Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[N:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cncc(Cl)c1
Product: O=C(O)c1cc(Cl)ccc1Oc1cncc(Cl)c1

Procedure:
The title compound was prepared according to the two steps procedure described in step 1 of Example 67 and step 2 of Example 99. Firstly, methyl 5-chloro-2-fluorobenzoate was reacted with 5-chloropyridin-3-ol. Next, the crude product was hydrolyzed to the corresponding carboxylic acid: 1H-NMR (DMSO-d6) δ 8.36 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=2.6 Hz), 7.70 (1H, dd, J=8.8, 2.6 Hz), 7.50 (1H, dd, J=2.4, 2.0 Hz), 7.29 (1H, d, J=8.8 Hz).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:12][C:2]([F:1])([F:11])[C:3]1[CH:4]=[C:5]([OH:7])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccccc1
Product: Oc1cc(C(F)(F)F)nc2ccccc12

Procedure:
Ethyl trifluoroacetoacetate (3.7 g) and aniline (1.8 ml) were reacted together in polyphosphoric acid according to Joullie et al, J. Med. Chem., 16, 134 (1973), to give 2-trifluoromethyl-4-hydroxyquinoline (1.8 g). The latter was reacted with phosphorous oxychloride and phosphorous pentachloride in a similar fashion to Example VIII to give 2-trifluoromethyl-4-chloroquinoline, which was used in Stage a.
Reaction SMILES: [C:1](=[N:9]O)([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](=[S:13])=[S:12].C[O-].[Na+]>C(O)C>[SH:13][C:11]1[S:12][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: NC(=NO)c1ccccc1
Reactant: S=C=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Sc1nc(-c2ccccc2)ns1
Yield: 39 %

Procedure:
A mixture of benzamidoxime (270 parts) carbon disulphide (152 parts), 5-normal sodium methoxide (40 parts) and ethanol (200 parts) were heated at reflux for 16 hours. The solution was evaporated to dryness and the residue washed with 3-normal hydrochloric acid to give 5-mercapto-3-phenyl-1,2,4-thiadiazole (152 parts, 39% yield), melting point 147°-148° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:23])[CH:19]=[C:20]([CH3:22])[NH:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Reaction time: 4 h
Yield: 89 %

Procedure:
(4-Fluorophenyl)hydrazine hydrochloride (20.0 g, 0.123 mol) was added to a solution of triethylamine (20.5 mL) in methanol (350 mL). Then, a solution of ethyl acetoacetate (16.0 g, 0.123 mol) in methanol (50 mL) was added. The resulting reaction mixture was stirred for 4 hours under reflux and extracted with dichloromethane and sodium chloride aqueous solution. The aqueous layer was extracted again with dichloromethane. All the organic layers were collected, dried with Na2SO4 and then filtered. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2). The target compound was yielded (21.0 g, 89% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:18]=2)[N:13]=1)([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2[C:49]([F:52])([F:51])[F:50])N=1)(C)CO.C(O)(C(F)(F)F)=O>>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[C:18]=2[C:49]([F:52])([F:51])[F:50])[N:13]=1)([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC(C)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
{1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester Enantiomer 1 was synthesized as per {1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester Enantiomer 1 (Example 28) in 95% yield using 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propan-1-ol Enantiomer 1 as starting material (bis-TFA salt).
Reaction SMILES: CO[C:3]1[C:4]([O:12]C)=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.NC([C:20](O)=[O:21])CCSC.O>CS(O)(=O)=O>[OH:12][C:4]1[CH:3]=[C:8]([O:21][CH3:20])[CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cccc([N+](=O)[O-])c1OC
Reactant: CSCCC(N)C(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of dimethoxynitrobenzene (30.0 g, 0.163 mol) in 99% methanesulfonic acid (300 ml) was added dl-methionine (31.8 g, 0.212 mol) and the mixture was stirred at rt for 24 h. The solution was poured onto ice and stirred with water (1.5 l). The precipitate was filtered and washed with water. The title compound was collected as a yellow solid (23.1 g, 84%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][C:8]2=[S:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:18][CH2:19][CH2:20]CC)[CH2:15][CH2:16][CH3:17]>>[CH2:19]([O:18][C:14](=[C:10]1[S:9][C:8](=[S:13])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:12])[CH2:15][C:16]1[CH:17]=[CH:3][CH:2]=[CH:1][CH:6]=1)[CH3:20]
Reactant: O=C1CSC(=S)N1c1ccccc1
Reactant: CCCCOCCCC
Product: CCOC(Cc1ccccc1)=C1SC(=S)N(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
Alternatively, a mixture of 6 g. (0.029 m.) of 3-phenyl-rhodanine, 15 g. (0.063 m.) of triethylorthophenylacetate and 15 ml. of n-butyl ether is heated to reflux and then distillate is removed until the temperature of the mixture reaches 150°C. After heating at this temperature for one hour, an additional 5 g. of orthoester is added and heating is continued for 30 minutes. To the reaction mixture is added 5 ml. of acetic anhydride and heating is continued for 5 minutes. The resulting mixture is concentrated in vacuo and the residue is eluted through a column of silica gel with 2:1-cyclohexane-benzene. The product from the first eluates give 5-(1'-ethoxy-2'-phenylethylidene)-3-phenylrhodanine, m.p. 119°-121°C. Alkaline hydrolysis as described above of this intermediate furnishes the identical hydroxy derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:20][S:21][CH2:22][C:23]=2[C:24]([O:26]C)=O)=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:26])[C:23]3[CH2:22][S:21][CH2:20][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CSC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[4-(methoxycarbonyl)-2,5-dihydrothien-3-yl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-2,4-dioxothieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 180°-183° C.,
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH2:18][CH2:17][C:16]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:18][O:15][CH2:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C1CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCN(C2COC2)CC1
Reaction time: 1.25 h
Yield: 66.3 %

