Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(Cl)ccc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 62.6 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,5-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.95 g, 6.06 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.5 g, 8.18 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.35 g, 70%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[C:16]([Br:24])=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:26])=[C:17]3[C:16]([Br:24])=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Temperature: 120 °C

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate C) (9 g, 61% purity) was mixed with dioxane (100 ml) and ammonium hydroxide (100 ml) in a pressure vessel. The mixture was heated to 120° C. overnight. Solvent was removed and the residue was purified via flash column chromatography using ethyl acetate as the mobile phase to give 1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.94 (d, J=11.23 Hz, 2H), 2.21(m, 2H), 2.35 (m, 2H), 3.04 (d, J=11.48 Hz), 3.57 (s, 2H), 4.71 (m, 1H), 5.98 (s, 2H), 7.34(m, 5H), 8.33 (s,1H); LC/MS (MH+=389).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:9][O:8][C:5]1[N:4]=[C:3]([NH2:10])[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Br)c(N)n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2)c(N)n1
Temperature: 110 °C
Yield: 70.7 %

Procedure:
A mixture of 330 mg (1.625 mmol) 3-bromo-6-methoxy-pyridin-2-yl-amine, 396 mg (3.25 mmol) phenylboronic acid, 1 ml 2N Na2CO3 and 59 mg (0.08 mmol) dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloromethane adduct in 10 ml dioxane was heated to 110° C. for 2 h. The mixture was concentrated, diluted Na2CO3 aq. was added and extracted 2× with 100 ml diethyl ether. The combined organic phases were dried with MgSO4 and evaporated. The residue was purified by flash column chromatography on silica-eluting with a gradient of hexane/ethyl acetate to yield 230 mg (71%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:30][CH2:31][OH:32])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[ClH:81]>O1CCOCC1.CC(O)C.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]>[ClH:1].[Cl:81][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:21][C:22]4[CH:23]=[C:24]([NH:29][CH2:30][CH2:31][OH:32])[N:25]=[C:26]([CH3:28])[N:27]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]3=[N:10]2)=[C:12]([CH:15]=[C:16]([F:19])[CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cc(F)ccc1-n1cc2c(Cl)ncc(F)c2n1
Reactant: Cc1nc(N)cc(NCCO)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1nc(NCCO)cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(F)cc4C#N)cc23)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A mixture of 2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-fluorobenzonitrile (185 mg, 0.5 mmol), 2-(6-amino-2-methylpyrimidin-4-ylamino)ethanol (101 mg, 0.6 mmol), Pd2(dba)3 (11 mg, 0.0125 mmol), Xantphos (29 mg, 0.05 mmol) and cesium carbonate (326 mg, 1.0 mmol) in dioxane (5 mL) was de-gassed and purged with nitrogen. The reaction mixture was heated at 80° C. in a sealed vial overnight. After cooling, the resultant mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-2% methanol in ethyl acetate) to afford crude product. This was dissolved in 1.25 N HCl in propan-2-ol solution (10 mL) and was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and diethyl ether was added and the mixture was stirred for 5 minutes. The precipitate was filtered off and dried to afford the title compound as an off-white solid (68 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.52 (br s, 1H), 8.35-8.29 (m, 2H), 8.07 (s, 1H), 7.13 (br s, 1H), 3.66-3.59 (m, 2H), 3.59-3.49 (m, 2H), 2.59 (s, 3H). LCMS (Method B): RT=3.13 min, m/z: 457 [M+H+].
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[N:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][CH:6]=1>>[CH2:1]([NH:3][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:4])[N:10]=1)[CH3:2]
Reactant: CCN
Reactant: Cc1cccc(C=O)n1
Product: CCNCc1cccc(C)n1

Procedure:
prepared by reaction of ethylamine with 6-methyl-pyridine-2-carbaldehyde
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:25]=[CH2:26])=[C:4]([CH:8]=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH:25]=[CH2:26])=[C:4]([CH:8]=[C:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:18][CH:19]=2)[C:10]=1[O:11][CH3:12])[C:5]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35])=[O:7]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
To a solution of 3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid (0.06 g), trans-2-aminocyclohexanol hydrochloride (0.04 g), 1-hydroxybenzotriazole (0.03 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05 g) in dichloromethane (10.0 mL) was added triethylamine (0.03 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.08 g).
Reaction SMILES: [OH:1][C:2]([C:4]1[C:5]2[O:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14](=[O:23])[C:6]=2[N:7]([CH3:13])[C:8]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:3].Cl.[CH2:25](O)[CH3:26]>>[OH:3][C:2]([C:4]1[C:5]2[O:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14](=[O:23])[C:6]=2[N:7]([CH3:13])[C:8]=1[CH2:9][C:10]([O:12][CH2:25][CH3:26])=[O:11])=[O:1]
Reactant: Cn1c(CC(=O)O)c(C(=O)O)c2c1C(=O)c1ccccc1CO2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c2c(n1C)C(=O)c1ccccc1CO2
Yield: 89 %

