54 (m, 1 H), 1.73-1.88 (m, 2 H), 1.95-2.09 (m, 1 H), 2.27-2.39 (m, 1 H), 2.45-2.64 (m, 2 H), 2.95-3.17 (m, 2 H), 3.20-3.3 (m, 2 H), 3.39 (s, 3 H), 3.63 (s, 3 H), 6.62 (s, 1 H), 7.46-7.83 (m, 4 H), 7.73-7.81 (m, 2 H), 7.86 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]3)[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18](O)=[C:17]([O:24][CH3:25])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Cl.[CH2:47]([N:49]([CH2:52][CH2:53]Cl)[CH2:50][CH3:51])[CH3:48]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]3)[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:48][CH2:47][N:49]([CH2:52][CH3:53])[CH2:50][CH3:51])=[C:17]([O:24][CH3:25])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1O
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCc1c(OC)cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1OC
Reaction time: 24 h

Procedure:
Combine 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (1 mmol) and sodium hydride (2 mmol) in tetrahydrofuran (10 mL). Add diethylaminoethylchloride hydrochloride (1 mmol). After 24 hours, partition the the reaction mixture between water and ethyl acetate. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([O:18][CH2:17][C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])([CH3:20])[CH3:19])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)c1ccccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (1.4 g) was added portionwise to a stirred solution of 2-(2-fluorophenyl)-2-methylpropan-1-ol (example 90, step d) (1.3 g) and imidazole (0.631 g) in DMF (7 mL) at 20° C. The reaction mixture was stirred for 3 hours at room temperature and then partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 100% isohexane to 1% diethyl ether in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.4 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:28])[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[N:16][C:17]([O:20]CC4C=CC=CC=4)=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].COCCO>[OH:28][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[N:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: Cc1cccc(C2(O)CCN(c3ccc(OCc4ccccc4)nn3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: Cc1cccc(C2(O)CCN(c3ccc(O)nn3)CC2)c1
Yield: 97 %

Procedure:
A mixture of 6.1 parts of 4-(3-methylphenyl)-1-[6-(phenylmethoxy)-3-pyridazinyl]-4-piperidinol and 250 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was boiled in 2-propanol. The product was filtered off and dried, yielding 4.5 parts (97%) of 6-[4-hydroxy-4-(3-methylphenyl)-1-piperidinyl]-3-pyridazinol; mp. 264.6° C. (compound 269).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[C:5](O)=[O:6].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:57]([N:64]1[CH2:69][CH2:68][CH:67]([NH2:70])[CH2:66][CH2:65]1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[CH2:57]([N:64]1[CH2:69][CH2:68][CH:67]([NH:70][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)=[C:2]([Cl:1])[CH:3]=2)[CH2:66][CH2:65]1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(CN2CCC(Oc3ccc(C(=O)O)cc3Cl)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(Oc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a stirred mixture of 3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzoic acid in anhydrous dimethylformamide (0.5 mL) was added triethylamine (0.03 g, 0.30 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.03 g, 0.15 mmol) and 1-benzylpiperidin-4-amine (0.03 mg, 0.15 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=15/1/0.05) to afford N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-methoxybenzyl)-piperidin-4-yloxy)-benzamide as a white solid (0.01 g, 18%). 1H-NMR (CDCl3, 300 MHz): δ 7.76 (m, 1H), 7.60 (m, 1H), 7.30 (m, 7H), 6.94 (m, 1H), 6.87 (m, 2H), 5.83 (d, J=7.2 Hz, 1H), 4.52 (m, 1H), 3.97 (m, 1H), 3.80 (s, 3H), 3.54 (s, 4H), 2.86 (m, 4H), 2.11 (m, 8H), 1.58 (m, 4H); LCMS: >98%; MS (ESI): 548.2 (M+1), 546.2 (M−1).
Reaction SMILES: FC1C=C(S(C)(=O)=O)C=CC=1OC1N=CN=C2N(C3CCC(C4ON=C(C(C)C)N=4)CC3)N=CC=12.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[C:53]3=[N:54][CH:55]=[N:56][C:57](Cl)=[C:52]3[CH:51]=[N:50]2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].[F:59][C:60]1[CH:61]=[C:62]([OH:70])[CH:63]=[CH:64][C:65]=1[S:66]([CH3:69])(=[O:68])=[O:67]>CN(C)C=O>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[C:53]3=[N:54][CH:55]=[N:56][C:57]([O:70][C:62]4[CH:63]=[CH:64][C:65]([S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([F:59])[CH:61]=4)=[C:52]3[CH:51]=[N:50]2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CS(=O)(=O)c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)c(F)c4)ncnc32)CC1
Yield: 43 %