Procedure:
To a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (200 mg, 1.0 mmol) in DCE (6 mL) was added oxetanone (60 mg, 0.83 mmol) in DCE (2 mL). After 75 min, sodium triacetoxyborohydride (282 mg, 1.33 mmol) was added in one portion. After 20 hours at ambient temperature, the reaction mixture was loaded directly onto a 5 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo followed by flash chromatography of the resultant residue (silica, 5 g column, Si-SPE, 0-10% methanol in dichloromethane) afforded the title compound as a white solid (141 mg, 67%). 1H NMR (300 MHz, CDCl3): 4.62-4.61 (m, 4H), 4.44 (s, 1H), 3.46-3.45 (m, 2H), 2.67 (d, J=10.9 Hz, 2H), 2.02-1.88 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][CH:16]=[C:15]([F:18])[CH:14]=2)[N:1]=1
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cc(F)ccc2nc(CCl)n1-c1ccccc1Cl
Yield: 12.1 %

Procedure:
Prepared according to Procedure B with 1r (850 mg, 3.21 mmol) and chloroacetyl chloride (0.77 mL, 9.63 mmol) in acetic acid (15 mL). Purified by extraction from aqueous K2CO3, followed by chromatography in EtOAc/hexanes. A second chromatography in acetone/hexanes afforded 125 mg of a white solid (12%). 1H NMR (CDCl3) δ: 7.95 (dd, J=2.9, 8.2 Hz, 1H); 7.81 (dd, J=4.8, 9.0 Hz, 1H); 7.61-7.66 (m, 1H); 7.57 (dd, J=2.7, 8.6 Hz, 1H); 7.57 (dd, J=2.7, 8.6 Hz, 1H); 7.52 (dd, J=3.2, 6.9 Hz, 1H); 7.52 (br s, 2H); 4.38 (d, J=12 Hz, 1H), 4.08 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5](C(O)=O)([CH2:6]3)[CH2:4]2.OS(O)(=O)=O.[N-:20]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:20])([CH2:6]3)[CH2:4]2
Reactant: COC12CC3CC(C1)C(C(=O)O)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC12CC3CC(C1)C(N)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To the suspension of 1-methoxytricyclo[3.3.1.03,7]nonane-3-carboxylic acid obtained from step IV (0.39 g, 2.0 mmol) in CHCl3 (10 mL) was added conc. H2SO4 (1.0 mL, 20 mmol). Solid NaN3 (0.39 g, 6.0 mmol) was added in portions by keeping the reaction temperature below 40° C. After stirring at room temperature for 2 hrs, the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-methoxytricyclo[3.3.1.03,7]nonan-3-amine (0.23 g) in 69% yield. m/z (M+1) 168; 1H NMR (CDCl3) 300 MHz δ 3.27 (s, 3H), 2.40-2.34 (m, 1H), 2.16-2.08 (m, 1H), 1.97 (ddd, J=2.0, 6.8, 8.7 Hz, 1H), 1.92-1.53 (m, 7H), 1.51-1.38 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[OH:15])=[CH:5][CH:4]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:15][C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@:9]2([OH:16])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@@]2(O)CCCC[C@@H]2O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@]2(O)CCCC[C@@H]2OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
[1S*,2S*]-1-(4-methoxyphenyl)cyclohexane-1,2-diol (2.02 g, 9.1 mmole, prepared in Part A above) was dissolved in pyridine (25 mL) and cooled in ice bath, then p-toluenesulfonyl chloride (2.71 g, 14.3 mmole) was added in portions. The resultant orange solution was allowed to warm to ambient temperature over a period of about 1 hours, stirred at ambient temperature overnight, and then added slowly to ice-water with stirring. The resultant gray solids were filtered and dried to yield the desired crude product (1.073 g). Recrystallization from benzene/petroleum ether gave the purified product as pale straw-colored plates.(0.88 g, 0.23 mmole, 25% yield based upon the diol starting material). Treatment of a saturated benzene solution of this purified product with charcoal and recrystallization by addition of petroleum ether to the benzene solution resulted in a product in the form of white plates.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:13])[CH:6]=[C:5]1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:6]=[C:5]1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1
Reactant: COCn1c(-c2nccs2)cc2cccc(N)c21
