Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39]Cl>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCCCl
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(CCCN(C)C)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and 3-dimethylamino-1-propyl chloride.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]([OH:29])=O)[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>C1C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]([Cl:32])=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Solvent: c1ccccc1
Product: O=C(Cl)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6 g of 3-(3,4-dibenzoyloxyphenyl)propionic acid was dissolved in 20 ml of benzene, and 2 g of thionyl chloride was added thereto. After stirring at 60° C. for 2 hours, the solvent was distilled off in order to obtain crude 3-(3,4-dibenzoyloxyphenyl)propionic acid chloride. To 50 ml of chloroform was added 2.8 g of morpholine, and the above-mentioned acid chloride was then slowly added dropwise thereto under cooling. After stirring at room temperature for 2 hours, the reaction solution was washed with a saturated saline solution and then dried over Glauber's salt, and the solvent was then distilled off under reduced pressure. The resultant residue was purified through a silica gel column chromatography. 0n eluting with ethyl acetate, 6.7 g of N-[3-(3,4-dibenzoyloxyphenyl)propionyl]morpholine was obtained.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methoxybenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:13]([O:15]CC3C=CC(OC)=CC=3)=[O:14])=[C:8]([CH:11]=[CH2:12])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(=O)(O)[O-].[Na+:31]>C1(OC)C=CC=CC=1.ClCCl.P([O-])([O-])([O-])=O>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:13]([O-:15])=[O:14])=[C:8]([CH:11]=[CH2:12])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+:31]
Reactant: C=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C=CC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
to -60° C. To this mixture was added a solution of 33.7 mg (0.0944 mmol) of the compound prepared in Example 5 in 1.4 ml of anisole and 0.2 ml of dichloromethane, and the mixture was stirred for 30 minutes at the same temperature. And then, to the mixture was added a solution of 143 mg (1.7 mmol) of sodium bicarbonate in 4 ml of 0.1 M phosphate buffer (pH 7.0), and the mixture was stirred for 30 minutes under ice-cooling. After the reaction mixture was filtered, the filtration was washed twice with dichloromethane. The aqueous layer was separated, and purified by reverse phase silica gel column chromatography (elution with 10% methanol-water) to give 5.74 mg (yield: 23.5% of the title compound.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.Cl[C:9]([O:11][CH3:12])=[O:10]>>[CH3:12][O:11][C:9]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10]
Reactant: COC(=O)Cl
Reactant: COP(OC)OC
Product: COC(=O)P(=O)(OC)OC

Procedure:
One hundred and thirty parts of trimethyl phosphite are heated to 125° C. and treated with 100 parts of methyl chloroformate at a rate sufficient to maintain a reaction temperature of at least 100° C. After gas evolution stops, the residue is distilled to obtain 131 parts of dimethyl methoxycarbonylphosphonate, b.p. 83°-85° C./1.2 mm., nD25 = 1.4210.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([O:47][CH3:48])=[O:46])=[CH:35][CH:34]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(CN2C(=O)C(NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl ]-butanamide (Example 51, Step A) and methyl 4'-bromomethyl-1,1'-biphenyl-2-carboxylate (prepared by the method of D. J. Carinie et al, EPO publication 324,377) by the procedure described in Example 1, Step K. 1H NMR (300 MHz, CDCl3): 1.37 (s,3H), 1.39 (s,3H), 1.75 (m,1H), 2.3-2.6 (m,5H), 3.52 (s,3H), 4.50 (m,1H), 4.80 (d,14Hz,1H), 5.06 (s,2H), 5.34 (d,14Hz,1H), 5.65 (s,1H), 6.72 (d,7Hz,1H), 7.1-7.4 (m,15H), 7.48 (dt;2,8Hz;1H), 7.78 (dd;2,8Hz;1H). FAB-MS: calculated for C38H39N3O6 633; found 634 (M+H,60%).