Procedure:
4-[4-(3-Fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared using the procedure described for the preparation of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (Example 129) by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-4-methanesulfonyl-phenol (Intermediate 2) in dimethylformamide. The product was purified by flash chromatography, eluting with 40% ethyl acetate/hexanes to give 4-[4-(3-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (75 mg, 43%) as a white solid. Mass spectrum: Observed 491.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.O>[Cl:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:26])[CH2:9][CH2:8][CH2:7]2
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(Cl)c2CC1)NCCC3
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCCc2cc3c(c(Cl)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 205 mg of t-butyl 11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 3 ml of acetonitrile were added 0.077 ml of 36% formalin, 58 mg of sodium cyanoborohydride, and 0.5 ml of acetic acid, followed by stirring at room temperature. To the reaction mixture was added water, followed by extraction with EtOAc, the organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 96 mg of t-butyl 11-chloro-1-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as an orange viscous substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21]([O:23][C:24](=[O:46])[CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=2)=[CH:32][CH:31]=1)[C:27]#[C:28][CH3:29])[CH3:22]>C(#N)C>[N:1]1([CH2:44][C:41]2[CH:40]=[CH:39][C:38]([CH2:37][O:36][C:33]3[CH:34]=[CH:35][C:30]([C@@H:26]([C:27]#[C:28][CH3:29])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:46])=[CH:31][CH:32]=3)=[CH:43][CH:42]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2ccc(CBr)cc2)cc1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CN3CCC4(CCc5ccccc54)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2,3-dihydrospiro[indene-1,4′-piperidine] (0.37 g, 1.68 mmol) in acetonitrile (20.0 mL), is added Cs2CO3 (1.37 g, 4.21 mmol at room temperature, followed by the addition of 3-[4-(4-bromomethyl-benzyloxy)-phenyl]-hex-4-ynoic acid ethyl ester (0.70 g, 1.68 mmol). The reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The crude product is purified by silica gel column chromatography (gradient 3% methanol in DCM) to give the title compound as colorless gel, (0.82 g, 93.7%). ESI/MS 522.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Product: COc1cccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)c1
Yield: 44.4 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(3-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to obtain the title compound 340 mg (yield 44%) as an oily substance.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OC(C)=O)(C)C>[CH2:24]([NH:31][C:3](=[O:4])[C:2]([F:10])([F:1])[CH2:6][C:7]([OH:9])=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: O=C(O)CC(F)(F)C(=O)NCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a solution of 2,2-difluorosuccinic acid (2.15 g, 14.0 mmol) in iPrOAc (23 mL) was added trifluoroacetic anhydride (2.34 mL, 16.7 mmol) in one portion at ambient temperature. The reaction solution was stirred at 50° C. for 2 hr. The reaction solution was allowed to cool to 5° C. in an ice bath. Benzyl amine (2.29 mL, 20.9 mmol) was added dropwise while the reaction temperature was maintained below 20° C. The solution was stirred at ambient temperature for 2 hr. The reaction was quenched with water (10 mL) followed by saturated Na2CO3 to pH 8-9. The separated organic phase was discarded. The aqueous phase was acidified with 6 N HCl to pH 1 and extracted with EtOAc (2×100 mL). The combined organic phase was washed with 2 N HCl, brine (100 mL), dried over MgSO4 filtered and concentrated. The intermediate was carried forward without further purification (2.89 g, 56.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.42 (m, 5 H) 7.14-7.21 (m, 1 H) 6.77 (br. s., 1 H) 4.54 (d, J=5.87 Hz, 2 H) 3.39 (t, J=14.18 Hz, 2 H).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].Cl.C[O:7][C:8]1[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2>C1(C)C=CC=CC=1>[ClH:2].[OH:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC1CCc2c(ccc(O)c2O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41.4 g of dry AlCl3 (310.4 moles), 230 ml of toluene and 20.0 g of 5,6-dimethoxy-2-methylaminotetralin HCl (77.6 moles) are placed into a 4-necked round-bottomed flask, with stirring, under a slight stream of dry nitrogen. Temperature is brought to 80° C. to obtain a stirrable brown mixture, is left at 80° C. for 4 hours, then cooled to room temperature and poured into ice-water (about 1000 ml total). The aqueous phase is separated and evaporated under vacuum (T about 80° C.). The whitish solid is triturated at room temperature in 750 ml of absolute ethanol, then dried at 60° C. Yield: 16.1 g, 90% (moles), 80% (weight); M.P.>280° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=[O:21])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:21])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The product from Example 30B was subjected to the conditions outlined in Example 26F, followed by chromatography (7:3 hexane/ethyl acetate) to provide the title compound
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH:3]([CH3:5])[CH3:4].C1COCC1.Br[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[Cl:24]>>[Cl:24][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:13]=1[CH2:2][CH:3]([CH3:5])[CH3:4])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(Br)c(Cl)c1
Reactant: CC(C)C[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(C)C)c(Cl)c1

Procedure:
A solution of isobutylzinc bromide in THF (0.5 M, 30 mL, 15.0 mmol) was added under argon to ethyl 4-bromo-3-chlorobenzoate (D16) (2.00 g, 7.60 mmol) and then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (930 mg, 1.14 mmol) was added. The reaction was heated to reflux for 4.5 h. The mixture concentrated in vacuo and the residue partitioned between ethyl acetate (125 mL) and water (125 mL). A solid formed, which was filtered off and discarded. The organic layer was washed with water (100 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by silica chromatography, eluting with 0-5% EtOAc in hexane over 30 minutes to give the title compound as a colourless oil (1.76 g, 7.33 mmol). δH (d6-DMSO, 400 MHz): 7.91 (1H, d), 7.80 (1H, dd), 7.46 (1H, d), 4.30 (2H, q), 2.66 (2H, d), 1.88-2.01 (1H, m), 1.32 (3H, t), 0.89 (6H, d).