Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[C:23]([C:29]([OH:31])=[O:30])[NH:24]3)[CH2:16][CH2:15]1.[F:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[C:23]([C:29]([O:31][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:30])[NH:24]3)[CH2:16][CH2:15]1
Reactant: Oc1ccc(F)cc1
Reactant: CN1CCN(c2cccc3[nH]c(C(=O)O)cc23)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3[nH]c(C(=O)Oc4ccc(F)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.8 %

Procedure:
A solution of carbonyl diimidazole (0.95 g, 5.86 mmol, 2.1 equivalents) and 4-(4-Methylpiperazin-1 yl)indole-2-carboxylic acid (0.710 g, 2.74 mmol) in anhydrous tetrahydrofuran (5 mL) was heated at 50° C. under nitrogen for 5 hours. The reaction was cooled to room temperature, and a preformed solution of 4-fluorophenol (2.90 g, 25.9 mmol, 9.4 equivalents) and sodium hydride (60% in oil, 1.17 g, 29.2 mmol, 10,7 equivalents) in anhydrous tetrahydrofuran (15 mL) was added rapidly. The resulting reaction solution was stirred at room temperature under nitrogen for 12 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the resulting solution was extracted with a saturated solution of sodium hydrogen carbonate (2×25 mL). The organic layer was dried (magnesium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 100 g) and elution with 20% methanol in ethyl acetate to afford crude 4-methyl-1-(2-(4-fluorophenoxycarbonyl)-1H-indol-4-yl)piperazine (0.225 g, 0.68 mmol crude, 25% crude).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH:17]1([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][C:11]=2[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]3)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(OC)c1nc2c(cc1C1CC1)CCCN2
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A tube was charged with 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 670 mg, 2.333 mmol), cyclopropylboronic acid (401 mg, 4.67 mmol), tricyclohexylphosphine (6.54 mg, 0.023 mmol), K3PO4 (1733 mg, 8.17 mmol) and dioxane (10 ml) and flushed with argon. Then Pd(OAc)2 (26.2 mg, 0.117 mmol) was added, the tube was sealed and the reaction mixture was stirred at 100° C. for 1 day. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed twice with water. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified twice by normal phase chromatography (40 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 50:50) to give the title compound as an orange solid. (UPLC-MS 3) tR 0.64 min; ESI-MS 249.2 [M+H]+.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])[CH:3]1[O:7][C:6](=[O:8])[CH:5]=[C:4]1[O:9][CH3:10].[Br:21]Br>C(#N)C>[Br:21][C:5]1[C:6](=[O:8])[O:7]/[C:3](=[CH:2]\[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])/[C:4]=1[O:9][CH3:10]
Reactant: BrBr
Reactant: COC1=CC(=O)OC1C(O)c1ccccc1C(F)(F)F
Solvent: CC#N
Product: COC1=C(Br)C(=O)O/C1=C\c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 6 %

Procedure:
A stirred solution of 5-{hydroxy-[2-(trifluoromethyl)phenyl]methyl}-4-methoxy-5H-furan-2-one (2.9 g, 10.1 mmol) in acetonitrile at room temperature is treated dropwise with bromine (0.52 ml, 10.1 mmol), stirred for 24 h and concentrated in vacuo. The resultant residue is diluted with CH2Cl2 and triethylamine (4.25 ml), cooled in an ice bath, treated with methane sulfonyl chloride (1.6 ml), stirred for 0.5 h at ice bath temperatures, allowed to warm to room temperature for 2 h and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. This residue is flash chromatographed (SiO2, hexane/EtOAc as eluent) to afford the title product as a white solid, 0.20 g (6% yield), mp 136-138° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]([CH:36]([CH2:49][CH2:50][C:51]1[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][CH:52]=1)[CH2:37][CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)=O.[Cl-].[NH4+]>CCCCCC.C1COCC1.O.C(OCC)(=O)C>[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1/[CH:10]=[CH:34]/[CH:36]([CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:47][CH:48]=1)[CH2:49][CH2:50][C:51]1[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][CH:52]=1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CCC(C=O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Reaction time: 0.75 h

Procedure:
At 0° C., 2.95 ml (7.39 mmol) of a 2.5 M solution of n-butyllithium in hexane are slowly added dropwise to a solution of 1422 mg (3.2 mmol) of (2-hydroxybenzyl)(triphenyl)phosphonium bromide in 40 ml of THF. The reaction mixture is stirred at this temperature for 45 min. At 0° C., 1080 mg (2.64 mmol) of dimethyl 4,4′-(3-formylpentane-1,5-diyl)dibenzoate in 10 ml of THF are then metered in slowly. The reaction solution is stirred at 0° C. for 5 h, saturated ammonium chloride solution is then added and the mixture is diluted with water and ethyl acetate. The organic phase is separated off and the aqueous phase is extracted two more times with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered, and the solvent is removed to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 169 mg (0.37 mmol, 14% of theory) of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][N:14]=2)[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(C(C)C)C(C)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH:3]1[CH2:2][NH:1][C:30](=[O:32])[N:12]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]=[C:11]12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 210.9 %

