Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([NH:23][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:30]([O:37][C:38]([NH:40][C:41]1([C:44](O)=[O:45])[CH2:43][CH2:42]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:16]([N:23]([C:44]([C:41]1([NH:40][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH2:42][CH2:43]1)=[O:45])[C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: COC(=O)[C@H](C)NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)[C@H](C)N(Cc1ccccc1)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N,N′-dicyclohexylcarbodiimide (6.0 g, 29.0 mmol) was added to a dichloromethane (150 ml) solution of methyl N-benzyl-L-alaninate (5.20 g, 26.9 mmol) and 1-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylic acid (6.30 g, 26.7 mmol) under ice cooling and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate, insoluble matter was removed by filtration and then the filtrate was washed with 1 N aqueous hydrochloric acid solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:3 (v/v)] to give the title compound (7.80 g, 71%) as a colorless oil.
Reaction SMILES: S1C=CN=C1.Br[CH2:7][C:8](=O)[C:9]([OH:11])=[O:10].[NH2:13][C:14]([NH2:16])=[S:15]>>[NH2:16][C:14]1[S:15][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[N:13]=1
Reactant: NC(N)=S
Reactant: O=C(O)C(=O)CBr
Agent: c1cscn1
Product: Nc1nc(C(=O)O)cs1

Procedure:
Thiazole derivative IIb can be prepared according to any of a variety of methods. Ester of 2-amino-4- and 5-thiazolecarboxylic acids can be prepared by any method described in "Heterocyclic Compound", Elderfield, 5, 624. For example, reaction of bromopyruvic acid with thiourea gives 2-amino-4-thiazolecarboxylic acid (J. Am. Chem. Soc. 68, 266 (1946)) which is subjected to the Gattermann reaction to give 2-halogeno derivatives. Ester of 2-halogeno-5-methyl-4-thiazolecarboxylic acid can be obtained from 2-chloro-2,3-epoxybutyric acid ester with thiourea (Bull. Chem. Soc. Jap. 43, 2997 (1970)). Ethyl 2-halogeno-4-methyl-5-thiazolecarboxylate can be prepared from ethyl α-chloroacetoacetate with thiourea (J. Pharm. Soc. Jap., 76, 301 (1956)). These compounds are subjected to the Arndt-Eistert reaction with diazomethane or diazoethane or alkylation to give the corresponding acetic or propionic acid. Further, ethyl 2-chloro-4-methyl-5-thiazolecarboxylate can be prepared from ethyl 3-thiocyano-3-acetoxypropionate according to the method shown in U.S. Pat. No. 2,319,570. Ethyl 2-(2-bromo-4-thiazolyl)propionate is also prepared from ethyl 2-bromoacetylpropionate with thiourea (J. Am. Chem. Soc. 63, 2946 (1941)). Thiazole derivative IIb substituted with an alkyl group other than methyl can be prepared by condensation following the method described above or alkylation of the thiazole derivatives prepared above.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)(OC(C)(C)C)=O.[F:17][C:18]1[C:19](I)=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])/[C:21]/2=[CH:28]\[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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.[Cu]I>[NH2:8][C@@H:12]([CH2:11][OH:10])[C:13]#[C:14][C:19]1[C:18]([F:17])=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:22](=[O:27])[NH:23]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](N)CO)c21
Reaction time: 2 h

Procedure:
Using Method C above, (R)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (141 mg, 0.62 mmol) (Example 91A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 8.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-50% THF in hexanes gradient. The intermediate that resulted from this operation was directly dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.6 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 10 mg, 14%).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][Cl:22])[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCOc1ccnc(CO)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCCCCCOc1ccnc(CCl)c1C
Yield: 90.2 %

Procedure:
16.0 g (0.05 mol, 1.0 eq.) of 4-nonyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 320 mL of ethyl acetate, and 6.5 g (0.055 mol, 1.1 eq.) of thionyl chloride was added dropwise at 8 to 12° C. Subsequently, the mixture was allowed to react for 0.5 hours at room temperature, and then a 7% aqueous solution of sodium bicarbonate (200 g) was added to adjust the reaction liquid to pH 7.5. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (160 g), dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 12.8 g of 4-nonyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:15]=[C:14]([S:16][CH3:17])[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([S:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>CO.O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([S:18][CH3:19])[C:8]([C:9]([OH:11])=[O:10])=[C:14]([S:16][CH3:17])[CH:15]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(SC)cc(OC2CC2)cc1SC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1cc(OC2CC2)cc(SC)c1C(=O)O