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][C:7]1([CH3:21])[CH2:12][O:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C@H:8]1[CH:19]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:21][C:7]1([CH3:6])[CH2:12][O:11][CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:9][C@H:8]1[CH:19]=[CH2:2]
Reactant: CC1(C)COC(c2ccccc2)O[C@H]1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C[C@@H]1OC(c2ccccc2)OCC1(C)C
Yield: 85.6 %

Procedure:
Following the general procedure for methylenation via Wittig-olefination of Description 8, a phosphorous ylide, generated from 17.86 g (50.0 mmol) of methyltriphenylphosphonium bromide and 31.0 mmol of n-BuLi in 125 mL of anhydrous tetrahydrofuran (THF) was reacted with 5.5 g (25.0 mmol) of (4R)-5,5-dimethyl-2-phenyl-1,3-dioxan-4-carbaldehyde (7b). Aqueous work-up followed by purification using column chromatography with mixtures of methyl tert-butyl ether (MTBE) and hexanes (Hxn) as eluent (MTBE/Hxn=9:1→MTBE/Hxn=6:1) provided 4.67 g (86% yield) of the title compound (7c) as a yellowish liquid. Rf=0.66 (MTBE/Hxn=1:6). 1H NMR (400 MHz, CHCl3): δ=0.82 (s, 3H), 1.16 (s, 3H), 3.67 (d, J=10.8 Hz, 1H), 3.78 (d, J=10.8 Hz, 1H), 4.05 (d, J=6.0 Hz, 1H), 5.24-528 (m, 1H), 5.31-5.37 (m, 1H), 5.55 (s, 1H), 5.87 (ddd, J=17.6, 10.4, 6.0 Hz, 1H), 7.30-7.40 (m, 3H), 7.52-7.55 (m, 2H) ppm. MS (ESI) m/z: 219.1 (M+H)+. The analytical data was consistent with that given in the literature (Ito, et al., Synthesis 1993, 137-140).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1I.[Br-].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Zn+]>CC(N(C)C)=O.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Cl)c(-c2ccccn2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
The 2-chloro-5-nitro-iodobenzene (5 g, 17.6 mmol) was dissolved in 5 mL DMA in an oven dried flask and a 0.5M solution of 2-pyridylzincbromide (53 mL, 26.5 mmol, 0.5 M in THF) was added. The solution was degassed with N2 for ½ hr., the PPh3 (0.185 g, 0.7 mmol) and Pd(PPh3)4 (0.825 g, 0.7 mmol) were added, rinsed in with several mLs THF and the solution was degassed for a further 10 min before heating to 60° C. under N2. The reaction was complete by TLC in ˜8 h, cooled to RT, and poured into a 1:1 mixture of EtOAc/2.5N NaOH (500 mL). This solution was stirred for 10 min, passed through a course fritted filter containing celite to remove the solid, and then extracted. The organics were washed with brine and concentrated to a brown solid. The combined aqueous layers were backextracted with Et2O (1×200 mL). This was used to suspend the crude product, which was extracted with 1N HCl (1×200 mL, 3×100 mL). The combined aqueous extracts were cooled to 0° C., diluted with EtOAc (250 mL), and made basic with 10N NaOH (100 mL). This solution was separated, the aqueous layer extracted with EtOAc, and the combined organics were dried over Na2SO4 and charcoal with stirring. This solution was filtered through celite and concentrated to yield pure 4-chloro-3-(pyridin-2-yl)nitrobenzene (2.47 g, 10.5 mmol, 60% yield) which was used in the next reaction without further purification.
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10])([O-:5])=[O:4].Cl>O>[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[C:8]([C:9]([OH:1])=[O:10])[C:7]=1[C:12]([NH2:11])=[O:13])([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0° C. The suspension was stirred at 0° C. for 3 hours, and then heated to 30° C. for 3 hours. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0° C. for 1 hour. The suspension was filtered and washed with cold water (2×10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) δ 7.69 (brs, 1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13 (dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) δ 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:35]2[N:34]3[CH2:38][CH2:39][C:40](=O)[C:33]3=[CH:32][C:31]=2[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:35]2[N:34]3[CH2:38][CH2:39]/[C:40](=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])/[C:33]3=[CH:32][C:31]=2[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CCn2c1cc1cc(OCc3ccccc3)ccc12
Reaction time: 2 h

Procedure:
To a 5000 mL 3-neck round bottom flask at room temperature under N2 equipped with a mechanical stirrer, an addition funnel, and a temperature probe containing a solution of ethyl 2-(diethoxyphosphoryl)acetate (114 mL, 577 mmol) in THF (2.0 L) was added potassium t-butoxide (1.0 M in THF, 554 mL, 554 mmol) via addition funnel over 10 minutes (temp increase from 22° C. to 29° C.). The reaction mixture was stirred for 2 h and 7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (123 g, 444 mmol) was added in 4 portions. An additional amount of THF (750 mL) was added to further dissolve ketone. The mixture was stirred at room temperature for 16 h. Anaylasis of an aliquat from the reaction mixture using LC/MS revealed approximately 75-85% conversion to the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21][CH:22]=[O:23])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>C(Cl)Cl>[CH3:30][CH:29]([CH3:31])[C:28]([O:27][C@@H:26]1[C@@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[O:34][C@@H:24]([N:12]2[C:13]3[N:14]=[C:15]([NH:21][CH:22]=[O:23])[N:16]=[C:17]([O:19][CH3:20])[C:18]=3[C:10]([Cl:9])=[C:11]2[Cl:1])[CH2:25]1)=[O:32]
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
N-chlorosuccinimide (117 mg, 0.9 mmol) is added to a solution of compound (45) (200 mg, 0.4 mmol in 5 ml of DMF). After it had been stirred (at room temperature for 16 h), the solution is added to a mixture of CH2Cl2 /5% aq. NaHCO3 (50 ml, 9:1). The organic phase is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2 /acetone, 95:5). The main zone is separated off. Colorless crystals (149 mg, 72%) are obtained after evaporating off the solvent and crystallizing from cyclohexane. Melting point: 127-128° C. 1H-NMR ([D6 ] DMSO): δ=1.01 (dd, CH3), 1.14 (d, J=7.0, CH3), 2.44, 2.47, 2.60, 3.53 (4 m, CH and Hα,β --C(2')), 4.05 (s, OCH3), 4.17 (m, H--C(5')), 4.30 (m, H--C(4')), 5.56 (m, H--C(3')), 6.41 (m, H--C(1')), 9.44 (d, J=9.1, NH), 10.94 (d, J=9.8, HCO). Anal. calculated for C21H26Cl2N4O7 (517.4): C, 48.75, H, 5.07, N, 10.83; found: C, 49.04, H, 5.09, N, 10.66.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]=O)[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(c1cccc2ccccc12)N1CC(CN2CCOCC2)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.03 g (0.073 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine and 0.013 mL (0.145 mmol) of morpholine in 2 mL of dichloroethane at rt was added 0.046 g (0.27 mmol) of sodium triacetoxyborohydride. After stirring for 1.5 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, CH2Cl2: MeOH, 95:5) to give the title compound.
