Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O.Cl>CO.C(Cl)Cl.CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:28])[F:26])[CH:13]=[N:12]2)[C:3]([OH:29])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid methyl ester (149.4 mg, 0.36 mmol) in methanol (0.61 mL, 0.6M) was treated with a 4N aqueous sodium hydroxide solution (0.1 mL, 0.40 mmol) and stirred at 25° C. for 3 h. After this time, the reaction was poured into water (50 mL) and 90/10 methylene chloride/methanol (30 mL) and was acidified with a 2N aqueous hydrochloric acid solution and then was extracted into a 90/10 methylene chloride/methanol (3×30 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (130.6 mg, 90%) as a yellow solid. This material was used without further purification; ES+-HRMS m/e calcd for C20H21N2O3F3 [M+H+] 395.1577, found 395.1574.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][CH:15]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:14]=2)[CH2:16][CH2:17]1)(=[O:23])=[O:22]
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a stirred solution of {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (120 mg, 0.24 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (50 mg, 1.2 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (105 mg, 90%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H), 7.96-8.01 (m, 2H), 7.94 (d, J=4.4 Hz, 1H), 7.80-7.83 (m, 2H), 7.69 (s, 1H), 7.41 (t, J=8.8 Hz, 1H), 7.36 (s, 1H), 3.91 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.08 (t, J=11.5 Hz, 2H), 1.90-1.96 (m, 2H), 1.67-1.77 (m, 2H); MS cald. for C23H19Cl2FNO4S [(M−H)−]: 494, obsd. 494.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][C:15]1=[O:28])[C:11]([OH:13])=O.[C:29](Cl)(=O)C(Cl)=O.Cl.[OH:36][C@@H:37]([CH2:67]O)[CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH:44]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:40]1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][C:15]1=[O:28])[C:11]([NH:44][C:41]1[CH:42]=[CH:43][N:39]([CH2:38][C:37]([OH:36])([CH3:67])[CH3:29])[N:40]=1)=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: O=C(O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(Cc2c(Cl)cccc2Cl)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
In a round bottom flask under argon was placed 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (38 mg, 0.089 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was then added a 2.0M solution of oxalyl chloride in dichloromethane (50 μL, 0.10 mmol) dropwise which resulted in gas evolution. The mixture was then stirred for 15 min at 25° C. and concentrated in vacuo. The residue was taken up in dichloromethane (3 mL) and added dropwise into a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 17 mg, 0.107 mmol), dichloromethane (3 mL) and 2,6-lutidine (50 μL, 0.18 mmol) at 25° C. The mixture was then stirred for 1 h at 25° C. and then quenched with methanol and diluted with dichloromethane. This mixture was then washed with a 1N aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (25% ethyl acetate/hexanes) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (18 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C26H24N4O4Cl2F2 [M+H]+ 565.1216, observed 565.1216; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.05 (s, 3H), 3.34-3.51 (m, 2H), 3.88 (s, 2H), 4.19 (d, J=18.3 Hz, 1H), 4.55 (d, J=18.3 Hz, 1H), 4.66 (s, 1H), 4.98 (s, 1H), 5.03 (dd, J=8.2, 6.0 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.2, 7.7 Hz, 1H), 7.35 (t, J=8.7 Hz, 2H), 7.38-7.48 (m, 3H), 7.54 (d, J=2.1 Hz, 1H), 10.68 (s, 1H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[NH:5]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.[F:34][C:35]([F:40])([F:39])[C:36]([O-:38])=[O:37]>O1CCCC1.O1CCCC1.CN1CCCC1=O>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[C:16]([CH:12]1[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=3)[NH:5][C:4]1=[O:3])=[N:17][CH:18]=[CH:19]2
Reactant: COCCOCCOc1ccc2c(Cl)nccc2c1
Reactant: O=C([O-])C(F)(F)F
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COCCOCCOc1ccc2c(C3C(=O)Nc4ccc(C#N)cc43)nccc2c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 27 %

Procedure:
A suspension of sodium hydride (92 mg, 3.55 mmol, 95% powder) in tetrahydrofuran (10 mL) was slowly added via a cannula to a solution of 2-oxo-5-indolinecarbonitrile (292 mg, 1.85 mmol) in tetrahydrofuran/N-methylpyrrolidinone (15 mL, 2:1) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 25 min. A solution of chloro-6-[2-(2-methoxyethoxy)ethoxy]isoquinoline (400 mg, 1.42 mmol) in tetrahydrofuran (10 mL) was added and the reaction solution was stirred at room temperature over night. The reaction was quenched by slow addition of hydrochloric acid (1 M) and concentrated in vacuo to a slurry. The slurry was diluted with acetonitrile (5 mL) and purified by prep RP-HPLC (C18 2″ column, gradient:acetonitril/water, 20:80→0:100+0.1% TFA). The appropriate fractions were pooled and lyophilized giving 193 mg (27% yield) of the title compound as an orange trifluoroacetate salt. MS (AP+) m/z 404 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>>[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:7]2[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]2)=[O:21])=[CH:15][CH:14]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Product: Cc1ccc(NC(=O)N2CC(C)(C)NC(C)(C)CC2=O)cc1

Procedure:
Using the same procedure as described in Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 14.3 parts of p-tolyl isocyanate were reacted together and afforded a solid material which was recrystallised from petroleum ether (of boiling range 60° to 80°C) to yield 21 parts of 4-p-tolylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one of melting point 126°C. This material gave the following elemental analysis by weight:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[CH2:19][CH2:18][CH2:17]4)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]1[C:20]2[C:16](=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCC4)CC2)nc1Cl
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCC5)CC3)ccc2C)cn1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxamide (0.132 g, 0.4030 mmol), 6-methoxypyridin-3-ylboronic acid (0.092 g, 0.6045 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.046 g, 0.04030 mmol) in 1,2-dimethoxyethane (4.4 mL), 2 M Na2CO3 (600 μL) was added. The reaction mixture was stirred and heated at 80° C. for 22 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydro-1H-inden-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a white solid (0.150 g, 93.17%). ESI-MS m/z calc. 399.48, found 400.5 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:28])[CH2:30][CH2:31][N:38]4[C:34](=[O:44])[C:35]5=[CH:43][CH:42]=[CH:41][CH:40]=[C:36]5[C:37]4=[O:39])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CCN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butanol (6.9 g, 23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped and the residue was stirred in ether (200 ml). The insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g; eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and SiO2, 100 g; eluted with DCM, 1 l; and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated. The lower compound on TLC 3.66 g) was treated with HCl/ether in ethanol, and the solid salt was precipitated with hexane. Recrystallization from ethanol and isopropyl ether yielded white crystals 3.26 g, m.p. 210°-214° C. dec.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:5])=[O:4].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>C1N2CCN(CC2)C1>[CH3:1][N:2]([CH3:17])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:23]=[O:24])(=[O:15])=[O:14])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cc1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CN(C)S(=O)(=O)Cc1ccccc1S(=O)(=O)N=C=O
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
A solution of 14.0 g of the product of Example 4, 5.0 g of n-butyl isocyanate and 0.1 g of DABCO in 90 ml of mixed xylenes was heated to 136°. To this solution was added 3.6 ml of liquid phosgene over a 2 hour period to maintain the temperature between 125° and 136°. The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled, and filtered under a nitrogen atmosphere and concentrated at 60°-70° in vacuo to give 16.0 g of crude 2-[(dimethylamino)sulfonylmethyl]benzenesulfonyl isocyanate as a moisture sensitive oil. An infrared peak at 2200 cm-1 confirmed the presence of the --SO2NCO group.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[C:4]([I:12])[CH:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].CCOCC.CCCCC>O1CCOCC1>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:7][C:6]=2[CH:5]=[C:4]([I:12])[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(I)cc(Br)c2s1
Solvent: C1COCCO1
Solvent: CCCCC
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Temperature: 80 °C
Reaction time: 0.58 h
Yield: 88.5 %

Procedure:
To a stirred solution of 7-bromo-5-iodobenzothiazol-2-amine (250 g, 0.70 mol) in 1,4-dioxane at rt was added ethylisocyanate (278 mL, 3.52 mol). The resulting reaction mixture was heated to 80° C. for 10-12 h under N2 atmosphere. After reaction completion (by TLC), the solvent was evaporated then n-hexane added and the evaporation procedure repeated. The resulting residue was stirred in hot water (2 L) at 60-65° C. for 30-40 min then filtered. The residue thus obtained was treated with a mixture of Et2O and n-pentane and filtered to obtain the desired product (264 g, 88%). 1H NMR (DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 3.20 (q, J=6.80, 2H), 6.73 (br s, 1H), 7.72 (s, 1H), 7.96 (s, 1H) and 11.07 (br s, 1H). MS: 426.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[N:33]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCC3)cc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.41 mmol) in dry dichloromethane (20 mL) and MeOH (2 mL) was added acetic acid (120 mg) followed by azetidine (70 mg, 1.23 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added at 0° C. After the addition, the mixture was stirred at this temperature for 5 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=100:1 to 15:1) to give the title compound (84 mg, yield 51%) as yellow solid. LC-MS (ESI) m/z: 409 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[Cl:18])=[CH:6][CH:7]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=3[Cl:18])[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: FC(F)(F)c1ccc(Cl)c(-c2ccc(Cl)nn2)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cc(C(F)(F)F)ccc3Cl)nn12

Procedure:
As in Example 36, a mixture of 2.2 g. of 3-chloro-6-[2-chloro-5-(trifluoromethyl)phenyl]pyridazine and 1.11 g. of acetylhydrazine in 50 ml. of n-butanol is refluxed for 48 hours to give the product of the example.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([CH3:56])[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][NH2:55])[CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:55][CH2:54][CH2:53][C:49]4[CH:48]=[C:47]([CH3:56])[CH:52]=[CH:51][CH:50]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1cccc(CCN)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCc2cccc(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(2-m-tolyl-ethyl)-amine (Oakwood) to give the title compound. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([NH:13][CH3:14])[CH3:12])[O:10][C:6]=2[C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([N:13]([CH3:29])[CH3:14])[CH3:12])[O:10][C:6]=2[C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: CNC(C)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC(c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)N(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
0.5 g (1.2 mmol) of 3-[4-chloro-6-fluoro-2-(1-methylaminoethyl)benzofuran-7-yl]-1-methyl-6-trifluoromethyluracil and 0.40 g (2.9 mmol) of potassium carbonate were suspended in 50 ml of N,N-dimethylformamide, and 1.0 g (7.0 mmol) of methyl iodide was added thereto, followed by stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.35 g (yield: 68%) of the desired product as a purple glassy substance. Refractive index: 1.5341 (20° C.)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([N:47]3[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]3)=[O:22])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: OC1CCNCC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(O)CC3)(CC1)CC2
Yield: 82.9 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-hydroxypiperidine (11.7 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-hydroxypiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (39.0 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:24])[CH:21](O)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(O)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:36][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:24])([CH3:34])[CH3:35])=[CH:30][CH:31]=1
Reactant: CC(C)(N)Cc1ccc(F)cc1
Reactant: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)C(O)O)N1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(Cc1ccc(F)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
300 mg (0.91 mmol) of 6-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 183 mg (1.09 mmol) of 2-(4-fluorophenyl)-1,1-dimethylethylamine were dissolved in 3 mL of ethanol. Molecular sieve was added and the mixture was heated to 80° C. for 30 minutes. After cooling to ambient temperature, 35 mg (0.91 mmol) of sodium borohydride was added. The mixture was stirred for 1 hour at ambient temperature, then sodium hydrogen carbonate solution was added to the reaction mixture and it was extracted with ethyl acetate. The organic phases were evaporated down and the residue was chromatographed (eluent: hexane-ethyl acetate-methanol). The ethanolamine thus obtained (223 mg) was dissolved in methanol to cleave the benzyl protecting group and hydrogenated with 150 mg palladium hydroxide as catalyst at ambient temperature and normal pressure. The catalyst was separated off by filtering through CELITE® filter agent, the filtrate was freed from solvent and the residue was chromatographed (silica gel; eluent: dichloromethane-methanol). Beige solid. Yield: 76 mg (22%); mass spectrometry: [M+H]+=375.