Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.3 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18; 5.4 g, 19.4 mmol) was added to a solution of 4-bromobenzoic acid (3.5 g, 17.4 mmol) and 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17; 4.3 g, 20.9 mmol) in DMF (100 ml) and stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The organics were washed with a saturated aqueous solution of sodium hydrogen carbonate, water, 1M aqueous hydrochloric acid, water and brine, before being dried over magnesium sulfate. The organics were then evaporated to give the title compound (7.1 g, quantitative), which was used without further purification. NMR Spectrum: (DMSO-d6): 1.45 (s, 9H), 7.18 (m, 2H), 7.54 (m, 2H), 7.76 (d, 2H), 7.90 (d, 2H), 8.63 (s, 1H), 9.86 (s, 1H); Mass Spectrum: (M+H+-Boc) 291.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:17]/[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Solvent: C1CCOC1
Product: CN(C)/C=C/c1ccc([N+](=O)[O-])cc1Cl

Procedure:
A reaction mixture of 8.49 g (48 mmol) of 2-chloro-4-nitrotoluene and 15.03 mL (72.8 mmol) of tert-butoxybis(dimethylamino)methane in 200 mL of THF is refluxed for 8 hours. The reaction solution is evaporated down and the residue is combined with petroleum ether. The precipitate is filtered off, rinsed with petroleum ether and dried at ambient temperature under a high vacuum. The product is used in other reactions without further purification. Yield: 11 g, C10H11ClN2O2 (M=226.66); calc.: molecular ion peak (M+H)+: 227/229; found: molecular ion peak (M+H)+: 227/229; Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate (3:1)).
Reaction SMILES: [P:1]([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:22])[CH3:21])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].CCO.[OH-].[Na+:54]>[Pd].O>[P:1]([O-:11])([O-:3])([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:21])[CH3:22])=[O:2].[Na+:54].[Na+:54]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCc4ccccc4)OCc4ccccc4)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)([O-])[O-])nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
A 1 L round bottom flask was charged with (R)-dibenzyl 2454243-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (24) (9.37 g, 13.61 mmol), EtOH (300 mL), water (150 mL), Pd/C (10 wt % dry basis, wet, Degussa type, 3 g) and 1 M aqueous NaOH (27.22 mL, 27.22 mmol). The suspension was evacuated for 3 min (needle to pump) then placed under an atmosphere of hydrogen gas (balloon). After stirring 2.5 h at 23° C., the reaction was filtered through a 0.22 μm PES membrane (disposable Corning filter system, 1 L, polystyrene, #431098) to remove catalyst and washed with EtOH (50 mL). The resulting solution was concentrated, the residue dissolved in water (80 mL), treated with MeCN (80 mL), then frozen and lyophilized to give disodium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (W) (7.10 g, 12.81 mmol, 94.12%) as a white solid. ESMS (M+1)=509.3; 1H NMR (300 MHz, D2O) δ 8.58 (s, 2H), 6.92 (d, J=6.3 Hz, 1H), 5.13 (t, J=7.5 Hz, 1H), 3.98-3.81 (m, 2H), 3.04 (q, J=7.2 Hz, 2H), 2.26 (t, J=5.7 Hz, 1H), 1.97-1.92 (m, 2H), 1.67 (s, 6H) and 1.01 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([C@H:5]([NH:47][C:48]([O:50][CH3:51])=[O:49])[C:6]([NH:8][C@H:9]([C@@H:17]([OH:46])[CH2:18][N:19]([NH:33][C:34]([C@@H:36]([NH:41][C:42]([O:44][CH3:45])=[O:43])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:32]=2)=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])[CH3:3].[S:52](=[O:56])(=[O:55])([OH:54])[OH:53].CC([C@H](NC(OC)=O)C(N[C@H]([C@@H](O)CN(NC([C@@H](NC(OC)=O)C(C)(C)C)=O)CC1C=CC(C2C=CC=CN=2)=CC=1)CC1C=CC=CC=1)=O)(C)C.OS(O)(=O)=O.CCCCCCC>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[CH3:4][C:2]([C@H:5]([NH:47][C:48]([O:50][CH3:51])=[O:49])[C:6]([NH:8][C@H:9]([C@@H:17]([OH:46])[CH2:18][N:19]([NH:33][C:34]([C@@H:36]([NH:41][C:42]([O:44][CH3:45])=[O:43])[C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:32]=2)=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:1])[CH3:3].[S:52](=[O:54])(=[O:53])([OH:56])[O-:55]
Reactant: O=S(=O)(O)O
Agent: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Solvent: CCO
Solvent: CCCCCC
Solvent: CCCCCCC
Product: O=S(=O)([O-])O

