Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20]C[CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].CNCC[OH:29].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]([CH2:17][CH2:18][OH:29])[CH3:20])=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N(C)CCO)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30), 0.38 g. (0.005 mole) of 2-methylaminoethanol and 0.53 g. (0.005 mole) of sodium carbonate in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from ethyl acetate to afford 0.5 g. of product, m.p. 111°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:17]([C:19]1[C:31](=[O:32])[N:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:37][CH:38]=2)[C:22]2[N:23]=[C:24](S(C)=O)[N:25]=[CH:26][C:21]=2[CH:20]=1)[CH3:18].CCN(C(C)C)C(C)C>C(O)CCC>[CH2:17]([C:19]1[C:31](=[O:32])[N:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:37][CH:38]=2)[C:22]2[N:23]=[C:24]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([N:10]4[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]4)=[CH:9][C:3]=3[O:2][CH3:1])[N:25]=[CH:26][C:21]=2[CH:20]=1)[CH3:18]
Reactant: CCc1cc2cnc(S(C)=O)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Temperature: 85 °C
Yield: 77.4 %

Procedure:
2-Methoxy-4-(4-methylpiperazin-1-yl)aniline (Combi-Blocks Inc, San Diego, Calif., catalog #: SS-3744; 386 mg, 1.75 mmol), tert-butyl (3-(6-ethyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (6a) (680 mg, 1.59 mmol) were treated with tort-butanol (10 mL) and DIEA (0.69 mL, 3.97 mmol) and heated to 85° C. for 14 h in a 250 mL round-bottomed flask with a reflux condenser. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and the crude solid was purified by chromatography on a silica gel column (1-20% MeOH in DCM) affording tert-butyl (3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (6b; 717 mg, 1.23 mmol, 77% yield) as a light brown film. m/z (ESI, +ve ion) 585.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14]
Reactant: COc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1cccc(C)n1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1cccc(C)n1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester CCLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[O:16])=[CH:10][CH:9]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: c1ccoc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)c2ccco2)cc1
Yield: 35.2 %

Procedure:
Furan (5 g, 73.5 mmol) in CH2Cl2 (10 ml) was added to a solution of p-methoxyphenylacetyl chloride (2.21 g, 14.7 mmol) and trifluoromethanesulfonic acid (150 μl) in CH2Cl2 (25 ml) at reflux. The reaction was quenched after 3 hours by pouring the solution over a 10% HCl/ice slurry. The organic layer was washed with 10% aqueous NaOH, dried over MgSO4, and the solvent was removed under reduced pressure. The crude oil was chromatographed ion SiO2 (85 g), eluting with Hexane/EtOAc, 4/1, to give 20 (1.12 g, 35.3%) 41.5°-43.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH:12]=[O:13])=[N:7]2.[Na].CO.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH2:12][OH:13])=[N:7]2
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (113 mg, 0.37 mmol) and sodium triacetoxyhydroborate (78 mg, 0.37 mmol) in THF (7.5 mL) was stirred at 25° C. for 10 min. MeOH (1.0 mL) was added, and the resulting mixture was stirred at 25° C. for 10 min. Additional sodium triacetoxyhydroborate (78 mg, 0.37 mmol) was added, and the resulting mixture was stirred at 25° C. for 10 min. Further sodium triacetoxyhydroborate (78 mg, 0.37 mmol) was added, and the resulting mixture was stirred at 25° C. for 10 min. Saturated aq. NaHCO3 (10 mL) was then added, and the resulting mixture was partitioned between EtOAc (70 mL) and half-saturated aq. NaHCO3 solution (50 mL). The organic layer was separated, and the aq. layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide (5-bromo-3-(tert-butylamino)quinoxalin-2-yl)methanol (114 mg, 0.37 mmol, 100% yield) as a yellow-brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (1H, d, J=7.6 Hz), 7.76 (1H, d, J=8.0 Hz), 7.20 (1H, t, J=7.9 Hz), 5.10 (1H, br. s.), 4.72 (2H, s), 3.92 (1H, br. s.), 1.62 (9H, s). m/z (ESI, +ve) 310.0/312.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C@:3]([OH:8])([CH3:7])[C:4]([OH:6])=[O:5].[N+](=[CH2:13])=[N-]>CCOCC>[F:1][C:2]([F:10])([F:9])[C@:3]([OH:8])([CH3:7])[C:4]([O:6][CH3:13])=[O:5]
Reactant: C[C@](O)(C(=O)O)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (3.0 g, 17.4 mmol) in 60 ml of ether was added a solution of diazomethane in ether until a yellow coloration remained. The reaction mixture was then stirred 30 min at room temperature and concentrated to dryness to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 5.67 (s, 1H), 3.85 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]=[CH:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>ClCCl>[CH3:20][C:21]([Si:24]([CH3:26])([CH3:25])[O:14][CH2:13][CH:12]=[CH:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(SC=CCO)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC=CSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
A solution of a 1.5 to 1 mixture of (E) and (Z) 3-(4-nitrophenylthio)-2-propenol (3.53 g, 16.71 mmol) (JCS, Perkin Trans. I, 1974, 25) in dichloromethane (40 mL) was treated with imidazole (2.28 g, 33.4 mmol) and TBDMSCl (2.77 g, 18.4 mmol), stirred at room temperature for 24 hours, and then partioned between dichloromethane and water. The organic phase was dried, concentrated, and purified on silica gel by flash column chromatography eluting with 8 to 1 hexanes/ethyl acetate to give 5.1 g (94%) of the desired product. Rf: 0.8 (2:1 hexane:ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
3-chlorophenylacetic acid (20.90 g, 122.52 mmol) and NBS (23.50 g, 133.14 mmol) were dissolved in carbon tetrachloride (300 mL), then BPO (300 mg) was added, the resulting reaction was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid. 5.00 g of this acid was then reacted with 3,4-dimethyl benzenethiol (2.85 g, 20.62 mmol) and sodium hydride (60% oil dispersion, 4.50 g, 87.50 mmol) to yield Intermediate 3, which was used in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[Cl:7].C([Li])CCC.CON(C)[C:23](=[O:25])[CH3:24]>C(OCC)C>[Cl:7][C:6]1[S:5][C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][C:2]=1[C:23](=[O:25])[CH3:24]
Reactant: CON(C)C(C)=O
Reactant: Clc1sc(CN2CCOCC2)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 36.1 %