Procedure:
A solution of 9a (7.4 g, 28 mmol) and DIPEA (5 ml, 28 mmol) in CH2Cl2 (300 ml) was slowly added to a solution of triphosgene (2.82 g, 10 mmol) in CH2Cl2 (740 ml) and the mixture was stirred at room temperature for 30 min. The organic mixture was washed with saturated aq. NH4Cl and with water. The organic solution was dried and evaporated to give a diastereomeric mixture (1:1) of 10a (6.06 g, 76%).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][C:6]([CH2:10][OH:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18](O)=[O:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:11][CH2:10][C:6]12[CH2:9][C:2]([NH:1][C:18]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][N:12]=3)=[O:19])([CH2:8][CH2:7]1)[CH2:3][CH2:4][CH2:5]2
Reactant: O=C(O)c1cnccn1
Reactant: NC12CCCC(CO)(CC1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC12CCCC(CO)(CC1)C2)c1cnccn1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a solution of (5-aminobicyclo[3.2.1]octan-1-yl)methanol (327 g, 2.1 mmol) and pyrazine-2-carboxylic acid (260 mg, 2.1 mmol) in DMF (10 mL) was added DIEA (680 mg, 5.22 mmol), followed by HATU (800 mg, 2.1 mmol). After stirring at room temperature for an hour, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under rescued pressure to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2/1) to afford 540 mg (100%) of the title compound, N-(5-(hydroxymethyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide as a colorless oil. ESI-MS m/z: 262 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:23][C:24]([F:31])([F:30])[C:25](OCC)=[O:26]>C(#N)C>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25](=[O:26])[C:24]([F:31])([F:30])[F:23])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a solution of 5.07 g (23.7 mM) of tert-butyl 4-aminomethylpiperidine-1-carboxylate and 5.0 ml (35.9 mM) of triethylamine in acetonitrile (40 ml) was added 5.6 ml (47.1 mM) of ethyl trifluoroacetate at room temperature and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The solvent was then distilled off under reduced pressure to provide the title compound as light-yellow solid (6.40 g, 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-bezo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (20%); 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.37 (s, 2H), 8.26 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8.90 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J=8.56 Hz, 1H), 7.40 (s, 1H), 7.22 (d, J=1.87 Hz, 1H), 6.98 (d, J=8.64 Hz, 1H), 6.78 (d, J=8.45 Hz, 1H), 6.55 (s, 1H), 3.86 (s, 3H), 2.16 (m, 2H), 1.95 (m, 2H), 1.24 (s, 6H); MS (m/e) 504.45 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](OCC)=[O:9])=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)cn1
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-fluoropyridine-2-carboxylate (25 g, 148 mmol) in tetrahydrofuran (250 mL) at −78° C. was added dropwise diisobutylaluminum hydride (1.0 M in hexanes; 296 mL, 296 mmol). After 1 h, the reaction was quenched with ethyl alcohol (10 mL). Saturated aqueous sodium potassium tartrate tetrahydrate (1.3 L) was added and the aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered. The solution mixture (1.4 L) was carried onto the next step without concentration. MS 125.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C@@:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CN1C(=O)[C@@]2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21

