Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=C[C:21]2[CH2:22][S:23][C@@H:24]3[C@H:44]([NH:45][C:46](=[O:53])[CH2:47][C:48]4[S:49][CH:50]=[CH:51][CH:52]=4)[C:43](=[O:54])[N:25]3[C:26]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:55](=O)[CH2:56][CH3:57].[CH2:59](Cl)Cl>>[CH:57]([C:21]1[CH2:22][S:23][C@@H:24]2[C@H:44]([NH:45][C:46](=[O:53])[CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[C:43](=[O:54])[N:25]2[C:26]=1[C:27]([O:29][CH:30]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[CH:56][CH2:55][CH3:59]
Reactant: ClCCl
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: CCC=O
Product: CCC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 16 h
Yield: 10 %

Procedure:
Diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (1.528 g., 2 mmole) was dissolved in a mixture of freshly distilled propionaldehyde (25 ml., 350 mmole) and dry methylene chloride (25 ml.). The solution was stirred at 25° or 16 hours, the solvent and residual propionaldehyde removed by rotary evaporation, and the residue dissolved in methylene chloride (200 ml.). The resulting solution was washed successively with N-hydrochloric acid (200 ml.), 2N-aqueous sodium bicarbonate (200 ml.), water (200 ml.), brine (100 ml.), dried and evaporated to a yellow foam. This material was purified by column cchromatography on Kieselgel. Combination of similar fractions (as judged by TLC) gave the title compound as pale yellow crystals (110 mg., 10%), RF 0.70, m.p. 156°-158° (decomp.), [α]D - 10° (THF), λmax. 289 nm. (ε8,700) inflexion at 235 nm. (ε 14.600), νmax. (CHBr3) (--NH), 1782 (β-lactam), 1720 and 1230 (ester) 1684 and 1510 (-CONH-) cm. -1 ; the p.m.r. spectrum indicated that the compound was mainly the cis-isomer (with ca. 15% trans), with signals at τ 3.98 (--CH=CH.CH2CH3, d, J = 11 Hz.), 4.23 (C(7)H, dd, J 5 and 9 Hz.), 4.61 (=CH.CH2CH3, complex m), 5.04 (C(6)H, d, J 5 Hz.), 6.6 and 6.83 (C(2) -CH2, AB-q,JAB 18 Hz.), 8.22 (-CH2CH3, complex m), 9.18 (--CH2CH3, methyl t, J 8 Hz.), [Found: C, 66.25; H, 5.2; N, 5.1; S, 11.6; C30H28N2O4S2 (544.7) requires C, 66.15; H, 5.2; N, 5.1; S, 11.8%].
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:24]1>CS(C)=O>[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:4][CH2:37]2)[CH2:24]1
Reactant: C[S+](C)C
Reactant: C=C(CO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1)C(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(CO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At room temperature, 12 mg of a 60 percent strength sodium hydride suspension are added to a suspension of 55 mg of trimethylsulfonium iodide in 2 ml of DMSO, and the mixture is stirred at room temperature for 20 min. At 10° C., 100 mg of ethyl (1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]acrylate, dissolved in 2 ml of DMSO, are then added, and the mixture is stirred at room temperature for 90 min. The mixture is poured into ice-water and extracted with methyl tert-butyl ether. The organic phase is dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=2:1). This gives ethyl (1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclopropanecarboxylate as a colorless oil. C25H33NO5 (427.55), MS (ESI): 428 (M+H+).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[N:16](S(C2C=CC=CC=2)(=O)=O)[C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)#[CH:4].O.C(OCC)(=O)C>C1COCC1>[C:3]([C:5]1[NH:16][C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)#[CH:4]
Reactant: C#Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 60 °C
Yield: 106.9 %

Procedure:
Sodium hydroxide (0.39 mL, 0.39 mmol, 1M in water) was added to a solution of 2-ethynyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.032 g, 0.10 mmol) in THF (0.5 mL). The reaction mixture was heated at 60° C. for 90 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to afford 2-ethynyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.02 g, quantitative yield).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:7]([C:11]#[C:12][Si](C)(C)C)=[C:8]([CH:10]=1)[NH2:9])([O-:3])=[O:2]>CN(C=O)C.[Cu]I>[N+:1]([C:4]1[CH:10]=[C:8]2[C:7]([CH:11]=[CH:12][NH:9]2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c([N+](=O)[O-])cc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2[nH]ccc2cc1C(F)(F)F
