Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:21][N:20]([CH3:22])[C:12]1([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C1(c2cccs2)CCNCC1
Yield: 88.6 %

Procedure:
HCl gas was passed through a solution of 10 g (1 eq.) tert-butyloxycarbonyl-4-(dimethylamino)-4-(thiophen-2-yl)piperidine in chloroform at 0° C. for ±1 h. Once the conversion was complete, 200 ml water were added to the reaction mixture, it was adjusted to a pH of ˜8 with Na2CO3 and then extracted with 15% IPA/CHCl3. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 6 g (89%) of product were obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[I:17]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[CH2:1]([C:4]([I:17])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)N1I
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(I)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following the method of Flynn and Zabrowski, J. Org. Chem. 55: 3673-3674 (1990), such reference herein incorporated by reference with regard to such synthetic teaching, diethyl allylmalonate (18.0 g, 90.0 mmol) was dissolved in tetrahydrofuran (THF) (50 mL). Sodium hydride (11.5 g, 288 mmol, 60% dispersion in oil) was added to the reaction. After 30 min of stirring at ambient temperature, a solution of N-iodosuccinimide (21.9 g, 97.2 mmol) in THF (100 mL) was added, and the reaction was stirred in the dark at ambient temperature for 15 min. The reaction was poured onto 100 g of silica gel. The contents were diluted with 400 mL of ether and stirred with a glass rod. The contents were then filtered through a bed of silica gel (100 g) in a sintered funnel. The silica gel was washed with ether (4×400 mL). The combined filtrates were concentrated by rotary evaporation to give diethyl 2-allyl-2-iodomalonate, as a yellowish orange liquid, that was used immediately in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH2:37]Cl)[C:32]([NH2:34])=[O:33])[CH2:25][CH2:24]1>CN(C)C=O>[CH3:19][O:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([C:32]([NH:34][CH2:5][CH2:6][CH2:7][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:33])[CH2:35][CH:36]2[CH2:37][CH2:9][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4]2)[CH2:25][CH2:24]1
Reactant: COCOC1CCN(CCN(CCCCl)C(N)=O)CC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOC1CCN(CCN(CC2CCCCCCC2)C(=O)NCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 0 °C

Procedure:
A solution of 1.6 g of 6-hydroxycarbostyril, 1.4 g of potasium carbonate and 4.2 g of N-cyclooctylmethyl-N-[2-(4-methoxymethoxy-1-piperidinyl)-ethyl-N-(3-chloropropyl)urea in 20 ml of dimethylformamide was stirred at 80° C. for 1 day. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 5% methanol/dichloromethane) to obtain 0.76 g of 6-[3-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-cyclooctylmethylamino}carbonylaminopropoxy]carbostyril.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)S(O[CH2:34][C:35]([CH2:46]OS(C(F)(F)F)(=O)=O)([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])(=O)=O>CC#N>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[N:1]3[CH2:46][C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34]3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)C(=O)OCC
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CN([C@@H]2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (247 mg, 0.62 mmol) in CH3CN (2 mL) at −10° C., under N2, was added diethyl 2,2-bis((((trifluoromethyl)sulfonyl)oxy)methyl)malonate INT-26 (3 mL of 0.25 mmol solution in CH3CN). The resulting mixture was warmed to room temperature over 30 min, then heated to 70° C. for 18 h. The mixture was concentrated, dissolved in DCM, and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide 93 mg (28%) of crude (R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate INT-27, which was used in the next step without further purification. LCMS-ESI (m/z) calculated for C30H32N4O6: 544.6. found 545.2 [M+H]+, tR=3.03 min.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[N:19]1[C:23]([N:24]([CH2:26][CH2:27]O)[CH3:25])=[C:22]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[C:21]([C:36]#[N:37])=[N:20]1>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:18][C:10]1[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([Cl:7])[C:9]=1[N:19]1[C:23]([N:24]([CH3:25])[CH:26]=[CH2:27])=[C:22]([S:29]([C:32]([F:35])([F:33])[F:34])(=[O:30])=[O:31])[C:21]([C:36]#[N:37])=[N:20]1
Reactant: CN(CCO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 25 %

Procedure:
To a solution of pyridine (0.186 g, 0.23 mmol) in dichloromethane (10 mL) was slowly added chromium (VI) oxide (0.119 g, 0.12 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 15 minutes before 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2-hydroxy-ethyl)(methyl)amino]-4-[(trifluoromethyl)sulfonyl]-1H-pyrazole-3-carbonitrile (0.200 g, 0.4 mmol) was introduced. The reaction mixture was allowed to stirr at room temperature for two additional hours. It was then concentrated to dryness and then diluted with diethyl ether. The mixture was then filtered through silica gel and then concentrated to afford a pale oil (0.04 g, 0.1 mmol). 19F NMR: −64.37, −80.74.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cc(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)n2)cc1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccc(O)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10−4 mol) in dichloroethane (5 mL) is treated with 1M BBr3 in DCM (896 μL, 8.96.10−4 mol). The mixture is then heated at 80° C. for 4 hours before 1M BBr3 in DCM (896 μL, 8.96.10−4 mol) is added. The reaction mixture is then heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual BBr3. The solvent is evaporated in vacuo and this evaporation step is repeated 3 times. 1M HCl(8 mL) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water/EtOH (3/1, 24 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and with diethyl ether to give-[2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.[NH2:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:14][CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCC1(O)CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC2(O)CCOCC2)c1C
Temperature: 25 °C
Yield: 17.9 %

