Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([OH:27])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:3]=12.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension of 2-(4-chloro-3-(4-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (150 mg, 0.39 mmol) in CH2Cl2 (3 mL) were added morpholine (34 mg, 0.39 mmol), diisopropylethylamine (DIPEA) (200 μL, 1.2 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (180 mg, 0.47 mmol). The solution obtained was stirred at room temperature for 75 min before being purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane) followed by preparative HPLC yielding Compound 75 as a clear glass solid (11.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:65])=[O:60]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@H](NC(=O)OC)c3ccccc3)[nH]2)ccc1-4)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (80 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (1.5 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (29 mg, 0.14 mmol) and COMU (52 mg, 0.12 mmol). To the resulting solution was added diisopropylethylamine (0.057 mL, 0.33 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate: (42 mg, 45%). LCMS-ESI+: calculated for C48H52N8O7: 852.4; observed [M+1]+: 854.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(C)(=O)=O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (833 mg, 1.86 mmol) in anhydrous CH2Cl2 (27 ml) was added methanesulfonyl chloride (0.95 ml, 12.2 mmol) and Triethylamine (2.34 ml, 16.3 mmol). The reaction stirred at room temperature for 2 hours, was diluted with dichlormethane and washed with sat. NaHCO3, and brine, dried and filtered to give a yellow oil. Purification by silica gel chromatography (Isco) gave the product as an off white solid, (662 mg, 68% ). Calcd for C27H34FNO4S (M+H) 525.62, Found 526.3
Reaction SMILES: [CH2:1]([N:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([CH2:13][CH3:14])[C:5]2[CH:15]=[N:16][CH:17]=[CH:18][C:4]1=2)[CH3:2].C(N1CCN(C(=O)C)C2C=CN=CC1=2)(=[O:21])C.N1C=CN=C2C=NC=CC=12.CN1CCN(C)C2C=NC=CC1=2>CCOC(C)=O.CCN(CC)CC>[CH2:1]([N:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([C:13](=[O:21])[CH3:14])[C:5]2[CH:15]=[N:16][CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1c2ccncc2N(CC)C2CCCCC21
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Agent: CN1CCN(C)c2cnccc21
Agent: c1cc2nccnc2cn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN1c2ccncc2N(C(C)=O)C2CCCCC21

Procedure:
29 (0.250 g, 1.15 mmol) and 10 ml of THF were placed in a 100 ml Schlenk flask. The solution was cooled to −78° C., 0.51 ml of n-BuLi (1.27 mmol, 1.1 eq; 2.5 M in hexane) were added and the reaction solution was stirred without cooling for 30 minutes. After 30 minutes, the reaction solution was cooled back down to −78° C. and 0.09 ml (0.109 g, 1.4 mmol, ρ=1.1051 g/ml) of acetyl chloride were added, the cooling bath was removed and the mixture was stirred without cooling for 1 hour. The reaction was subsequently stopped by means of 4 ml and extracted three times with 20 ml of DCM. The combined organic phases were dried over Na2SO4 and the solvent was distilled off on a rotary evaporator. The crude product was purified on silica gel (EtOAc/MeOH, 10:2) to give 48 mg (0.18 mmol, 16%) of a colorless solid. Rf=0.16 (EtOAc/NEt3, 10:1). 1H NMR: (300 MHz, CDCl3): δ=1.19 (t, 3J=7.2 Hz, 3H, H3C—CH2—N-5), 1.24 (m, 2H), 1.45 (m, 2H), 1.58 (m, 2H), 1.74 (m, 1H), 2.18 (m, 1H), 3.34 (m, 2J=14.4 Hz, 3J=7.2 Hz, 1H, H3C—CHAB—N-5), 3.53 (m, 1H, C—H), 3.57 (m, 2J=15.2 Hz, 3J=7.2 Hz, 1H, H3C—CHAB—N-5), 4.90 (bs, 1H, C—H), 6.62 (d, 3J=5.6 Hz, 1H, H-4), 8.12 (s, 1H, H-1), 8.08 (d, 3J=5.6 Hz, 1H, H-3). 13C NMR (100 MHz, CDCl3): δ=12.4 (H3C—CH2—N-5), 18.9 (C-7), 22.8 (H3C—CO—N-10), 24.7 (C-8), 25.8 (C-6), 28.5 (C-9), 40.0 (H3C—CH2—N-5), 48.7 (C-9a), 53.7 (C-5a), (C-4), 106.4 (C-4), 120.1 (Cq, C-10a), 145.1, 145.2 (C-1, Cq, C-4a), 147.1 (C-3), 167.1 (C═O) ppm. GC-MS (EI): RT 10.39 min, m/e (%) 260 (11), 259 (M+, 100), 230 (8), 218 (9), 217 (79), 216 (40), 203 (4), 202 (23), 203 (3), 202 (23), 201 (4), 189 (6), 188 (31), 187 (4), 186 (3), 174 (11), 162 (4), 161 (6), 160 (5), 158 (4), 148 (5), 146 (6), 136 (3), 132 (4), 131 (12), 120 (6), 43 (3); IR (neat): ν=3398 (s), 2933 (s), 2863 (m), 1731 (m), 1637 (vs), 1595 (vs), 1512 (s), 1546 (w), 1449 (m), 1397 (s), 1365 (s), 1334 (m), 1285 (s), 1239. (m), 1198 (m), 1168 (vs), 1123 (w), 1067 (w), 1068 (w), 1016 (w), 802 (vs), 718 (w), 668 (m). HRMS (EI): calculated for C15H21N3O 259.1685 [M+], found: 259.1687.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]([NH:29][OH:30])=[NH:28])=[N:19]3)[CH:12]([CH3:32])[CH2:11]2)=[C:4]([F:33])[CH:3]=1.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]4[N:28]=[CH:34][O:30][N:29]=4)=[N:19]3)[C@@H:12]([CH3:32])[CH2:11]2)=[C:4]([F:33])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(C(=N)NO)c4cccnc43)C(C)C2)c(F)cc1Cl
Solvent: COC(OC)OC
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncon4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 248.1 %

