Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:22]1[CH2:23][CH2:24][CH2:25][N:26]=[C:21]1[NH:20][C:19]([CH2:18][CH2:17][C:14]1[S:13][C:12]([C:10]([NH:9][CH2:8][C@H:7]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[C:6]([OH:42])=[O:5])=[O:11])=[CH:16][CH:15]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)s1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 868.7 %

Procedure:
0.096 g (0.15 mmol) of the compound obtained in step b) were dissolved in dichloromethane (1 ml). Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred for 3 h at room temperature. After evaporation of the solvents lyophilization gave the title compound (0.75 g, 86%) as a white amorphous solid.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1)[CH3:3].[OH-:24].[Na+].OO.O>CO>[O:24]1[C@H:14]2[C:13](=[O:23])[CH:12]=[C:11]3[C@:16]([CH3:17])([C@@H:15]12)[C@@H:18]1[C@H:8]([C@H:7]2[C@:21]([CH3:22])([CH2:20][CH2:19]1)[C@@H:4]([C@H:2]([OH:1])[CH3:3])[CH2:5][CH2:6]2)[CH:9]=[CH:10]3
Reactant: [OH-]
Reactant: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of 2.79 g (8.92 mmol) of (20R)-20-hydroxy-pregna-1,4,6-trien-3-one in 27 ml of methanol is treated with 0.83 ml of 10% methanolic sodium hydroxide, cooled to 0° C., and 5.4 ml of 30% hydrogen peroxide solution are added dropwise during 10 minutes with stirring. The solution is stirred at 0° C. for 45 minutes and then at room temperature for 3 hours. The suspension formed is treated with a total of 60 ml of water in portions, cooled to 0° C. and excess peroxide is destroyed by the addition of sodium hydrogen sulphite solution. The mixture is freed from methanol in a water-jet vacuum and the residue is extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. Chromatography of the residue on 80 g of silica gel with hexane/ether (1:1) gives 1.77 g (60.4%) of uniform (20R)-1α,2α -epoxy-20-hydroxy-pregna-4,6-dien-3-one in the form of colourless crystals. The analytical sample is obtained by recrystallisation from methylene chloride/ether; melting point 206°-207° C., [α]D25 =+231.6° (c=0.5 in chloroform); UV (ethanol): λmax 292 nm (ε=21050).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1.C(O)(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
N-Bromosuccinimide (NBS) (35.8 g, 0.20 mol) was added in several portions to a solution of 1,1-dimethylethyl 4-methylbenzoate (prepared by the reaction of the respective acid chloride with t-butanol.) (38.0 g, 0.20 mol) and benzoyl peroxide (0.36 g. 1.5 mmol) in carbon tetrachloride (1200 mL) at vigorous reflux. Another portion of benzoyl peroxide (0.36 g. 1.5 mmol) was added just before the final addition of NBS. After the foaming subsided, the reaction mixture was cooled to room temperature, washed with water (2×60 mL) and dried over magnesium sulfate. Filtration and concentration provided an oil that was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give 1,1-dimethylethyl 4-bromomethylbenzoate (21.4 g) in 40% yield.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.[OH:17]O.Cl>C(OCC)C>[OH:17][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: OO
Agent: Cl
Solvent: CCOCC
Product: Oc1cccc2c1oc1ccccc12
Temperature: 0 °C