Procedure:
Under a nitrogen atmosphere 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) was added to a solution of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (17 g, 130 mmol) in DMF (375 mL). Triethylamine (18 mL, 130 mmol) was added slowly and the reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (700 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was washed with water (3×100 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an orange solid. This material was triturated with ethyl acetate to provide 6.38 g of 4-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol as a yellow solid. An additional 4.36 g of product was recovered from the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>>[Cl:15][C:13]1[CH:14]=[C:2]2[C:3](=[CH:11][CH:12]=1)[N:4]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[C:17](=[O:18])[C:16](=[O:22])[NH:1]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Cl)ccc1NC1CCCCC1
Product: O=c1[nH]c2cc(Cl)ccc2n(C2CCCCC2)c1=O
Yield: 63 %

Procedure:
34.5 g (0.15 mol) of 2-amino-4-chloro-N-cyclohexylaniline were refluxed in 500 ml of diethyl oxalate for 4 h. After cooling, the precipitate was filtered off with suction, washed with n-pentane and dried to yield 26.8 g (63%) of the product. Melting point 265°-266° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:22]=[CH:23][CH:24]=3)=[O:17])[C:7]=2[CH:30]=1)#[N:2].O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[O:17])[C:7]=2[CH:30]=1)#[N:2]
Reactant: COC(=O)Cc1cccc(NC(=O)N[C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(CC(=O)O)c2)[C@@H]1O

Procedure:
A solution of (3S-trans)-3-[[[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) amino]carbonyl]amino]-benzeneacetic acid, methyl ester (0.7 g, 1.7 mmol, title compound from Example 24) in methanol (15 ml) under argon was treated with lithium hydroxide hydrate (0.14 g, 3.4 mmol) and the reaction was stirred at room temperature for 16 hours. More lithium hydroxide (two equivalent) was added and the reaction mixture was stirred for 48 hours. It was concentrated in vacuo and the residue was diluted with water (50 ml) and extracted with ethyl acetate. Organic layer was discarded and aqueous layer was acidified to pH~1 with 10% hydrochloric acid and extracted with ethyl acetate (3×100 ml). It was washed with water (100 ml) and concentrated in vacuo. The residue was flash chromatographed on silica gel eluting with methylene chloride/methanol/acetic acid (1800:200:5) to give (3S-trans)-3-[[[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]carbonyl]amino]benzeneacetic acid as a colorless solid (0.5 g, 73.9%), m.p. 135-138° C. (with foaming): 1H NMR (DMSO-d6) δ 8.76 (s, 2 H), 7.62 (m, 2 H), 7.42 (m, 2 H), 7.25 (m, 2 H), 6.96 (d, J=8.3 Hz, 1 H), 6.90 (d, J=7.0 Hz, 1 H), 6.70 (d, J=8.2 Hz, 1 H), 4.77 (m, 2 H), 3.76 (m, 2 H), 1.51 (s, 3 H), 1.28 (s, 3 H); 13C NMR (CDCl3) 172.8, 156.3, 155.9, 140.3, 135.6, 132.7, 132.4, 128.6, 126.0, 122.4, 119.1, 118.8, 117.9, 116.2, 102.7, 80.3, 71.6, 49.4, 26.5, 18.9; IR (KBr) 1132.1, 1267.2, 1491.3, 1559.3, 1611.2, 1659.3, 1713.2, 2228.1, 2980.1, 3379.0 cm-1 ; [α]25D=-6.7° (c=0.683, DMF).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[C:19]([NH2:20])=[CH:18][NH:17][N:16]=1)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:12][C:13]([C:15]1[C:19]([NH:20][C:8](=[O:10])[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:18][NH:17][N:16]=1)=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1n[nH]cc1N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1n[nH]cc1NC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A mixture of p-toluic acid (272 mg), 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (310 mg), EDC (460 mg) and HOBt (324 mg) in DMF (8 ml) was stirred at ambient temperature for 48 h. The mixture was reduced in vacuo, partitioned between EtOAc and saturated aqueous NaHCO3 and then the organic portion washed with brine, dried (MgSO4) and reduced in vacuo to give 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester (486 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL), and acetic acid (0.070 mL) was added NaBH3CN (0.63 mmol) in methanol (1.3 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5/1 (6 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (44 mg, 53%): ESI/MS m/e 596.3 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13](Cl)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]1([CH:35]=[CH:34][CH:33]=[C:31]([OH:32])[CH:30]=1)[OH:29].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:33]3[CH:34]=[CH:35][C:28]([OH:29])=[CH:30][C:31]=3[OH:32])[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Temperature: 85 °C
Yield: 97.2 %