Procedure:
5,10-Dihydro-3-hydroxycarbonyl-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetic acid (360 mg, 1.14 mmol) is suspended in absolute ethanol (5 ml) and heated to reflux under nitrogen. Then concentrated HCl (75 μl) is added, and the mixture is heated at reflux for 30 minutes. The homogeneous solution is allowed to cool, and the product crystallizes. The solid is filtered and washed with ice-cold ethanol and dried to give 350 mg (89%) of ethyl 5,10-dihydro-3-hydroxycarbonyl-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetate. M.P. 201°-202° (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([C:23]([F:25])([F:24])[F:26])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A solution of nickel (II) chloride hexahydrate (102 mg, 0.428 mmol) and (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylic acid methyl ester (814 mg, 2.14 mmol) in methanol (20 mL) was cooled to 0° C. and then treated with sodium borohydride (265 mg, 7 mmol) in five portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (50 mL) and ethyl acetate (75 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C18H21F3N4O2 (M+) 382.1617, found 382.1617.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.O[Li].O.[ClH:22].[Cl:23][CH2:24][C:25]1[C:26]([N:38]([CH3:40])[CH3:39])=[N:27][C:28]2[CH:29]=[C:30]3[O:37][CH2:36][O:35][C:31]3=[CH:32][C:33]=2[CH:34]=1.Cl.CO>C1(C)C=CC=CC=1>[ClH:23].[ClH:22].[CH3:40][N:38]([CH3:39])[C:26]1[C:25]([CH2:24][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][O:37][C:30]3=[CH:29][C:28]=2[N:27]=1
Reactant: CN(C)c1nc2cc3c(cc2cc1CCl)OCO3
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc4c(cc3nc2N(C)C)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 13 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.0 mmol) in toluene in a 20 mL microwave vial was added LiOH.H2O (84 mg, 2.0 mmol) and 7-(chloromethyl)-N,N-dimethyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride RBO 35172 (301 mg, 1.0 mmol). The mixture was stirred at 150° C. for 1.5 h under microwave irradiation then cooled to RT. The volatiles were removed under vacuum and the residue was taken back in dichloromethane (30 mL), washed with water (3×10 mL), brine (10 mL), dried over Na2SO4, filtered and evaporated to give an orange solid. This solid was purified by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) to give after evaporation and drying 4-((6-(dimethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol (142 mg). This free base was dissolved in MeOH (5 mL) and a HCl 0.19 N solution in MeOH (1.35 mL, 0.26 mmol) was slowly added. The reaction mixture was stirred at 4° C. for 15 min. After evaporation and drying under vacuum pump under P2O5, 4-((6-(dimethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 63 was obtained as a yellow solid (148 mg, 55% yield).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([C:25]2([CH3:28])[CH2:27][CH2:26]2)[OH:24])[CH:9]=1)(C)C.CO.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCOC(C)=O>[F:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][OH:6])=[CH:9][C:10]=1[CH:23]([C:25]1([CH3:28])[CH2:27][CH2:26]1)[OH:24]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C2(C)CC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(O)C2(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A 200 mL round bottom flask was charged with 83.18E (0.80 g, 1.9 mmol), MeOH (10 mL), and PPTS (0.047 g, 0.19 mmol). The solution was stirred overnight at room temperature and diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (20-55% EtOAc/hexane) to afford 83.18F (0.52 g, 88%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH2:22]O)[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].CCOC([S-])=[S:29].[K+]>>[SH:29][CH2:22][C@@:21]12[C@@H:11]3[C@H:12]([C@H:7]4[C@:8]([CH3:24])([CH2:9][CH2:10]3)[C@@H:4]([C:2](=[O:3])[CH3:1])[CH2:5][CH2:6]4)[CH2:13][CH2:14][C:15]1=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]2
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CS)[C@H]3CC[C@]12C

Procedure:
Other compounds can be prepared by starting with 19-hydroxyprogesterone. This is converted to the corresponding trifluoromethanesulfonate ester and the sulfonate is displaced with potassium ethyl xanthogenate. Hydrolysis of the resulting xanthogenate then gives the desired 19-mercaptopregn-4-ene-3,20-dione. This 19-mercapto compound can then be reacted with the appropriate acid halide or anhydride to give the corresponding ester.
Reaction SMILES: C(N(CC)[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH:12]=[O:13])C.CCCCCC.C(OCC)(=[O:25])C>Cl.O>[OH:25][CH:12]1[C:6]2[C:5](=[CH:10][CH:9]=[C:8]([CH3:11])[CH:7]=2)[C:4](=[O:14])[O:13]1
Reactant: CCN(CC)C(=O)c1ccc(C)cc1C=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)C(O)OC2=O
Temperature: 25 °C