Temperature: 135 °C
Yield: 30.6 %

Procedure:
To a solution of 5-nitro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (6.0 g, 19.85 mmol) in DMF (30 mL) was added CuI (1.9 g, 9.976 mmol) under an atmosphere of nitrogen. The reaction mixture was heated at 135° C. in a sealed pressure flask overnight. The reaction mixture was then filtered and the filtrate was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (5 to 20% EtOAc in petroleum as eluant) to obtain 6-nitro-5-(trifluoromethyl)-1H-indole (1.4 g, 31%). 1H NMR (400 MHz, CDCl3): δ 8.83 (br s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.58-7.57 (m, 1H), 6.80-6.79 (m, 1H); 19F NMR (282.4 MHz, CDCl3): δ-57.82; MS (ESI): m/z [M−H]− 229.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15]>C(O)C.C(O)(=O)C>[C:18]([O:17][C:13]([NH:14][N:15]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)CCC2=NNC(=O)OC(C)(C)C

Procedure:
A solution of 5-methoxyindan-1-one (5.46 g) and tert-butyl carbazate (4.45 g) in ethanol (100 ml) and glacial acetic acid (1 drop) was stirred and boiled under reflux for 2 hours. The volume was reduced by half under reduced pressure and the solid which crystallized was collected by filtration to give 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]12CC(C=C1)C=[CH:14]2.[O-]Cl.[Na+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH:14]=[CH:13][O:10][N:9]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Reactant: C1=CC2C=CC1C2
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccon2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
4-Nitrobenzaldehyde oxime (Intermediate 3, 20 g, 120.5 mmol) and bicyclo[2.2.1]hepta-2,5-diene (32.45 ml, 3015.25 mmol) were added to THF (200 ml) followed by dropwise addition of bleach (6.15% NaOCl, 861.5 ml). The reaction was allowed to stir overnight and then the THF and H2O layers were separated, the THF layer was dried over Na2SO4 and then concentrated under vacuum. The dried material was added to dioxane and heated to 100° C. for 7 days. The crude material was purified by column chromatography using 5–50% EtOAc in hexanes to yield the final product (10 g).
Reaction SMILES: [C:1]([NH:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].C(O)(=O)C>C(#N)C.ClCCl>[CH2:20]([O:19][C:15]([C:16]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[N:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:17]=1)=[O:18])[CH3:21]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)NN=Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1cn(C(C)(C)C)nc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
Add dropwise a solution of N-tert-butyl-N′-(4-fluorobenzylidene)hydrazine (Tetrahedron, 1986, 42, 4223-4234) (8.4 g, 43.2 mmol) in acetonitrile (43 mL) to a well stirred mixture of ethyl propiolate (4.4 mL, 43.2 mmol) and acetic acid (37 mL, 648 mmol) at RT. Warm the mixture at 50° C. for 2 days and at 60° C. for 1 day. Cool at RT and dilute with dichloromethane (250 mL). Wash the mixture with water (50 mL), a saturated aqueous solution of Na2CO3 (2×50 mL), dry (MgSO4), concentrate and purify (Biotage system eluting with CH2Cl2). Dissolve the yellow solid obtained in dichloromethane (43 mL) and acetic acid (37 mL) and bubble a stream of O2 at RT for 10 days. Dilute the mixture with dichloromethane (100 mL) and wash with a saturated aqueous solution of Na2CO3 (2×50 mL), dry (MgSO4) and concentrate and purify (Biotage system eluting with CH2Cl2) to provide the desired compound as yellow solid (6.4 g, 51% yield).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:6]1=2)[CH3:4].