Procedure:
4-dibenzofuran boronic acid (4.02 g, 18.9 mmoles) is suspended in diethyl ether (50 mL). The suspension is cooled to 0° C. and hydrogen peroxide (30% in H2O) is added dropwise; the resulting mixture is heated to reflux for 1.5 hours to complete conversion of the starting material. The reaction mixture is then cooled to 0° C. and 1N HCl (4 mL) is added. The organic layer is washed with an aqueous solution containing 10% FeCl2, dried over Na2SO4 and evaporated to dryness to give 3.48 g of the desired compound which is employed in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH:16]1[C:28]2[NH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>[Cu](I)I.O1CCOCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]3[CH:14]=[CH:15][C:2]([C:25]4[C:26]5[NH:27][C:28]6[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=6)[C:21]=5[CH:22]=[CH:23][CH:24]=4)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Brc1ccc2oc3ccc(-c4cccc5c4[nH]c4ccccc45)cc3c2c1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
A three-necked flask was charged with 2,8-dibromodibenzofuran (39.12 g, 120 mmol), carbazole (20.07 g, 120 mmol), K3PO4 (50.94 g, 240 mmol), copper iodide (11.43 g, 60 mmol), 1,2-trans-diaminocyclohexane (20.55 g, 180 mmol), and 1,4-dioxane (120 ml), and the mixture was refluxed for 9 h. After the reaction, the reaction product solution was cooled to room temperature and extracted with CH2Cl2 using a separatory funnel. The extract was dried over anhydrous magnesium sulfate, filtrated and concentrated. The obtained solid product was purified by a column chromatography (hexane:toluene=8:2). The above operations were all performed in an argon atmosphere (16.0 g, 32% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[F:13][C:14]([F:25])([F:24])[CH2:15][S:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH2:15][C:14]([F:25])([F:24])[F:13])[N:22]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccnc(SCC(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccnc(SCC(F)(F)F)n1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-nitrobenzoyl chloride (1.85 g, 10 mmol) in CH2Cl2 (10 mL) was slowly added to a solution of 2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidin-4-ylamine (2.1 g, 10 mmol) and triethylamine (2 g, 20 mmol) in CH2Cl2 (80 mL) between 0 and max 7° C. The mixture was stirred overnight at room temperature and then poured into ice-water. The phases were separated and the organic part was dried with Na2SO4, filtered and concentrated in vacuo to provide a viscous oil. The crude product was purified by prep-HPLC (1.5 g, 41.8%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[C:26]([F:29])[C:27]=1O>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[C:3]([CH2:2][O:1][C:27]3[C:26]([F:29])=[CH:25][C:24]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:23][C:22]=3[F:21])=[C:7]([C:8]([F:11])([F:9])[F:10])[S:6][N:5]=2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CC(=O)c1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling 1-(4-(4-(hydroxymethyl)-5-(trifluoromethyl)isothiazol-3-yl)phenyl)ethanone and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 8.08 (d, J=7.2 Hz, 2H), 7.87 (d, J=7.2 Hz, 2H), 6.78-6.85 (m, 2H), 5.19 (s, 2H), 2.80-2.85 (m, 2H), 2.64 (s, 3H), 2.53-2.58 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H16F5NO4S, 484.1 (M−H). found 484.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(F)c3)c2O1)OCc1ccccc1
Yield: 93.7 %

Procedure:
Treatment of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.798 g, 2.856 mmol) with diisopropylethylamine (0.554 g, 4.286 mmol) and benzyl chloroformate (0.536 g, 3.143 mmol) generally according to the procedure described for Intermediate 12 afforded 1.01 g (94%) of (±)-benzyl[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. Rf=0.40 (silica, ethyl acetate:hexanes 1:4); Anal. Calcd. for C23H20FNO3: C, 73.2; H, 5.34; N, 3.71. Found: C, 92.96; H, 5.38; N, 3.59.
Reaction SMILES: [NH2:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9](=O)([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[O:10]N1C(=O)CCC1=O.C(N(CC)CC)C.S([O-])(O)(=O)=O.[Na+]>O1CCOCC1.O>[CH3:7][CH:6]([CH3:8])[C@@H:2]([NH:1][C:9]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])[C:3]([OH:5])=[O:4]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@@H](NC(=O)OCC[Si](C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
A mixture of (R)-2-amino-3-methylbutanoic acid (2.01 g, 17.16 mmol) and 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (4.89 g, 18.87 mmol) in 1:1 dioxane/water (40 mL) was treated with triethylamine (3.59 mL, 25.7 mmol), and the mixture was stirred for two days at room temperature. The mixture was acidified with saturated sodium hydrogen sulfate and extracted 3× with ethyl acetate. The combined organic phases were washed with saturated sodium hydrogen sulfate, water, and brine, then dried over sodium sulfate and concentrated in-vacuo to yield the title compound (4.17 g, 15.96 mmol, 93% yield) as an amber oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:41])(=[O:40])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH:37]1[CH2:39][CH2:38]1)[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:40])(=[O:41])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH:37]1[CH2:39][CH2:38]1)[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 31).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C(O)(=O)C.[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:18]=1[NH2:19]>C(Cl)Cl>[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:18]=1[N:19]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(F)cc1F