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: COCn1c(-c2nccs2)cc2cccc(NS(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of 1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indole-7-amine (1.87 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (1.57 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.69 g, yield 92%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 95-97° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22](=O)N(C)C)=[CH:17][CH:16]=2)=[CH:10][C:9]=1[O:27][CH2:28][O:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C([CH:36]1[O:38][CH2:37]1)Cl>CO>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][CH:37]3[CH2:36][O:38]3)=[CH:17][CH:16]=2)=[CH:10][C:9]=1[O:27][CH2:28][O:29][CH3:30])([CH3:2])([CH3:4])[CH3:3]
Reactant: ClCC1CO1
Reactant: COCOc1cc(Oc2ccc(SC(=O)N(C)C)cc2)ccc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOc1cc(Oc2ccc(SCC3CO3)cc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of compound 18 (0.65 g, 1.5 mmol) in anhydrous MeOH (10 mL) was added potassium hydroxide (0.42 g, 7.5 mmol). The mixture was refluxed for 4 h and then cooled to room temperature. Epichlorohydrin (0.21 g, 2.3 mmol) was added dropwise and the mixture was stirred at room temperature for 15 min, after which the solvent was removed under reduced pressure. The concentrate was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the suspension was filtered, followed by concentration of the filtrate in vacuo. Purification by silica gel chromatography (hexanes/EtOAc=4/1) gave 19 in 68% yield (0.43 g) 1H NMR (500 MHz, CDCl3) δ 1.53 (s, 9H), 8.03 (br. s., 1H), 2.47 (dd, J=2.6, 5.0 Hz, 1H), 2.77 (t, J=4.4 Hz, 1H), 2.85 (dd, J=6.1, 13.9 Hz, 1H), 3.12-3.05 (m, 1H), 3.18-3.12 (m, 1H), 5.18 (s, 2H), 3.48 (s, 3H), 6.66 (dd, J=2.6, 8.8 Hz, 1H), 6.92-6.85 (m, 3H), 6.98 (br. s., 1H), 7.44-7.37 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 28.5, 38.2, 47.6, 51.3, 56.5, 80.6, 95.4, 106.8, 113.1, 118.4, 119.4, 125.1, 128.0, 131.8, 133.8, 146.6, 151.2, 152.9, 157.9. HRMS (FAB) calcd for C22H28NO4S (M+H+) 434.1632. found 434.1637.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CO
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Product: CC(C)COC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of isobutanol and the suspension is saturated with hydrogen chloride gas for 31/2 hours at 70°. After concentration, the residue is dissolved in 10 ml of isobutanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 163°-164°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[CH3:13][O:14][C:15](=[O:31])[C:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH:29]=O)([CH2:19][CH3:20])[CH2:17][CH3:18].N1CCCC1>CO>[CH3:13][O:14][C:15](=[O:31])[C:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1/[CH:29]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][C:3]([F:12])=[C:2]([Cl:1])[CH:10]=2)([CH2:17][CH3:18])[CH2:19][CH3:20]
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Solvent: CO
Solvent: C1CCNC1
Product: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)c(F)cc21)C(=O)OC
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (500 mg, 2.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-ethyl-butyric acid methyl ester (844 mg, 2.97 mmol) in methanol (5 mL) was added pyrrolidine (95 mg, 1.35 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was partitioned between EtOAc and diluted HCl solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product as a red-yellow solid, which was used for the next step reaction without further purification.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.Br[C:20]1[CH:33]=[CH:32][C:31]2[O:30][C:29]3[C:24](=[CH:25][C:26]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:27][CH:28]=3)[C@@:23]3([N:44]=[C:43]([NH2:45])[CH2:42][O:41][CH2:40]3)[C:22]=2[CH:21]=1.O>O1CCOCC1>[CH3:37][C:36]([CH3:39])([CH3:38])[CH2:35][O:34][C:26]1[CH:27]=[CH:28][C:29]2[O:30][C:31]3[C:22](=[CH:21][C:20]([C:15]4[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=4)=[CH:33][CH:32]=3)[C@:23]3([N:44]=[C:43]([NH2:45])[CH2:42][O:41][CH2:40]3)[C:24]=2[CH:25]=1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 135 °C