Procedure:
To a microwave heating vial was add ethyl 4-(cyclopropyloxy)-2,6-difluorobenzoate (1 g, 4.13 mmol) and DBU (2.18 ml, 14.5 mmol). The reaction mixture was cooled with dry ice acetone bath. Methanethiol (˜1 ml) was condensed into the vial. The vial was sealed and the resulting reaction mixture was heated at 100° C. with microwave for 1 hour. The volatiles were removed by a stream of nitrogen. The residue was diluted with 60 ml ether, extracted with 2×30 ml 5% KOH. The aqueous portion was acidified with concentrated HCl to cause precipitation. The mixture was filtered and the precipitate was washed with 15 ml water. The resulting solid was air dried to give 0.37 g desired product as white solid. The organic portion was washed with 60 ml 1N HCl, dried over sodium sulfate, filtered and concentrated to give 0.78 g oil which contains mostly ethyl 4-(cyclopropyloxy)-2,6-bis(methylthio)benzoate. It was dissolved in 20 ml methanol and 3 ml water. LiOH (2 g) was added. The resulting reaction mixture was refluxed for 24 hours. The volatiles were removed, and the residue was dissolved in 40 ml water, washed with 30 ml ether, acidified with concentrated HCl to cause precipitation. It was filtered, washed with 20 ml water, air dried to give 0.52 g desired product as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:8][C:4]1[CH:3]=[C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(Br)ccn1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-n2cccn2)ccn1
Temperature: 120 °C
Yield: 91.9 %

Procedure:
To a mixture of 4-bromo-2-methylpyridine [22282-99-1] (350 mg, 2.05 mmol), 1H-pyrazole (140 mg, 2.05 mmol), 1,10-phenanthroline (74 mg, 0.41 mmol) and K2CO3 (567 mg, 4.1 mmol) in toluene (2 mL), CuI (19 mg, 0.1 mmol) was added and the reaction mixture was heated at 120° C. for 70 h in a sealed tube. The reaction mixture was cooled to rt, quenched with water (50 mL) and extracted with dichloromethane (150 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified flash column chromatography (eluent: 30% ethyl acetate in hexane) to yield the title compound (300 mg, 92%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.53 (d, 1H), 8.02 (d, 1H), 7.77 (d, 1H), 7.55 (d, 1H), 7.44-7.40 (m, 1H), 6.52 (t, 1H), 2.62 (s, 3H); TLC Rf=0.28 (ethyl acetate/hexane 30:70)].
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(C)=[O:20])(F)(F)F.OO>C([O-])([O-])=O.[K+].[K+]>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:20][C@@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C(=C/c1ccccc1)\c1ccccc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 310.8 %