Procedure:
To a 2-neck flask equipped with a reflux condenser, an argon inlet, a magnetic stirring bar and a glass stopper was introduced 3.79 g of 2,4-bis(4-tert-butylphenyl)-6-chloro-1,3,5-triazine of example 1. To it was added 30 mL of chlorobenzene, 1.21 g of resorcinol and 2 g of aluminum chloride at room temperature. The reaction mixture was heated at 85° C. for 6 hr. The heating was discontinued and the reaction was allowed to cool to room temperature. To it was then added 5% ice-cold aq. HCl, and the mixture concentrated under reduced pressure. The residue was washed with water and dried to give 4.4 g of a product characterized to be 2,4-bis(4-tert-butylphenyl)-6-(2,4-dibydroxyphenyl)-1,3,5-triazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.CCN(CC)CC.[Cl:38][CH:39]([CH2:43]Cl)[C:40](Cl)=[O:41]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[C:39]([Cl:38])=[CH2:43])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Reactant: O=C(Cl)C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(Cl)C(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 463 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.28 mL (2.0 mmol) of Et3N in 8 mL of THF was added 0.131 mL (1.2 mmol) of 2,3-dichloropropanoyl chloride. The solution was stirred 0.5 h, warming to ambient temperature. The solution was quenched with water and filtered. The solid was washed with 0.1 N aq. HCl, then water, then 1:1 hexanes-ether. The product was air-dried briefly to afford 390 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-chloroacrylamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1H NMR (300 MHz, DMSO) δ 12.49(br. s, 1H); 10.14(br. s, 1H); 7.97(s, 2H); 7.53(d, 2H, J=8.4 Hz); 7.22(d, 2H, J=8.4 Hz); 6.36(d, 1H, J=2.6 Hz); 6.03(d, 1H, J=2.5 Hz); 3.82(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17]O)=[CH:11][CH:10]=1.[OH-].[Na+].[OH-].[NH4+]>>[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][O:6][CH3:7])=[CH:11][CH:10]=1
Reactant: OCC#Cc1ccc(I)cc1
Reactant: COS(=O)(=O)OC
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: COCC#Cc1ccc(I)cc1
Reaction time: 2.5 h
Yield: 92 %

Procedure:
Dimethylsulphate (2.2 g) was added dropwise over 5 min to a vigorously stirred mixture of the product of stage (i) (3.0 g), TAB (0.15 g) 50% w/v aqueous sodium hydroxide (2.8 ml) in H (10 ml) and MC (5 ml) and stirring was continued for a further 2.5 h. Concentrated ammonium hydroxide solution (5 ml) was added and the mixture was stirred for 30 min to destroy the excess dimethylsulphate. Water (50 ml) was added, the mixture extracted with ER (2×35 ml), the organic layer dried and concentrated in vacuo at 35° to afford a brown oil. This was purified by FCC eluting with ER-CX (1:10) yielding the title compound as a cream crystalline solid (2.91 g) m.p. ca20°. T.l.c. (ER-H 1:8) Rf 0.44.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([OH:27])=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:5]=[C:6]2[C:10]=1[N:9]([C:25]([C:21]1[O:20][CH:24]=[CH:23][CH:22]=1)=[O:27])[N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccco1
Reactant: Nc1cc(F)c2[nH]nc(/C=C/c3cccnc3)c2c1
Product: O=C(Nc1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(=O)c1ccco1)c1ccco1
Yield: 37.9 %

Procedure:
Following amidation using 217 mg of 7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-ylamine and 286 mg of 2-furancarboxylic acid in accordance with the method of Example 127, purification by LC-MS was carried out, to afford 143 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([S:18]([OH:21])(=O)=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([S:18]([Cl:24])(=[O:21])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)O)cc1OC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)Cl)cc1OC(=O)c1ccccc1

Procedure:
A solution of 3-benzoyloxy-4-methoxybenzenesulfonic acid (7.69 g) in dry toluene (70 mL) is treated with thionyl chloride (9 mL), and the mixture is heated at reflux for 6 hours. Concentration gives 3-benzoyloxy-4-methoxybenzenesulfonyl chloride (8.4 g), in the form of a brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:47])([F:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:34][CH:33]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([N:6]1[C@@H:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3][C:2](=[O:1])[C@H:7]1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:46])([F:47])[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[CH:36][CH:37]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(F)(F)c1ccc(C[C@@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution at −78° C. of benzyl (2R, 3S)-(−)-6 oxo-2,3 diphenyl-4 morpholine carboxylate (10.5 g) and tert butyl 2-{4-(bromomethyl)phenyl}-2,2-difluoroacetate (6.2 g) and HMPA 55 mL in THF 550 ml. was added LiHMDS (28 mL, 1 M in THF) over a period of 1 hour 20 minutes. The reaction mixture was stirred further at −78° C. for 1 hour.