[NH2:23][CH2:24][CH2:25][N:26]1[CH:31]=[CH:30][C:29]2[O:32][C:33]([CH3:35])=[CH:34][C:28]=2[C:27]1=[O:36]>CO>[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH2:21][NH:23][CH2:24][CH2:25][N:26]3[CH:31]=[CH:30][C:29]4[O:32][C:33]([CH3:35])=[CH:34][C:28]=4[C:27]3=[O:36])[CH:19]=[CH:20][C:6]1=2)[CH3:4]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: Cc1cc2c(=O)n(CCN)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCn3ccc4oc(C)cc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride(0.15 g) was added to a methanol solution (150 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde(1.1 g) and 5-(2-aminoethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one(1.0 g), and the mixture was stirred at room temperature overnight. The reaction liquid was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][C:17]1([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O.C(N(CC)CC)C>O1CCCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:25][C:23](=[O:24])[C:17]2([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[N:16]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccco2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
6.0 g (44 mmol) of isobutyl chloroformate was added dropwise to a solution of 10 g (42 mmol) of 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid obtained in Reference Example 14 and 6.1 ml (44 mmol) of triethylamine in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystal was removed by filtration and the filtrate was concentrated. The obtained crystal was washed with water to obtain 8.95 g (97%) of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:1].[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCC1OCCO1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of 25 g. (0.138 mmole) of 2-(2-bromoethyl)-1,3-dioxolane and 36.2 g. (0.138 mmole) of triphenylphosphine in 30 ml. of toluene was heated at 100° C. for 18 hours. The reaction was cooled to yield two phases. The toluene phase was decanted and the oil remaining crystalized at -78° C. in ethyl acetate. Decantation of the ethyl acetate and warming of the crystals to room temperature gave an oil. The oil was dried under vacuum (0.05 torr) at 100° C. for 16 hours to yield 15 g. (27%) of the title compound as a solid glass which was ground to a powder.
Reaction SMILES: N1C(C)=CC=CC=1C.S(Cl)([Cl:11])=O.O[CH:14]([N:28]1[CH:31]([S:32][CH3:33])[CH2:30][C:29]1=[O:34])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]>O1CCCC1.C(OCC)(=O)C>[Cl:11][CH:14]([N:28]1[CH:31]([S:32][CH3:33])[CH2:30][C:29]1=[O:34])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C

Procedure:
2,6-Lutidine (626 mg) and thionyl chloride (695 mg) were successively added dropwise to a solution of p-nitrobenzyl 2-hydroxy-2-(4-methylthio-2-azetidinon-1-yl)acetate (1.59 g) in tetrahydrofuran (30 ml), whilst stirring at -20° C. The reaction mixture was stirred at -20° to -15° C. for 30 minutes, diluted with ethyl acetate, washed with water (once), neutralized with a dilute aqueous solution of sodium bicarbonate solution and further washed with water.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cnc(NC(=O)c3cccc(OC)c3)c(Cc3ccccc3)n2)cc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 82.5 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (800 mg, 2.75 mmol) in pyridine (10 mL) were successively added 4-(dimethylamino)pyridine (33.6 mg, 275 μmol) and m-anisoyl chloride (18) (773 μL, 5.50 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 22 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 100 g, dichloromethane/ethyl acetate=9/1). The residue was recrystallized from ethyl acetate to give Compound 11y (967 mg, 2.27 mmol, 82.5%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1), 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 6H), 4.19 (s, 2H), 7.05-7.12 (AA′BB′, 2H), 7.14-7.28 (m, 6H), 7.42-7.49 (m, 2H), 7.53 (d, 1H, J=7.5 Hz), 8.06-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.77 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 41.5, 55.3, 55.4, 112.5, 114.3 (2C), 118.6, 119.3, 126.7 (2C), 128.1, 128.55, 128.61 (2C), 128.5 (2C), 129.6, 135.0, 136.8, 137.7, 143.3, 149.2, 149.9, 159.8, 160.9, 165.7; IR (KBr, cm−1) 700, 746, 833, 1022, 1040, 1117, 1179, 1254, 1300, 1325, 1373, 1416, 1441, 1501, 1607, 1655, 2936, 3265; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.55; H, 5.36; N, 9.86.