Procedure:
To a mixture of suspension of trans-stilbene (18.02 g, 0.1 mol) and CF3COCH3 (3.36 g, 0.03 mol) in CH3CN-DMM (½ v/v, 750 mL) and aqueous K2CO3 (1.5 M in 4×10−4 M EDTA, 150 mL) was added H2O2 (30%, 40 mL, 0.4 mol) at 0° C. Upon stirring at 0° C. for 1 h and at room temperature for 5 h, the reaction mixture was extracted with hexane (3×500 mL). The combined organic layers were washed with aqueous Na2S2O3 (1 M) (3×50 mL) and brine (100 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography on silica gel (buffered with 1% NEt3) using hexane-ether as eluent to give trans-stilbene oxide as a white solid (18.3 g, 93.3%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:20][C:19]3([CH3:22])[CH2:21][CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18]3)=[O:13])=[CH:8][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:14]2[CH2:20][C:19]3([CH3:22])[CH2:21][CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18]3)=[O:13])=[CH:10][CH:11]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Solvent: C1CCOC1
Product: COCCN(C(=O)c1ccccc1)c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a mixture of [4-(2-methoxy-ethylamino)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.1 g, 0.303 mmol) and TEA (0.13 ml, 0.91 mmol) in dry THF (20 ml) was added dropwise benzoyl chloride (0.07 ml, 0.61 mmol). The mixture was stirred for 1 hr. and evaporated in vacuo. The residue was purified on column chromatography (silicagel) using EtOAc-Heptane (1:1) as eluent. Pure fractions were collected; the solvent evaporated in vacuo affording 90 mg (68%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)O)c1
Temperature: 150 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a solution of 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C, 1.00 g, 4.36 mmol) in DMF (20 mL), was added 2-bromo-5-methoxybenzoic acid (1.01 g, 4.36 mmol), potassium carbonate (723 mg, 5.23 mmol), and copper (II) acetate (32 mg, 0.17 mmol). The mixture was stirred at 150° C. for 18 h and then cooled to rt. The solution was adjusted to pH 4 using glacial acetic acid. The mixture was extracted with dichloromethane (3×5 mL), and then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by HPLC (45-90% acetonitrile in water) to afford the product (500 mg, 33%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (s, 9H), 1.98 (s, 3H), 3.69 (s, 3H), 6.19 (s, 1H), 7.14 (dd, 1H), 7.26-7.37 (m, 6H), 9.49 (s, 1H), 13.25 (s, 1H); ES-MS m/z 380.3 (MH+); HPLC RT (min) 3.18.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:11])[CH3:8]>C1C=CC=CC=1.CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([C:15]([Cl:4])=[O:17])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C1(C(=O)O)CC1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Cl)CC1

Procedure:
Oxalyl chloride (6.0 g. 47 mmol) was added to a stirred mixture of 1-ethoxycarbonylcyclopropane carboxylic acid (1a) (6 g, 38 mmol) in benzene (25 ml) plus two drops of dimethylformamide. After the gas evolution ceased, the stirring was continued at room temperature for another hour. The reaction mixture was concentrated. The residue was purified by distillation. A fraction collected at 91°-2° C./15 mm was redistilled to give the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:33][C:34]1[CH:42]=[C:41]2[C:37]([CH2:38][CH2:39][CH:40]2[NH2:43])=[CH:36][CH:35]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:43][CH:40]2[C:41]3[C:37](=[CH:36][CH:35]=[C:34]([Cl:33])[CH:42]=3)[CH2:38][CH2:39]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: NC1CCc2ccc(Cl)cc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NC1CCc2ccc(Cl)cc21)C1COCCN1c1nc(Cl)ncc1Br

Procedure:
The title compound was prepared in a manner similar to PREPARATION x31 using 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 750 mg, 2.325 mmol), EDC (669 mg, 3.49 mmol), HOBt (534 mg, 3.49 mmol), 6-chloro-2,3-dihydro-1H-inden-1-amine hydrochloride (712 mg, 3.49 mmol), and triethylamine (0.486 mL, 3.49 mmol) in DMF (15 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.95 (m, 1H), 2.36-2.47 (m, 1H), 2.70-2.96 (m, 2H), 3.48-3.80 (m, 3H), 3.86-3.98 (m, 1H), 4.21-4.44 (m, 2H), 4.77-4.93 (m, 1H), 5.28-5.43 (m, 1H), 7.27 (s, 3H), 8.47 (d, J=7.58 Hz, 2H). ESI-MS m/z [M+H]+ calc'd for C18H17Br2Cl2N4O2, 470.99. found 471.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2(O)[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][CH:17]23)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=4)[O:9][N:8]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][C:17]=23)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=4)[O:9][N:8]=1
Reactant: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccn2)c1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.8 %