Procedure:
4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column (CHIRALPAK-IA, Chiral Technologies, Inc.) eluted with 5% acetonitrile in tert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether (1:1). (7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.14 g, 86%) was the first enantiomer to elute and was obtained as a crystalline colorless solid: mp 226-228° C. (acetonitrile/tert-butylmethylether); 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7 Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][C@@H:16]4[F:19])[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[F:19][C@H:16]1[CH2:15][C@H:14]2[CH2:18][C@@H:17]1[C@@H:12]([C:6]1[NH:7][C:8](=[O:11])[C:9]3[S:10][C:2]([C:32]4[CH:31]=[N:30][NH:29][C:28]=4[CH3:27])=[CH:3][C:4]=3[N:5]=1)[N:13]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1c1nc3cc(Br)sc3c(=O)[nH]1)[C@@H](F)C2
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4C[C@H](C[C@@H]4F)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
tert-Butyl (1R*,3S,4R*,5S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylate (300 mg) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (416 mg), sodium carbonate (215 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (55 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was purified by high performance liquid chromatography {column: L-column 2 ODS (20 mm i.d.×50 mm L), mobile phase: 0.1% aqueous trifluoroacetic acid solution/0.1% trifluoroacetic acid-acetonitrile solution}. The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. The residue was collected by filtration and washed with water (3 mL) to give the title compound (106 mg) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(OCC)(=O)C.C1CCCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccc(O)cc1)c1cccc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(c1ccc(OS(C)(=O)=O)cc1)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[1-(3-bromo-phenyl)-vinyl]-phenol (1.5 g, 5.45 mmol, 1.0 eq) in dichloromethane (15 mL), triethylamine (2.26 mL, 16.35 mmol, 3.0 eq) was added and the reaction mixture cooled to 0° C. Then methanesulfonyl chloride (0.465 mL, 6.0 mmol, 1.1 eq) was added dropwise and the mixture was allowed to warm to room temperature and stirred 16 h. The reaction was examined by TLC (ethyl acetate/cyclohexane 20%) which showed complete conversion to the desired product. After night time water was added and organic and water phase were separated. Organic solution was dried over magnesium sulfate filtered and evaporated. The crude was purified by flash chromatography eluting with cyclohexane, then ethyl acetate/cyclohexane 20%. 1.6 g of clean product was obtained as colorless liquid (yield: 65%).
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].C[O:6][CH:7]1[CH2:15]C2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=O.ClCCl.C([O:23][CH2:24][CH3:25])(=O)C.Cl>C1C=CC=CC=1>[OH:6][C:7]1[CH:15]=[C:25]2[C:10]([CH2:11][CH:12]([CH3:13])[C:24]2=[O:23])=[CH:9][CH:8]=1
Reactant: COC1Cc2ccccc2C1=O
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC1Cc2ccc(O)cc2C1=O

Procedure:
To a stirred solution of anhydrous aluminum bromide (69.82 g, 0.261 mole) in anhydrous benzene (250 mL) kept under nitrogen is added dropwise over 30 minutes a solution of the methoxy indanone (18 g, 0.102 mole) of Step C, in benzene (60 mL). The mixture is gently refluxed for 3 hours (TLC, dichloromethane-ethyl acetate 8:2, UV), cooled in an ice bath and treated dropwise with 6N-HCl (ca. 200 mL) to decompose the aluminum complex. The aqueous phase is extracted with ether (3 times), the extracts are concentrated at reduced pressure and extracted with 2.5N-NaOH (2×75 mL and 1×50 mL). The basic extracts are neutralized (ice bath) with concentrated HCl and the oil that separates is extracted with ether (3 times). The combined extracts are washed with brine, dried (MgSO4) and evaporated to yield an oil that readily solidifies. The crude material is flash chromatographed (on silica Merck-60, gradient CH2Cl2, CH2Cl2 -ethyl acetate 85:15 ) to provide the pure title compound (13.60 g, nearly colorless solid, 82%).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1>O1CCOCC1.O.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>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:8][CH:9]=3)[N:4]([CH3:15])[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cn1nc(Cl)c2cnc(NCCO)nc21
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCO)nc21
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a solution of 2-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (244 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhydrous potassium carbonate (443 mg, 3.21 mmol, 3 eq), followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (350 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphosphine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The system was then heated under reflux for 24 hours and cooled to room temperature. The layers were separated. The organic solution was treated with ethyl acetate (50 mL) and water (10 mL). The resulting organic layer was then separated, washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography (100% ethyl acetate) to give 130 mg (42% yield) of pure 2-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol; 1H-NMR (DMSO): δ 3.44 (m, 2H), 3.59 (m, 2H), 3.79 (s, 3H), 4.70 (br s, 1H), 5.32 (br s, 2H), 6.65 (d, 2H, J=8.5 Hz), 7.23 (br s, 1 H) 7.64 (d, 2H, J=8.5 Hz), 9.05 (br, 1H); LC/MS (m/e)=285.4 (MH+), Rt=1.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH:27]1([CH2:32][CH2:33][C:34]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCC1CCCC1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution containing 2.9 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide, 50 parts by volume of acetonitrile and excess aqueous potassium carbonate is added 1.6 parts of 3-cyclopentylpropionyl chloride and the resulting reaction mixture is stirred at room temperature for about 2 days. The solvent is stripped under reduced pressure and the resulting residue is purified by chromatography on a silica gel column, using ethyl acetate-benzene solutions as the eluants. The 5% ethyl acetate in benzene eluate, after removal of the solvents, affords 1-(3-cyclopentylpropionyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, characterized by the following structural formula ##SPC6##
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:20](=[O:38])[C:19]=3[C:18]=2[O:39][CH3:40])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.CO.[OH-].[Na+]>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:20](=[O:38])[C:19]=3[C:18]=2[O:39][CH3:40])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1ccccn1)c1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1ccccn1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 2-[4-({[3-methoxy-1-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl]carbonyl}amino)piperidin-1-yl]-2-oxoethyl acetate (60 mg) in THF (2 mL)-methanol (2 ml) was added 2N sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization from ethyl acetate-diisopropyl ether gave the title compound (25 mg, 45%) as beige crystals.