Procedure:
4-((4-Bromo-5-chloro-2-thienyl)methyl)morpholine (Preparation 62, 7.65 g) is dissolved in diethyl ether (75 mL) and is cooled to −75° C. A solution of n-butyllithium (2.5 M in hexane, 11.0 mL) is added via addition funnel, maintaining the temperature below −68° C. The reaction is stirred for 15 minutes at −70° C. and allowed to warm to 0° C. A solution of N-methoxy-N-methylacetamide (3.09 g) in ether (5 mL) is added via addition funnel, maintaining the temperature below 5° C. The reaction is stirred at 0° C. for 1 h and allowed to warm to rt. The reaction is quenched with saturated aq. NH4Cl solution (50 mL) and made basic with sat. aq. NaHCO3. The mixture is extracted with ethyl acetate (3×125 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is chromatographed, eluting with 25% ethyl acetate/heptane to afford 2.42 g (37%) of the title compound. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ7.33, 3.64, 3.58, 2.51; IR (liq.) 2854, 2809, 1673, 1456, 1372, 1351, 1328, 1243, 1212, 1165, 1118, 1034, 1008, 867, 618 cm−1; HRMS (FAB) m/z 260.0506 (C11H14ClNO2S+H). Anal. Found: C, 50.77; H, 5.51; N, 5.35; Cl, 13.24; S, 12.00.
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[O:13][CH2:14][C:15](=[O:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:23])[CH:6]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>C(O)C>[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:14]2[O:13][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][OH:25])=[CH:6][C:7]=3[CH3:23])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:22])=[CH:27]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCC(O)CO)cc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCC(O)CO)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22.5 %

Procedure:
To a stirred solution of ethyl 2-{[4-(2,3-dihydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.17 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.054 g, y. 23%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]CC=C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([O:35]C(OC(C)(C)C)=O)[C:25]([C:43]([F:46])([F:45])[F:44])=[CH:24][CH:23]=1>>[C:31]([O:30][C:28]([C:27]1[C:26]([OH:35])=[C:25]([C:43]([F:44])([F:45])[F:46])[CH:24]=[CH:23][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: C=CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(C(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Yield: 80 %

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (13-5), using allyl 4′-hydroxy-1,1′-biphenyl-4-carboxylate (190 mg, 0.75 mmol) obtained in Example (43-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (400 mg, 0.88 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (293 mg, three-step total yield: 80%).
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]([CH:18]3[CH2:23][CH2:22][N:21]([CH: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].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](Cl)=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42](=[O:43])[C:39]4[CH:40]=[CH:41][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:37][CH:38]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.450 g, 1.03 mmol) in pyridine (8 mL) at −5° C. was treated with a solution of 4-(trifluoromethoxy)-1-benzenecarbonyl chloride (0.231 g, 1.03 mmol) in dichloromethane (2.5 mL) drop-wise. The reaction mixture was stirred at −5° C. for 30 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. 1 N sodium hydroxide solution (10 mL) was added, and stirred for 1 h. The organic solvent was removed under reduced pressure. Dichloromethane (10 mL) was added and the layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure and the crude compound was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent to give 0.430 g (67%) N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (0.430 g, 0.688 mmol) in ethyl acetate (15 mL) was treated with a hot solution of maleic acid (0.240 g, 2.07 mmol) in ethyl acetate. A precipitate was formed, filtered under nitrogen, and dried under high vacuum to give N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide tris-maleate salt.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14]>C1C=CC=CC=1>[CH3:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:14])[CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCNC
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: CN1CCN(C)C1c1ccccc1