Procedure:
A mixture of 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (1.2 g), trimethyl orthoformate (20 ml) and para-toluene sulfonic acid (PTSA) (0.1 g) was stirred at 100° C. overnight. The reaction mixture was concentrated in vacuo to provide a crude residue which was purified by flash chromatography to provide 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-[1,2,4]oxadiazol-3-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (0.7 g). LCMS Retention time: 2.61 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water/94.9% acetonitrile). LCMS observed for (M+H)+: 486.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1>[Cl:30][C:31]1[N:36]=[C:35]([CH2:37][C:5]([C:4]2[C:3]([O:2][CH3:1])=[C:12]([NH:13][C:14](=[O:15])[O:16][CH2:17][CH:18]=[CH2:19])[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH:34]=[CH:33][N:32]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of methyl 2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (123 g, 464 mmol,) in dry THF (800 mL) at −10° C., LiHMDS (1M in THF, 1440 mmol, 1440 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (72 g, 560 mmol) in THF (150 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step E (109.9 g, 67.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.64-13.68 (br, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.15-8.21 (m, 1H), 7.31-7.39 (m, 2H), 7.15-7.18 (m, 1H), 6.87 (d, J=5.3 Hz, 1H), 6.19 (s, 1H), 5.92-6.15 (m, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H), 3.76 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:15]2[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:40])[CH3:8])[CH3:10])[C:19](=[O:20])[N:18]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:33][CH3:34])[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]2=3)=[O:49])=[CH:46][CH:45]=1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)N2C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc3c(OC)ccc4cc(Br)ccc34)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (1.5 g, 2.455 mmol) in pyridine (20 mL) at 0° C. was added terephthalic acid monomethyl ester (884 mg, 4.91 mmol). The mixture was stirred for 10 min at 0° C. and POCl3 (0.472 mL, 5.155 mmol) was slowly added, the cooling bath removed and the mixture stirred at RT. After 16 h the mixture was evaporated and the residue diluted with ice water and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound. The sequence was repeated to provide a total of 4.2 g of the title compound from as an off white solid. LC-MS: 773 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][S:13][C:14]#[N:15]>>[S:13]([CH2:12][O:8][C:6](=[S:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:14]#[N:15]
Reactant: N#CSCCl
Reactant: Cc1ccc(C(O)=S)cc1
Product: Cc1ccc(C(=S)OCSC#N)cc1
Yield: 80 %

Procedure:
20.5 g (0.11 mol) of the K salt of 4-methyl-thiobenzoic acid and 11.7 g (0.11 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 22.5 g of a light powder resulted and, after recrystallisation from ligroin, 18 g of white crystals resulted; melting point 55° (this corresponds to a yield of 80% of the theoretical conversion).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]Br)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:19]([NH2:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22].C([O-])(=O)C.[Na+]>O>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]([NH2:28])=[O:27])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccccc1N
Reactant: Oc1ccc(N2CCN(CCBr)CC2)cc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccccc1NCCN1CCN(c2ccc(O)cc2)CC1
Yield: 40 %