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.Cl.[NH2:34][CH2:35][C:36]1[C:37]([NH2:43])=[N:38][C:39]([CH3:42])=[N:40][CH:41]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:43][C:37]1[C:36]([CH2:35][NH:34][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[CH:41][N:40]=[C:39]([CH3:42])[N:38]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1ncc(CN)c(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ncc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)c(N)n1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 5-(aminomethyl)-2-methylpyrimidin-4-amine-2HCl (22.02 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (17.5 mg, 0.032 mmol, 45.6% yield): LCMS=552.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.53 Hz), 7.93 (1 H, s), 7.50-7.70 (7 H, m), 5.15 (1 H, s), 4.25 (2 H, d, J=4.02 Hz), 2.40 (3 H, s); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:37][CH2:36][O:35][C:34]1=[O:38]>>[O:38]=[C:34]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])[CH2:37][CH2:36][O:35]1
Reactant: NCc1ccccc1N1CCOC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)phenyl)oxazolidin-2-one, derived from reduction of intermediate 116, 2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (1H, t, J=6.0 Hz), 7.58-7.32 (7H, m), 7.22 (2H, t, J=7.5 Hz), 5.08 (2H, s), 4.48 (2H, t, J=7.8 Hz), 4.44 (2H, d, J=6.0 Hz), 4.06-3.97 (4H, m), 3.88 (2H, m), 1.56 (6H, s); LCMS (M+H)+ m/z 505.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1.[CH3:32][NH2:33].C1COCC1>C1COCC1>[CH3:32][NH:33][C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1
Reactant: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(SC)nc2c1C(=O)N(c1cccc(-c3nn(C)c(=O)o3)c1)C[C@@H]1CCCN21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 71.2 %

Procedure:
(S)-5-[3-(7-Chloro-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (50.0 mg, 0.109 mmol) obtained in Step 8 was dissolved in THF (5 mL), and the mixture was stirred at room temperature for 75 minutes after adding a 2.0 mol/L methylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(7-methylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (35.2 mg, 71%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=O)[O:24]C4C=CC=CC=4)[CH:17]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:41][NH2:42]>CN1C(=O)CCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][CH3:41])=[O:24])[CH:17]=3)=[CH:32][CH:33]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: CN1CCCC1=O
Product: CNC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2)ccn1
Temperature: 40 °C
Yield: 52 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (100 mg, 0.187 mmol), NMP (3 mL) and methylamine solution (25%, 0.2 mL) was heated at 40° C. overnight. The solvent was evaporated under reduced pressure at 40° C., and then diluted with water (10 mL). The precipitate was collected by filtration, and then purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=1/1/0.01) to give the title compound as a white solid (46 mg, 52%).
Reaction SMILES: C[C:2]1([OH:19])[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[C:9]4[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=4[S:7][CH2:6][C:5]=3[C:4]=2[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=C[CH:26]=1>C(Cl)Cl>[CH3:26][N:11]1[C:10]2[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[S:7][CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH:3]=2
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: CC1(O)C=Cc2[nH]c3c(c2C1)CSc1ccccc1-3
Solvent: ClCCl
Product: Cn1c2c(c3cc(OS(C)(=O)=O)ccc31)CSc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (35 mg, 0.131 mmol), CH3SO2Cl (15 μL, 0.197 mmol, 1.5 eq.), pyridine (20 mg, 0.262 mmol, 2.0 eq.) in CH2Cl2 (1 mL) was stirred at 25° C. for 2 hours. The mixture was then partitioned between CH2Cl2 and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material. The crude material was purified by chromatography to yield the title compound as a white solid.