Procedure:
The Form E3 is prepared by slurrying atazanavir free base in ethanol; treating the slurry with concentrated sulfuric acid employing a molar ratio of acid: free base with the range from about 1:1 to about 1.1:1, heating the resulting solution at from about 30 to about 40° C., seeding the solution with ethanol wet E3 crystals of atazanavir sulfate, treating the mixture with heptane (or other solvent such as hexane or toluene), filtering, and drying to yield atazanavir bisulfate Form E3 (triethanol solvate).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.C([O-])(=O)C.[Na+].[C:18]1([C:24]2[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OC(=O)C)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:12][C:10](=[O:11])/[C:9](=[CH:29]/[C:27]2[O:28][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:25][CH:26]=2)/[N:8]=1
Reactant: O=Cc1ccc(-c2ccccc2)o1
Reactant: O=C(O)CNC(=O)c1ccco1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccco2)=N/C1=C\c1ccc(-c2ccccc2)o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
As illustrated in Scheme 2, N-2-furoylglycine (131 mg, 0.776 mmol) is suspended in acetic anhydride (1 mL) and sodium acetate (76 mg, 0.931 mmol) and 5-phenylfuraldehyde (170 mg, 1 mmol) are added. The reaction mixture is shaken at 60° C. for one hour, and cooled to 0° C. The resulting orange solid is filtered and washed with ice water (75 mL) and heptane (50 mL). The solid is then dried under vacuum at 40° C. to afford 79 mg of (4Z)-2-(2-furyl)-4-[(5-phenyl-2-furyl)methylene]-1,3-oxazol-5(4H)-one which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Agent: Cl
Product: CCCC1(C)C(=O)N(C2CCN(S(=O)(=O)c3cccc(C)c3)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B8*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2--Chloro-5-nitro benzene sulphonic acid (484 parts) was charged to a flask then quickly added thionyl chloride (1190 parts) and dimethyl formamide (12 parts). The resultant slurry was heated to 60° C. and stirred at 60°-65° C. for a total of 5 hours. The mixture was cooled to room temperature then poured onto ice/water. The precipitated solid was filtered off and washed with cold water before drying in vac oven to yield the product 2-chloro-5-nitro benzene sulphonylchloride (395 parts).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)(F)F)ccc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 33.1 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.064 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.10 (s, 2H), 7.30 (s, 1H), 7.53-7.63 (m, 2H), 8.45 (s, 2H), 8.87 (d, J=6.6 Hz, 1H), 10.20 (s, 1H), 11.02 (br s, 1H), 11.59 (br s, 1H); MS [M+H]+: 551.97.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[N:11]O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[ClH:13]>CO>[ClH:13].[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: ON=Cc1ccc2[nH]cnc2c1
Agent: Cl
Solvent: CO
Product: NCc1ccc2[nH]cnc2c1
Reaction time: 3 h

Procedure:
1H-benzo[d]imidazole-5-formaldehyde oxime (0.55 mmol, 1 eq.) was dissolved in 10 mL methanol and 300 μL of concentrated hydrochloric acid was added. The mixture was flushed with argone and palladium on activated carbon (10% Pd) was added to the solution. The mixture was hydrogenated at 4 bar for 3 hours. The resulted mixture was filtrated through a pad of celite, the solvent was removed and the residue was dried over phosphorus pentoxide in a exsiccator to give a white solid.
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([Br:36])=[CH:13][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:36][C:14]1[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Br)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Br)cn1
Temperature: 25 °C
Reaction time: 63 h
Yield: 67 %