Procedure:
A mixture of 61 g 1-(p-hydroxyphenyl)-4-(2-bromoethyl)piperazine dihydrobromide, 18.5 g anthranilamide, 33.5 g sodium acetate, and 250 ml water was refluxed 16 hours, cooled, filtered and the solid washed with water and isopropanol. The solid was suspended in water and made alkalline with Na2CO3. The solid was filtered, suspended in 75% ethanol and added dilute HCl until acidic. The solution was cooled and the solid filtered and recrystallized from 1200 ml water to give 18.5 g product, m.285°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([OH:18])[C:10]=1[O:19][CH3:20])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:31](OS(OCC)(=O)=O)[CH3:32].C(#N)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH2:31][CH3:32])[C:10]=1[O:19][CH3:20])=[O:8]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC

Procedure:
A mixture of 66B (1.15 g), potassium carbonate (1.0 g), diethylsulfate (0.54 g) and acetonitrile (20 ml) is heated to reflux for 3 hours. Upon cooling to room temperature water is added. The solid material is collected and the residue is re-crystallized from methanol yielding white crystals, 1.07 g (85.6% ), mp 131-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:10].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=O.C>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][C:11]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH3:10]
Reactant: COC(=O)C=O
Reactant: COc1ccc(N)cc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CNc1ccc(OC)c(C)c1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 4-methoxy-3-methylaniline (5 g, 0.0364 mol), methyl glyoxylate (5.5 g, 0.0619 mol) and palladium over charcoal (3.7 g; 10%) in methanol (300 ml) was stirred under a hydrogen atmosphere for 1 hour. The suspension was filtered through hyflo and evaporated to give a yellow solid. This was triturated with ether at ~-78° C. and filtered to give the title compound as a pale yellow solid (3.8 g, 50%) m.p. 69°-71° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1.CN(C)C=O>ClCCl>[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH:69][C:8](=[O:10])[CH:7]([CH:3]3[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]3)[CH3:11])[CH:66]=[CH:67][CH:68]=2)=[N:31]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C(=O)O)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCNC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-piperidyl propanoic acid (0.125 g, 0.796 mmol) in 7 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.190 g, 0.99 mmol). After 10 min at room temperature, 3-{1-perhydro-2H-pyran-2-yl -5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.59 mmol) was then added as a solid followed by 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature overnight. The completion of the reaction mixture was achieved after reacting an additional equivalent of reagents and stirring at room temperature for 24 hours. The crude mixture was partitioned between water and dichloromethane. The crude was not purified (yield not calculated). ES-MS (m/z) 742 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:17][OH:18]>C(O)C.[OH-].[Na+].C1CCCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:17][OH:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: ON=C(Cc1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
This compound was prepared by suitable modification of the procedures described by Niemers and Hiltman, Synthesis, 1976, 593 as follows. To a solution of 1-(2-pyridinyl)-2-phenylethanone (Case and Buttle, J. Org. Chem., 1961, 26, 4415) (49.05 g, 0.249 mol) in 95% ethanol (400 ml) was added a solution of hydroxylamine hydrochloride (51.91 g, 0.747 mol) in 10% sodium hydroxide (200 ml). The solution was heated to reflux under nitrogen for 1.25 hours, and stirred at room temperature for 48 hours. The majority of the solvent was removed and the residue was added to water (500 ml). The aqueous solution was extracted with ether (1×1000 ml, and 3×250 ml). The combined ether extracts were washed with saturated NaCl and dried over MgSO4. Removal of solvent gave 55.61 g of the crude product as a brown solid. The above solid was dissolved in cyclohexane (400 ml) and ether (500 ml) and filtered while hot. The filtrate was concentrated to a volume of 500 ml and cooled to room temperature. The solid which formed was isolated by filtration to yield 20.77 g of 1-(2-pyridinyl)-2-phenylethanone oxime; mp 151°-153° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][CH:35]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 27.7 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.226 mmol), 4-(anilinocarbonyl)phenylboronic acid (60 mg, 0.249 mmol), palladium tetrakistriphenyphosphine(16 mg, 0.014 mmol) and sodium carbonate (58 mg, 0.544 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was by preparative thin layer column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:05) as mobile phase to give cis-N1-phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide (32 mg, 27%). 1H NMR (DMSO-d6) δ 1.60 (m, 4H), 1.73 (m, 2H), 2.08 (m, 2H), 2.19 (s, 3H), 2.28 (m, 11H), 4.84 (m, 1H), 7.12 (m, 1H), 7.38 (m, 2H), 7.81 (m, 4H), 8.16 (d, J=8.30 Hz, 2H), 8.27 (s, 1H), 10.34 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =511.2, Rt=2.41 min.