Procedure:
N,N-diethyl-2-formyl-4-methyl-benzamide (7.98 g, 36.39 mmol) was taken up in 100 mL of 6N HCl and heated to reflux for 48 h. The reaction was then cooled to room temp and diluted with 50 mL of water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane/ethyl acetate) Yield 4.66 g. 1H NMR (CDCl3, 300 MHz): δ 2.47 (s, 3H), 6.05 (bs, 1H), 7.12 (s, 1H), 7.33 (d, J=9, 1H), 7.95 (d, J=9, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22](OC2C=CC=CC=2)=[O:23])C(=O)OC2C=CC=CC=2)[CH:7]=1.Cl.Cl.[CH3:52][N:53]([CH2:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[CH3:54].C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH2:55][CH:56]1[CH2:61][CH2:60][N:59]([C:22]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:23])[CH2:58][CH2:57]1)[CH3:54]
Reactant: CN(C)CC1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.2 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(dimethylaminomethyl)piperidine dihydrochloride (67.0 mg), triethylamine (0.0523 ml) and water (0.050 ml), followed by stirring at room temperature for 10 hr. To the reaction mixture were added triethylamine (0.0523 ml) and water (0.050 ml), followed by further stirring at room temperature for 24 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added hexane, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (22.4 mg, 50.4%).
Reaction SMILES: [Ce+4].[NH4+].[CH3:3][O:4][C@@H:5]1[C@@H:10]2[CH2:11][C@@H:7]([C:8](=[O:21])[N:9]2CC2C=CC(OC)=CC=2)[CH2:6]1>O.CC#N>[CH3:3][O:4][C@@H:5]1[C@@H:10]2[CH2:11][C@@H:7]([C:8](=[O:21])[NH:9]2)[CH2:6]1
Reactant: COc1ccc(CN2C(=O)[C@H]3C[C@H](OC)[C@@H]2C3)cc1
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CO[C@H]1C[C@H]2C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ammonium cerium(IV) (3.3 g, 6.06 mmol) in water (10 mL) was added to (1S,4R,6S)-6-methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (527 mg, 2.02 mmol) in CH3CN (40 mL). The reaction mixture was stirred at ambient temperature for 2 h and extracted by EtOAc (60 mL). The organic extract was washed with water and brine, dried over Na2SO4, and evaporated to give the crude (1S,4R,6S)-6-methoxy-2-azabicyclo[2.2.1]heptan-3-one. MS (ESI+): m/z 142 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:13]([CH2:14][CH2:15][O:16][CH3:17])[C:11](=[O:12])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCCNC(=O)NNC(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCn1c(-c2ccc(Cl)s2)n[nH]c1=O

Procedure:
Of the compound from Example 167A, 4.85 g (17.46 mmol) were dissolved in 17 ml (52.39 mmol) of 3M aqueous sodium hydroxide solution and heated under reflux for 168 h. During this, after 16, 40, 64 and 88 h, 1.05 g portions (26.19 mmol, in total 104.76 mmol) of solid sodium hydroxide were added. The batch was acidified to pH 10 using 1M hydrochloric acid, and the mixture was extracted with twice 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, freed from the solvent on a rotary evaporator and dried in an HV. This gave 2.44 g (54% of theory) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][C@@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[C@@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCN[C@@H](C)C1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)[C@@H](C)C1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 63 mg HATU and 28 mg (S)-3-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:20]([O:32][CH3:33])=[CH:21][C:22]2[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=2[CH:31]=1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:7][C:2]([NH:18][C:19]2[C:20]([O:32][CH3:33])=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3OC)n1)CCOC(=O)N2C
Yield: 69 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a white solid (70 mg, 69%). mp: 192-194° C., MS (ESI+): 456 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.96 (d, 1H), 7.63 (s, 1H), 7.14 (q, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 6.92 (t, 1H), 4.27 (t, J=6 Hz, 2H), 3.82 (s, 6H), 3.28 (s, 3H), 2.69 (t, J=6 Hz, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:25][C@@:14]([O:23][CH3:24])([C:15]([CH3:22])([SiH3:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@:13]([CH3:27])(O)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=S>ClCCCl>[C:1]([O:9][CH2:10][C@H:11]1[O:25][C@@:14]([O:23][CH3:24])([C:15]([CH3:22])([SiH3:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C@@H:13]([CH3:27])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(C(C)([SiH3])OC(C)(C)C)O[C@H](COC(=O)c2ccccc2)C[C@]1(C)O
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CO[C@@]1(C(C)([SiH3])OC(C)(C)C)O[C@H](COC(=O)c2ccccc2)C[C@@H]1C

Procedure:
A solution of 3.8 g of the compound of Step 1A and thiocarbonyldiimidazole (7.0 g) in 1,2-dichloroethane (75 mL) was refluxed for 3 days and then worked up and deoxygenated as described above, Step 8A, Example 1. Yield of product was 1.2 g. 1H NMR (CDCl3) d: 8.05 (dm, 2H), 7.56 (m, 1H), & 7.44 (m, 1H, 2H) (6-O-benzoate hydrogens), 4.48 (m, 1H, H-5), 4.36 (dd, 1H, H-6a, J6a,5 =Hz, J6a,b =Hz), 4.27 (dd, 1H, H-6b, J6b,5 =Hz), 3.75 (d, 1H, H-1a, J1a,b =11.0 Hz), 3.57 (d, 1H, H-1b), 3.28 (s, 3 H. OMe), 2.17 (m, 2H, H-3a, H-4a), 1.95 (m, 1H, H-3β ), 1.70 (m, 1H, H-4β), 0.90 (s, 9H, (Me)3 -}, 0.06 (2×s, 6H, (Me)2 -Si}.