Procedure:
A solution of 5.3 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated with 5 parts of 2,4,6-trifluoroaniline at once. After refluxing for 24 hours, the acetic acid was stripped from the reaction mixture under 300 mm hg pressure. The residue was dissolved in 100 parts of methylene chloride and washed with 100 parts of 10% aqueous sodium carbonate. After drying over anhydrous sodium sulfate, the solution was stripped under 300 mm hg pressure. The resulting pink oil was crystallized from 70 parts of methanol at -40°C to yield 4.7 parts white crystals of 2-(2,4,6-trifluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 91°-92°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23][C:24]2[CH:25]=[C:26]([O:39][CH2:40][CH3:41])[C:27](I)=[C:28]([O:30][S:31]([CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:32])[CH:29]=2)=[CH:18][N:17]=1>>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:27]2[C:26]([O:39][CH2:40][CH3:41])=[CH:25][C:24]([CH2:23][C:19]3[C:20]([NH2:22])=[N:21][C:16]([NH2:15])=[N:17][CH:18]=3)=[CH:29][C:28]=2[O:30][S:31]([CH2:34][CH:35]([CH3:36])[CH3:37])(=[O:32])=[O:33])=[CH:7][CH:6]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1I
Reactant: O=C(Nc1ccc(Br)cc1)C(F)(F)F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1-c1ccc(N)cc1

Procedure:
Starting from 225 mg (0.84 mmol) N-(4-bromo-phenyl)-2,2,2-trifluoro-acetamide and 214 mg (0.42 mmol) 2-methyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 78 mg of the tide compound are obtained as a brown foam after two chromatography operations.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:19])[C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[N:11][CH:10]=2)[O:4][N:3]=1.C(Cl)(Cl)(Cl)[Cl:21].ClN1C(=O)CCC1=O.O>CCCCCC.C(OCC)(=O)C>[Cl:21][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][C:8](=[O:19])[C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: Cc1cc(NC(=O)c2cnccc2C(F)(F)F)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(NC(=O)c2cnccc2C(F)(F)F)c1Cl
Yield: 61 %

Procedure:
To N-(3-methyl-5isoxazolyl)-4-(trifluoromethyl)nicotinamide (Compound No. 1-2, 101.7 mg, 0.37 mmol) prepared according to Example 1, carbon tetrachloride (2 ml) and N-chlorosuccinimide (64.6 mg, 0.48 mmol) were added, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by thin layer chromatography (a developing solvent: hexane/ethyl acetate=1/1) to obtain the title compound (69.3 mg, yield 61%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH2:15][OH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[C:9]1([CH2:15][O:16][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCCO1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(CCCCCO)OCc1ccccc1
Temperature: 50 °C
Yield: 25.8 %

Procedure:
A mixture of 6-hexanolactone (40 g, 0.35 mol), phenylmethanol (70 g, 0.647 mol), and conc. sulfuric acid (40 drops) was heated at 50° C. overnight. The resulting mixture was purified by column chromatography (hexane, 5-30% ethyl acetate/hexane) and distilled to afford 20.1 g (26%) of 6-hydroxyhexanoic acid phenylmethyl ester, b.p. 70°-75° C./1 mm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:46](=[O:56])[N:47]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:48][CH2:49][CH2:50][CH3:51])=[N:4][N:5]([C:8]2[CH:29]=[CH:28][C:27]([C:30](=[O:45])[NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:34])=[O:33])=[CH:26][C:9]=2[C:10]([N:12]2[C@@H:21]([C:22](OC)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[C:6]=1[CH3:7].[BH4-].[Na+]>C1COCC1.CO>[CH2:52]([N:47]([CH2:48][CH2:49][CH2:50][CH3:51])[C:46]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:29]=[CH:28][C:27]([C:30](=[O:45])[NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:34])=[O:33])=[CH:26][C:9]=2[C:10]([N:12]2[C@@H:21]([CH2:22][OH:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[N:4]=1)=[O:56])[CH2:53][CH2:54][CH3:55]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@@H]2C(=O)OC)c(C)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@@H]2CO)c(C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of (3R)-methyl 2-(2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Intermediate 85, 40 mg, 0.050 mmol) in THF (835 μL) and MeOH (170 μL) was added NaBH4 (4 mg, 0.10 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. Additional NaBH4 (20 mg, 0.50 mmol) was added and stirring was continued at room temperature for 30 min. The reaction mixture was then quenched with water, poured into sat. aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by preparative HPLC to give the title compound (13 mg, 34%). 1H NMR (1:1 CD3OD:CDCl3, mixture of amide rotamers) δ 8.68-8.77 (m, 1H), 8.23 (s, 0.5H), 8.13-7.99 (m, 4.5H), 7.95 (d, J=7.0 Hz, 1.5H), 7.72-7.61 (m, 1H), 7.58-7.45 (m, 1H), 7.23-7.03 (m, 4H), 6.87 (br s, 0.5H), 5.24 (d, J=18.0 Hz, 0.5H), 4.87 (br s, 0.5H), 4.49 (br s, 0.5H), 4.28 (d, J=17.4 Hz, 1H), 4.12 (br s, 1H), 3.63-3.52 (m, 1H), 3.51-3.34 (m, 1.5H), 3.27-2.92 (m, 4H), 2.83-2.53 (m, 1H), 2.28-2.25 (m, 3H), 1.62-0.83 (m, 11H), 0.77-0.69 (m, 2H), 0.64 (br s, 1H); MS(ESI+) m/z 770.3 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].N([O-])=[O:19].[Na+]>O>[OH:19][C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)ccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(O)ccc1C
Reaction time: 1 h

