Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc(N)c(CCl)c1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Product: COc1ccc2[nH]c(SCc3cc(C)ccc3N)nc2c1
Yield: 41.8 %

Procedure:
The title compound (1.95 g) was prepared by the method of Example 1 using 2.81 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 3.00 g of 2-(chloromethyl)-4-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04; S, 10.71. Found: C, 63.71; H, 5.80; N, 13.86; S, 10.60.
Reaction SMILES: CN(C)C=O.[CH:6]([O:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:6]([O:9][N:10]=[C:11]([N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7]
Reactant: CC(C)CCc1cccc(C(Cl)=NOC(C)C)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCc1cccc(C(=NOC(C)C)n2cncn2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 100 ml of N,N-dimethylformamide was added 1.5 g (5.6 mmol) of O-isopropyl-3-isopentylbenzohydroximoyl chloride, 0.8 g (11.6 mmol) of 1,2,4-triazole, and 1.6 g (11.6 mmol) of potassium carbonate. The mixture was stirred at 120° C. for 3 hours to complete the reaction. The reaction mixture was allowed to sit and cool naturally to room temperature. The cooled reaction mixture was poured into water and extracted with ethyl acetate. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was then removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.2 g (yield: 71%) of the desired product having a refractive index of [nD20 ] 1.5317 at 20° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CC[CH2:14][CH2:13]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[CH:13]=[CH2:14])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: C=CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Nitrobenzaldehyde (1 g, 6.6 mMoles) and 30 ml of dry tetrahydrofuran (THF) was stirred at 0° C. in a septum sealed flask equipped with a pressure equalizing funnel. After purging with dry nitrogen, 7 ml of 1M vinyl magnesium bromide in THF was added dropwise under a nitrogen atmosphere. After addition of the Grignard reagent, the reaction was allowed to stir at room temperature for 30 min. The bulk of the THF was removed under vacuum and the reaction was quenched by pouring it into a slurry containing 200 ml of water, crushed ice and 100 ml of ether. The final pH of the slurry was adjusted to near neutral by dropwise addition of 2M sulfuric acid. The product was extracted with ether and the pooled extracts were washed twice with 30 ml of water and twice with 30 ml of saturated NaCl. Ether was removed under vacuum yielding a dense yellow oil which was chromatographed on preparative silica TLC plates using toluene:acetonitrile 10:1 (v/v) as running solvent. Elution of the product from silica with methanol yielded 700 mg of semi-crystalline 1-(4'-nitrophenyl)-2-propen-1-ol. Recrystallization from toluene and then ethanol gave needles of pure product. IR: (chloroform) (cm-1) --OH, 3600, 1040; intermolecular --OH, --C=CH2, 3020, 2870, 985, 935 aromatic, 1607, 858; --NO2, 1510, 1350, 872. NMR: δ (p.p.m.) ([2H]chloroform), 2.2 (1H, broad s, --OH, D2O exchangeable), 5.26 (1H, d, J2,3 cis 10.6 Hz, J3,3 gem 1 Hz, --C=CH2), 5.32 (1H, broad m, --CH=C), 5.42 (1H, d, J2,3 trans 17.2 Hz, J3,3 gem 1 Hz --C=CH2), 6.0 (1H, m, C--CH=C), 7.4 (2H, d, J 9 Hz, aromatic), 8.21 (2H, d, J 9 Hz, aromatic). UVmax 272 nm, ε= 10,500M-1 cm-1 ; Mp.=55° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:17]C.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:17]
Reactant: COc1ccc(S(=O)(=O)c2cccs2)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(c1cccs1)c1ccc(O)c(Cl)c1Cl
Temperature: 185 °C