Procedure:
Using the method of Birch and Dastur, Austral. J. Chem., 26, 1364 (1973), a solution of 5.5 g of benzaldehyde in 25 ml of benzene was added dropwise to a stirred solution of sym-dimethylethylenediamine in 15 ml of benzene, and heated at 60° for 2 hrs. Evaporation and distillation at 55° (0.35 mm) afforded 6.4 g, identified by nmr.
Reaction SMILES: [O:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH:4]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1cc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-benzo[b]furanbutanol (2 g), 1,6-dibromohexane (7.7 ml), TAB (500 mg) in 50% w/v sodium hydroxide solution (100 ml) was stirred at room temperature overnight. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and concentrated to give an oil. Purification by FCC eluting with hexane:ethyl acetate, 100:0→95:5) gave the title compound as a clear oil (2.1 g) t.l.c. (ether) Rf 0.83.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[CH2:6][OH:7]
Reactant: OCCc1cccc(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: OCC(c1ccccc1)c1cccs1

Procedure:
3-Bromophenethyl alcohol (4 ml, 29.8 mmol) was dissolved in 1,2-dimethoxyethane (225 mL) and mixed with tetrakistriphenylphosphine palladium[0] (2.6 g, 2.25 mmol) at room temperature. The reaction mixture was then added to a solution of 2-thienyl-boronic acid (12.6 g, 99 mmol) and 1N NaHCO3 (90 mL). The reaction mixture was heated to reflux under nitrogen atmosphere for 48 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was dried with MgSO4, filtered through a plug of silica and the solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30% EtOAc/hexane) to yield the title compounds as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: FC(F)(F)c1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-6-trifluoromethyl-pyrimidine (90 mg, 0.41 mmol) in n-butanol (1 mL), was added 4-chloro-phenylamine (52 mg, 0.416 mmol) and DIPEA (72 uL, 0.416). The mixture was stirred at 100° C. for overnight. The LC-MS showed the desired product mass [MS:(ESI), M/Z, 308 (M+1). Retention time: 2.70 min (FA-polar)]. This intermediate was used in situ without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:3]=1[NH:4][CH2:5][CH2:6][S:7][CH3:8].O.O.[Sn](Cl)Cl.Cl.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C(O)C>[CH3:1][C:2]1[C:3]2[N:4]([CH2:5][CH2:6][S:7][CH3:8])[C:27](=[O:28])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSCCNc1c(C)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CSCCn1c(=O)[nH]c2cccc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
To a solution of 2-methyl-N-[2-(methylthio)ethyl]-6-nitroaniline (2.6 g, 12 mmol) in ethanol (6.0 mL) was added a solution of Tin(II) chloride dihydrate (7.9 g, 35 mmol) in concd. hydrochloric acid (8.0 mL) at 0° C. and warmed to rt. After 4h, the reaction was quenched by addition of 6N sodium hydroxide (100 mL) and extracted with ethyl acetate (100 mL×2), dried over sodium sulfate, filtered and concentrated. The crude material was dissolved in THF (50 mL) and to this solution was added CDI (2.3 g, 14 mmol) and the mixture was stirred at rt. After 12 h, to the mixture was added CDI (1.5 g, 6.7 mmol) and the reaction mixture was refluxed for 5 h. Then the mixture was cooled to rt and evaporated to dryness. To this was added water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The obtained material was dissolved in methanol (30 mL) and to this solution was added 2N sodium hydroxide (3 mL) and stirred at rt for 2 h. Then the mixture was quenched by addition of sat. aq. sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20/1-10/1) to afford 1.8 g (69%) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCC(=O)C(Cc1ccc(S(=O)(=O)N2CCOCC2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.26 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (0.25 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of 4-(4-bromomethylbenzenesulfonyl)morpholine (0.53 g) in tetrahydrofuran (10 mL) was added and the resulting mixture warmed to room temperature over 1 hour and then stirred at this temperature for 17 hours. The mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) to afford title compound, 0.41 g.