Procedure:
A 0° C. solution of sulfuric acid (89 g, 908 mmol) in water (700 mL) was added to a flask containing methyl 5-amino-2-methylbenzoate (50 g, 303 mmol) in an ice-water bath. The resulting mixture was stirred until the mixture become a cloudy solution. A solution of sodium nitrite (21 g, 303 mmol) in cold water (200 mL) was added dropwise and stirring was continued for 1 h at 0° C. then at 100° C. for another 1 h. The reaction was cooled and the solid collected by filtration, and rinsed with water. The resultant dark red solid was re-dissolved in MeOH (500 mL). Charcoal (2 g) was added and the reaction was heated at reflux for 1 h. The mixture was filtered and concentrated. Chromatography over silica eluting with 0-50% EtOAc/hexane afforded the title compound as white solid. LC-MS: calculated for C9H10O3 166.17, observed m/e: no ionization (Rt 0.89/2 min). NMR (CDCl3): 7.48 (1H, s), 7.15 (1H, d); 6.95 (1H, d), 6.04 (1H, s); 3.95 (3H, s); 2.53 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH:21]=1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1.C(OC(C)C)(C)C>C1CCCCC1>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]2[CH2:32][CH2:33][CH2:34]2)[CH:21]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(Cl)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Solvent: C1CCCCC1
Solvent: CC(C)OC(C)C
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CCC4)c3)c(Cl)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
Reaction was carried out in the same manner as in Example 2-(b) except for using 0.26 g (0.51 mmol) of 3-chloro-2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 32-(a) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, to the reaction mixture were added diisopropyl ether and cyclohexane, and the precipitated solid was collected by filtration and washed with cyclohexane. To the obtained solid were added methanol and 28% aqueous ammonia, and the mixture was stirred at room temperature for 3 hours. Then, the solution was concentrated under reduced pressure, and the obtained solid was washed with chloroform and dried under reduced pressure to obtain 120 mg of the title compound as a white solid. (Yield: 62%)
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])[CH2:5][CH2:6][N:7]([C:37]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:38])[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)N2CCC(C#N)(NC(=O)C(CC3CCCCC3)NC(=O)N3CCOCC3)CC2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride and 4-methyl-piperzine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: Cl.[CH2:2]([C:4]1([N:14]([CH3:16])[CH3:15])[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1)[CH3:3]>Cl>[CH3:15][N:14]([CH3:16])[C:4]1([CH2:2][CH3:3])[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CCC1(N(C)C)CCC2(CC1)OCCO2
Agent: Cl
Product: CCC1(N(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(8-ethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine hydrochloride (6.67 g, 0.026 mmole) was dissolved in 6N HCl (40 ml) and stirred overnight at room temperature. The reaction mixture was extracted twice with diethyl ether (100 ml). The reaction mixture was then made alkaline with 5N NaOH while cooling with ice and extracted a further three times with Et2O (100 ml). The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed in vacuo.