Procedure:
A stirred mixture of 2,3-dichloro-4-(2-thienylsulfonyl)anisole (7.0 g.) and pyridine hydrochloride (70.0 g.) are heated in an oil bath at 185° C. for 1/2 hour and poured into water (300 ml.) to give 5.7 g. of 2,3-dichloro-4-(2-thienylsulfonyl)phenol which melts at 220° C. after recrystallization from ethanol.
Reaction SMILES: [CH:1](=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+].O>CO>[C:2]1([CH:1]2[C:8]3([C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[O:19]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)C12OC2c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-benzylidene-1,3-indandione (20 g) in methanol (200 ml) was added 30% hydrogen peroxide (19 ml). The suspension was cooled to 5° C. and 1 N sodium hydroxide (2.1 ml) was added dropwise at such a rate as to keep the temperature below 15 ° C. After completed addition, stirring was continued at room temperature for 30 minutes. The mixture was then poured into water (1.2 L). The resulting crystalline precipitate was collected by filtration, washed on the filter with water (3×100 ml) and dried under high vacuum at room temperature for 24 hours, affording 3-phenylspiro[oxirane-2,2'-indan]-1',3'-dione as a yellow solid (17 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CCNCC
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 50 ml of diethylamine, a reaction similar to that conducted in Example 107 was carried out. As a result, 4.75 g of N-(trans-4-methylcyclohexyl)-4-(2-diethylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(Br)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
500 mg of 3-bromo-2-chlorobenzoic acid are placed in 12.5 ml of tetrahydrofuran in a round-bottomed flask. The reaction mixture is cooled to 0° C. with an ice bath and then 228 mg of N,O-dimethylhydroxylamine hydrochloride, 814 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.21 ml of pyridine are added thereto. The reaction mixture is subsequently stirred at ambient temperature for 16 h and the solvent is evaporated under reduced pressure. The residue is taken up between water and dichloromethane. The separated organic phase is subsequently washed once with a saturated ammonium chloride solution and once with a saturated sodium hydrogencarbonate solution, then dried over magnesium sulphate and concentrated under reduced pressure. 500 mg of compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: C1CCC(NC2CCCC2)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)N(C2CCCC2)C2CCCC2)cn1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
To a suspension of 6-methylnicotinic acid (1.37 g, 10 mmol) in toluene (10 ml), N,N-dicyclopentylamine (1.84 g, 12 mmol) was added To the homogenous solution obtained, phosphorus oxychloride (0.23 mL, 12 mmol) was injected in dropwise fashion. The reaction mixture was then immersed in an oil-bath at 130° C. and refluxed for 8 h. The reaction flask was cooled and stirred at room temperature. After 16h, the reaction was quenched with water and extracted in ethyl acetate. The organic layer was successively washed with aq. potassium carbonate, water and brine. After drying (MgSO4), the solvent was removed. The crude product (2.5 g) was chromatographed (silica gel, ethyl acetate/acetonitrile 100/1.5) to give the title compound (1.2 g, 44%). IR (KBr)1625, 1590, 1450, 1430, 1375, 1340, 1290, 1130, 840, 750 cm-1 ; 1H NMR (CDCl3) 1.4-2.35 (m, 16H), 2.57 (s, 3H), 3.6-3.9 (m,2H), 7.17 (d, J=8 Hz, 1H), 7.6 (dd,J=3,8 Hz, 1H), and 8.5 ppm (d,J=3 Hz,1H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCCO
Reactant: COc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1
Product: COc1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 468 (0.22 mmol) and but-3-yn-1-ol (0.28 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.8, 160.8, 148.5, 141.1, 141.0, 138.1, 135.5, 134.8, 133.9, 132.6, 130.4, 127.8, 122.2, 120.7, 119.9, 116.6, 113.6, 113.2, 109.4, 107.3, 61.6, 55.4, 28.7, 19.9
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19]O>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:19][CH2:18][CH2:17][CH2:16][Cl:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCCCCl
Product: ClCCCCOC(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
Starting with benzhydrol and 4-chloro-1-butanol, the procedure of Reference Example 15 was otherwise repeated to provide the title compoun. Yield 90%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16]N1C=CN=C1.O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13](=[O:15])[CH3:16]
Reactant: Cn1ccnc1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Treat a solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (30.0 g, 0.11 mol) in acetic anhydride (30 mL) with 1-methylimidazole (4.5 g, 55 mmol), stir at RT for 2 h, treat with water, stir for 5 min, and extract with EtOAc. Wash the combined organics with water, saturated. Na2CO3, then brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (EtOAc/petroleum ether) to afford the title compound (12 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=8.0 Hz, 1H), 8.02 (d, J=10.8 Hz, 1H), 4.09 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:9])=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:25]([C:32]1[N:37]=[N:36][C:35]([N:38]2[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]2)=[C:34]([CH3:45])[C:33]=1[CH3:46])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([C:32]1[N:37]=[N:36][C:35]([N:38]2[CH2:39][CH2:40][C:41]([OH:44])([C:2]3[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:9])=[CH:4][N:3]=3)[CH2:42][CH2:43]2)=[C:34]([CH3:45])[C:33]=1[CH3:46])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)nc1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(=O)CC2)c1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(O)(c3ccc(C(C)(C)OCOCC[Si](C)(C)C)cn3)CC2)c1C
Temperature: -40 °C