Procedure:
In a microwave vessel, potassium phosphate (0.012 g, 0.056 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (0.985 mg, 1.391 μmol) and 2-fluoropyridin-3-ylboronic acid (5.23 mg, 0.037 mmol) were loaded as solids, and (3R)-2′-bromo-7′-(2,2-dimethylpropoxy)-6H-spiro[1,4-oxazine-3,9′-xanthen]-5-amine (0.008 g, 0.019 mmol) was added via cannula as a solution in dioxane (1 mL). Water (0.25 mL) was added to the vessel, and the mixture was purged with argon gas, then the vessel was sealed and heated in microwave radiation at 135° C. for 30 min. The material was taken up in water (10 mL) and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate, and concentrated. The material was purified by preparative TLC (13% MeOH/DCM) to afford (3S)-2′-(2,2-dimethylpropoxy)-7′-(2-fluoro-3-pyridinyl)-6H-spiro[1,4-oxazine-3,9′-xanthen]-5-amine.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Oc3ccc(Cl)cc3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 4-chlorophenol (0.22 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(4-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.59 g, 84%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)(O)[CH:9]=[C:10]([CH3:12])[CH3:11]>COCCOCCOC>[CH3:11][C:10]1([CH3:12])[CH:9]=[C:8]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CC(C)=CC(O)(c1ccccc1O)c1ncccc1C
Solvent: COCCOCCOC
Product: Cc1cccnc1C1=CC(C)(C)Oc2ccccc21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4.5 g of 1-(2-hydroxyphenyl)-3-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol were dissolved in 50 ml of diethylene glycol dimethyl ether and heated at reflux for 1 hour. The mixture was allowed to cool to room temperature and then evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) and then ethyl acetate/petroleum ether (1:2) for the elution to give 2.97 g of 2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[Li+].[OH-:16]>C1COCC1.CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]=[CH:7][C:5]([O:6][CH2:2][CH3:1])=[O:16]
Reactant: [OH-]
Reactant: Cc1oc(-c2ccccc2)nc1C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C=Cc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
5-Methyl-2-phenyloxazole-4-carbaldehyde [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] (5.62 g, 30 mmol), triethylphosphonoacetate (6.55 mL, 33 mmol), and LiOH (1.38 g, 33 mmol) were dissolved in anhydrous THF (150 mL) and stirred for 18 h at ambient temperature under an atmosphere of nitrogen. The reaction mixture was then diluted with ether (100 mL) and washed with saturated NH4Cl solution (100 mL), then water (100 mL). The aqueous layers were back-extracted with ether (100 mL) and the combined organic layers were again washed with water (100 mL). The ether layer was dried over MgSO4 and concentrated. The resultant residual solids were purified by column chromatography (250 mg silica, 100% hexanes to 10% EtOAc/hexanes) to provide a white crystalline solid (3.46 g, 45%): Rf=0.55 (50% hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.97-8.05 (m, 2H), 7.50 (d, 1H), 7.40-7.44 (m, 3H), 6.63 (d, 2H) 4.26 (q, 2H), 2.43 (s, 3H), 1.33 (t, 3H); MS(EI): 258 (M+1).