Procedure:
To an ethanol (2 ml) solution of t-butyl[5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate (130 mg, 0.227 mmol) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added saturated sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (72 mg, 0.152 mmol, 67%) as a pale yellow powder.
Reaction SMILES: [O:1]1CCC(C(O)=O)C1.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[CH:18]1([NH:17][C:16](=[O:1])[NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCOC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 3.16 g of tetrahydro-3-furoic acid (27 mmol; 1 equiv.) in 25 mL anhydrous dichloromethane was added 7.85 g of dicyclohexylcarbodiimide (38 mmol; 1.4 equiv.) and 4.54 mL triethylamine (32.6 mmol; 1.2 equiv.). N-methyl-methanolamine hydrochloride was then added, followed by 60 mg of DMAP (4-dimethylamino)pyridine. An exothermic reaction ensued and a further 25 mL of dichloromethane were added. The mixture was stirred at ambient temperature overnight, then filtered through diatomaceous earth and concentrated. The residue was treated with ether and the white solid filtered off and removed. The solvent was removed from the mother liquor and the residue purified by column chromatography on SiO2 using 15-25% EtOAc in hexanes as eluent mixtures to provide the desired amide as a colorless oil (55% of theoretical yield) that still contained 10% of dicyclohexyl urea. This was used without further purification in the next reaction.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:23]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)=[C:18]3[CH:17]=[N:16]2)=CC=1.[Li+].[OH-].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.CCOCC>[C:37]1([C:22]2[C:23]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[C:18]3[CH:17]=[N:16][NH:15][C:19]3=[N:20][CH:21]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
TFA (3 mL) was added to tert-butyl 4-(1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.7 g, 3.40 mmol, see Example 1) in DCM (10 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness and dried under vacuum for 3 hours. TFA (13.1 mL, 170 mmol) was then added, and the mixture was heated at 65° C. for 1 hour. The reaction was then concentrated to dryness. The resulting residue was added to THF (10 mL), an aqueous LiOH solution (6.81 mL, 2M) and Boc2O (2.23 g, 10.2 mmol) and stirred at room temperature for 3 days. Ether (50 mL) was then added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.1 g, 85%) as a solid. MS APCI (+) m/z 380.1 detected.
Reaction SMILES: [C:1]([C:3]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[CH2:13][N:14]([CH2:22][CH:23]=C)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])#[N:2].O=[O+][O-].CSC.Cl.[NH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C([BH3-])#N.[Na+]>CO.CCOC(C)=O>[C:17]([O:16][C:15]([N:14]([CH2:13][CH:7]1[C:8]2[C:4](=[C:3]([C:1]#[N:2])[C:11]([F:12])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[CH2:22][CH2:23][NH:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:21])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CN
Reactant: C=CCN(CC1CCc2c1ccc(F)c2C#N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=[O+][O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CSC
Product: CCOC(=O)CNCCN(CC1CCc2c1ccc(F)c2C#N)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of tert-Butyl [(4-cyano-5-fluoro-2,3-dihydro-1H-inden-1-yl)methyl]prop-2-en-1-ylcarbamate (45 mg, 0.14 mmol) in MeOH (5 mL) was bubbled ozone until the solution turned blue. Excess ozone was removed by bubbling nitrogen through. To the reaction was then added DMS (0.50 ml, 6.8 mmol), and it was allowed to warm to RT. The solvent was removed under reduced pressure, and the resulting material was further treated with ethyl aminoacetate hydrochloride (13 mg, 0.090 mmol) and sodium cyanoborohydride (6.0 mg, 0.090 mmol). When LC showed the reaction was done, the reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, and purified by MPLC to deliver the title product. LC-MS (IE, m/z): 420 [M+1]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=3[Cl:44])=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(Cl)cc2Cl)CC1
Yield: 32.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.23 g) as starting compound, potassium carbonate (0.34 g) and 6-bromo-1-(2,4-dichlorophenyl)-1-hexanone (0.20 g) were reacted and treated in the same manner as in Example 172 to give 0.11 g of 4-amino-5-chloro-N-((1-(6-(2,4-dichlorophenyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]3[O:21][CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].I[C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[O:21]1[C:20]2[CH:25]=[CH:26][C:17]([CH2:16][CH2:15][C:13]3[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=4)[CH:14]=3)=[CH:18][C:19]=2[O:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccc3c(c2)OCCO3)cc1N
Reactant: Oc1cccc(I)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccc3c(c2)OCCO3)cc1Nc1cccc(O)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-(2-(2,3-dihydro[1,4]benzodioxin-6-yl)ethyl)benzoate 0.14 g were added 3-iodophenol 0.22 g, cesium carbonate 0.52 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg at room temperature, and it was stirred at 110° C. for 6 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 18 hours and 30 minutes. 3-iodophenol 0.22 g, cesium carbonate 0.52 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 22 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-(2-(2,3-dihydro[1,4]benzodioxin-6-yl)ethyl)-2-((3-hydroxyphenyl)amino)benzoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH2:15])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1.CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:29]([C:28]1[CH:27]=[C:26]([C:24](=[O:25])[CH2:23][C:22]([NH:15][C:13]2[CH:14]=[C:9]([N:5]3[CH:6]=[CH:7][CH:8]=[C:4]3[CH2:3][O:2][CH3:1])[CH:10]=[CH:11][C:12]=2[N+:16]([O-:18])=[O:17])=[O:21])[CH:33]=[CH:32][CH:31]=1)#[N:30]
Reactant: COCc1cccn1-c1ccc([N+](=O)[O-])c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COCc1cccn1-c1ccc([N+](=O)[O-])c(NC(=O)CC(=O)c2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from 5-(2-methoxymethyl-pyrrol-1-yl)-2-nitro-phenylamine (Example F8) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a light brown solid (620 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([OH:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2]
Reactant: CCCCCC1CCC(c2ccc(OCC)c(F)c2F)CC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCC1CCC(c2ccc(OCC)c(F)c2F)CC1=O

Procedure:
48.2 g of 5-(4-ethoxy-2,3-difluorophenyl)-2-pentyl-cyclohexanol were dissolved in 600 ml of dichloromethane, and 30 g of Celite were added. 35.6 g of pyridinium chlorochromate were added with stirring, and the mixture was stirred at RT overnight. Conventional work-up gave 5-(4-ethoxy-2,3-difluorophenyl)-2-pentyl-cyclohexanone.