Procedure:
To compound 34 (272 mg, 0.786 mmol) in THF (6 mL) at −78° C. is added t-butyl lithium (1.7 M in pentane, 1.0 mL, 1.7 mmol). The mixture is stirred at −78° C. for 30 min, to which compound 24 (209 mg, 0.707 mmol) in THF (2 mL) is added at −78° C. The mixture is stirred and warmed up slowly to −40° C. in 1 h, then quenched at −40° C. with saturated ammonium chloride. THF is removed and the residue was extracted with ethyl acetate (3×). The organic phase is washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue is purified by silica gel chromatography (40-60% ethyl acetate in heptane) to provide recovered compound 24 (103 mg, 49%) and the title compound 35 (106 mg, 27%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1Br
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(Br)c1O
Reaction time: 1 h
Yield: 34.1 %

Procedure:
51.9 g (0.3 mol) of 2-bromophenol and 300 ml of acetic acid were fed into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer. Thereto was dropwise added 29.7 g (0.33 mol) of 70% nitric acid at a temperature of 15° C. or below, with ice-cooling. The reaction mixture was stirred at a temperature of 10° C. or below for 1 hour and poured into 600 ml of water. The mixture was subjected to extraction with 400 ml of ether. The ether layer was washed with 150 ml of water. The ether layer was subjected to distillation. The residue was transferred into a 1-liter flask provided with a stirrer and a distillation apparatus. Azeotropic distillation was conducted while water was added gradually. The amount of water required for azeotropic distillation was 2,100 ml. The distillate obtained was subjected to extraction two times using 500 ml of ether. The ether layer was dried over anhydrous sodium sulfate and subjected to distillation to remove ether. The resulting crude product was mixed with 10 ml of ethanol. The mixture was heated and then allowed to cool. The formed crystals were collected by filtration and then dried to obtain 22.3 g of 2-bromo-6-nitrophenol (yield: 34.1%, purity: 99.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 99.3 %

Procedure:
A mixture of 20.4 g of 2,6-dichloro-4-trifluoromethylbenzoic acid (11), 18.8 g of thionyl chloride and a small amount of anhydrous N,N-dimethylformamide was stirred at 90° C. overnight. The thionyl chloride was distilled off, and the resulting residue was distilled under reduced pressure to obtain 21.7 g of the desired compound in the form of a colorless liquid (quantitative yield).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C=[O:31])C.O=O>Cl[Pd]Cl.Cl[Cu].O>[Br:19][C:15]1[CH:14]=[C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][C:2](=[O:31])[CH3:3])[O:9][C:8]2=[O:10])[CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: O
Product: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Reaction time: 8 h
Yield: 86 %