Reaction SMILES: [N+:1]([C:4]([CH3:15])([CH3:14])[CH2:5][NH:6][CH2:7][C:8]([N+:11]([O-])=O)([CH3:10])[CH3:9])([O-])=O.[H][H]>[Ni].C(O)C>[NH2:11][C:8]([CH3:10])([CH3:9])[CH2:7][NH:6][CH2:5][C:4]([NH2:1])([CH3:14])[CH3:15]
Reactant: CC(C)(CNCC(C)(C)[N+](=O)[O-])[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(N)CNCC(C)(C)N
Yield: 52 %

Procedure:
Into a 2 L pressure reactor, 21.17 g (0.0965 mol) of compound III was placed along with 600 mL of ethanol (90%). Approximately 3 g of Raney Nickel was added and the bomb was pressurized to 90 PSI with hydrogen (99.9%). The solution was stirred and intermittently repressurized with hydrogen. Over the course of 5 days, 105 PSI (0.406 mol) of hydrogen were consumed. The bomb was then depressurized and the solution filtered through celite to remove the catalyst. The filtrate was evaporated under vacuum to remove all solvent and then was vacuum distilled at room temperature and a pressure of 50 mtorr. Purified product weighed 8.031 g, giving a yield of 52%. Purity was checked by NMR, with a singlet at 2.26 ppm and a singlet at 0.96 ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[C:32]([C:35]1[S:36][C:37](Br)=[CH:38][CH:39]=1)(=[O:34])[CH3:33]>CCCCCC.C(OCC)(=O)C>[C:32]([C:35]1[S:36][C:37]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:30])[CH3:31])[C:8]=2[CH3:29])=[CH:38][CH:39]=1)(=[O:34])[CH3:33]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: CC(=O)c1ccc(Br)s1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)s1
Yield: 65 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-acetyl-5-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 65%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=CC=1Cl)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1Cl)c1cc(Br)ccc1OCc1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (468 mg, 11.16 mmol) in water (25 m) was added dropwise to a stirred solution of (2-chlorophenyl)methyl 5-bromo-2-{[(2-chlorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 27; 520 mg, 1.12 mmol) in THF (25 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 hours. The organic phase was evaporated and the aqueous phase (25 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and was extracted by ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a light yellow solid. 350 mg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(CC)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(CC)nc3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M172) (214 mg, 0.374 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (167 mg, 98%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH:20]1([C:23]2[CH:30]=[CH:29][C:26](/[CH:27]=[C:14]3\[N:13]=[C:11]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:19][CH:18]=4)[O:17][C:15]\3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(C2CC2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A mixture of N-[4-(2-cyclopropylethoxy)benzoyl]glycine (184 mg, 0.699 mmol) prepared in Example 1 (1b), 4-cyclopropylbenzaldehyde (compound described in Tetrahedron Lett., (2002), 43, 6987-6990, 113 mg, 0.773 mmol), sodium acetate (75 mg, 0.914 mmol), and acetic anhydride (660 μL, 6.99 mmol) was stirred at 120° C. for 30 minutes and then allowed to cool to room temperature. The solidified product was ultrasonically washed with n-hexane (2 mL) and water (4 mL). Then, the precipitate was collected by filtration, washed with water and n-hexane, and dried by heating under reduced pressure to give 196 mg of the title compound (yellow powder, yield 74%). Hereinafter, the compound obtained by this cyclizing reaction is called oxazolone.