Procedure:
(R)-6-allyl-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (55 mg, 0.13 mmol), PdCl2 (6 mg, 0.3 equiv.), and CuCl (26 mg, 2.3 equiv.) were mixed with DMF (2 mL) and water (˜250 μL). A balloon of oxygen was attached to the flask and the mixture was stirred vigorously overnight. LC-MS found the reaction completed. The mixture was quenched by satd aq NH4Cl solution (2 mL), diluted with EtOAc (20 mL), washed by brine (7 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to afford (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (49 mg, 86% yield). LC-MS (3 min) tR=1.76 min, m/z=434, 436 (M+1).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1CCC2(CC1)OCCO2
Temperature: 0 °C
Yield: 141.9 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (13.7 g, 38 mmol) in 1,4-dioxane (60 mL) was added potassium tert-butoxide (4.3 g, 38 mmol). The resulting yellow mixture was cooled to 0° C. in an ice-water bath and 1,4-dioxaspiro[4.5]decan-8-one (5 g, 32 mmol) was added slowly over 15 min as a solution in 1,4-dioxane (15 mL) via dropping funnel. The reaction was let stir and warm to rt over 1 h. The resulting brown-yellow reaction mixture was partitioned between methyl tert-butyl ether and saturated aqueous NH4Cl solution. The aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to ˜20 mL. The resultant beige suspension was diluted with heptane and filtered. The filtrated was concentrated by rotary evaporation in vacuo to afford ˜7 g of crude 8-methylene-1,4-dioxaspiro[4.5]decane as a yellow liquid containing residual heptane.
Reaction SMILES: [Cl:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15]CCC[CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2.N1N2C(N=C3C(=C2O)C[O:23]C3)=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:3]2[C:7](=[CH:6][CH:5]=[N:4]2)[N:8]=[C:9]2[C:10]=1[CH2:11][O:23][CH2:15]2
Reactant: Clc1c2c(nc3ccnn13)CCCCC2
Reactant: Oc1c2c(nc3ccnn13)COC2
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3ccnn13)COC2

Procedure:
Using the method described for the preparation of 10-chloro-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 5H,7H-6-Oxa-1,4,8a-triaza-s-indacen-8-ol and phosphorus oxychloride provided the title compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH3:15])[C:4]1=[O:16])[CH3:2].[C:19](O)(=[O:21])[CH3:20]>[Ni]>[CH2:1]([C:3]1([CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:19](=[O:21])[CH3:20])[CH:10]=2)[N:5]([CH3:15])[C:4]1=[O:16])[CH3:2]
Reactant: CC(=O)O
Reactant: CCC1(CC)C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Product: CCC1(CC)C(=O)N(C)c2ccc(NC(C)=O)cc21

Procedure:
3,3-Diethyl-1-methyl-5-nitro-1,3-dihydro-indol-2-one (9.3 g) is dissolved in acetic acid (100 ml) and subjected to a catalytic hydrogenation with Raney-nickel (1 g) at 3 bar. After completion of the hydrogenation the mixture is filtered and evaporated. The residue is treated with acetic anhydride (10 ml) for 3 h at RT. The mixture is concentrated in vacuo and purified by flash chromatography on silica gel eluting with light petroleum/EtOAc. After re-crystallization from diisopropyl ether the compound (7.1 g) is obtained as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:12][C:11]1[N:10]=[C:9]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[O:2]
Reactant: COC(=O)NN=Cc1nc(-c2cccc(C(F)(F)F)c2)[nH]c1C
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2c(=O)[nH]ncc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 155.2 %

Procedure:
3-{[5-Methyl-2-(α,α,α-trifluoro-m-tolyl)-4-imidazolyl]-methylene}carbazic acid methyl ester (3.0 g) is added rapidly to diphenyl ether (50 ml) preheated to 297° C., and the mixture is then kept at 297° for 15 minutes. The mixture is rapidly cooled to room temperature, hexane (50 ml) is added and the mixture filtered to yield 4.2 g yellow solid. This material is chromatographed on a silica gel column using a hexane-ethyl acetate mixture as eluent. The fractions found to be identical by TLC are combined to afford 1.86 g of the title product, m.p. 194°-194.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][OH:51])[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][OH:51])[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
A mixture of Intermediate 81d (319 mg, 0.85 mmol), Intermediate 29c (335 mg, 0.85 mmol) and DIPEA (294 μL, 1.69 mmol) in dioxane (10 mL) was stirred at 80° C. for 18 hours. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (362 mg, 66%). LCMS (Method 4): Rt 3.29 min, m/z 649 [MH+].