Procedure:
To a stirred suspension of 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (Preparation 63E, 0.081 g, 0.190 mmol) in anhydrous toluene (2.0 mL) at room temperature was added thionyl chloride (0.028 mL, 0.379 mmol) followed by pyridine (3.07 μl, 0.038 mmol). The reaction mixture was stirred at room temperature for 30 min. and then at 80° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated. The solid residue was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a tan solid. The crude products were combined and triturated with methanol with sonication. The solid was collected to provide 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.098 g, 0.239 mmol, 64% yield) as a tan solid. The product had an HPLC with a ret. time=3.36 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=409.9.
Reaction SMILES: CO[C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].[NH3:25]>CO>[F:20][C:17]1([F:19])[C:16](=[O:21])[N:15]([CH3:22])[C:14]2[CH:23]=[CH:24][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:25])=[O:4])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18]1
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Reactant: N
Solvent: CO
Product: CN1C(=O)C(F)(F)Oc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 44 %

Procedure:
To a stirred solution of (5R)-3-(2,2-difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M NH3 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time the reaction is concentrated under reduced pressure and purified by silica gel chromatography (EtOAc) to give the title compound as a light yellow solid (21 mg, 44%), 1H NMR (300 MHz, DMSO) δ 7.86 (br s, 1H), 7.61 (d, 2H), 7.52–7.41 (m, 2H), 5.02 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.42 (s, 3H); MS for C13H11F2N3O5 m/z 328.5 (M+H)+.
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[C:11]([O:20][CH:21]([CH3:23])[CH3:22])[C:10]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:20][CH:21]([CH3:23])[CH3:22])[C:10]=2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc(OC(C)C)c(-c2ccc(F)cc2)c(C2CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(C=O)cc(C2CC2)c1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A THF (10 mL) solution of ethyl 2-cyclopropyl-4′-fluoro-6-isopropoxybiphenyl-4-carboxylate (1.22 g) was added to a THF (20 mL) suspension of lithium aluminum hydride (0.3 g) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (0.3 mL) and a 15% aqueous sodium hydroxide solution (0.3 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (0.9 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). Manganese dioxide (3.21 g) was added to a toluene (10 mL) solution of the obtained purified product, and the mixture was stirred at 70° C. for 30 minutes in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (850 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=1)=[O:17].O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1)=[O:17]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Yield: 48.2 %

Procedure:
A solution of ethyl {4-[({2-chloro-5-[(phenylmethyl)amino]phenyl}carbonyl)amino]phenyl}acetate (90 mg, 0.21 mmol) in acetic acid (2 ml) and 2M HCl (2 ml) was heated at 90° C. for 2 hours. On cooling water was added then solvent evaporated in vacuo and azeotroped with toluene. The residue was purified by MDAP to afford the title compound as a white solid (40 mg). MS (ES+) m/z 395 [M+H]+ (C22H1935ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 3.51 (2H, s), 4.30 (2H, d, J 4.4), 6.63-6.73 (3H, m), 7.15-7.36 (10H, m), 10.3 (1H, s).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH2:47])=[C:35]2[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([O:44][CH3:45])=[O:43])[CH2:37][C:36]2=O)=[CH:30][CH:29]=1>C1C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]3[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([O:44][CH3:45])=[O:43])[CH2:37][C:36]=3[S:2][N:47]=2)=[CH:30][CH:29]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C1CCCC(=C(N)c2ccc(Cl)cc2)C(=O)C1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: c1ccccc1
Product: COC(=O)C1CCCc2c(-c3ccc(Cl)cc3)nsc2C1
Yield: 34.5 %

Procedure:
2 g of dry diatomaceous earth were stirred in 15 ml of dry benzene and 2 g (9 mmol) of phosphorus pentasulfide and 0.4 g (1.6 mmol) of 2,3,5,6-tetrachloro-p-benzoquinone was added. 0.5 g (1.62 mmol) of methyl 4-[(4-chlorophenyl)(amino)methylene]-3-oxocycloheptanecarboxylate was added and the mixture was heated under reflux for 0.5 hour. The mixture was filtered and the filter cake was washed with six 20 ml portions of hot ethyl acetate. The combined filtrate and washings were evaporated and the residue, after chromatography on silica gel using 30% ethyl acetate/hexane for the elution and recrystallization from methylcyclohexane, gave 0.18 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isothiazole-7-carboxylate of melting point 108°-109° C.
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[OH:22])=[O:12])([CH3:9])[CH3:8])(C)(C)C.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C:7]([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[O:22][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][N:27]=1)=[O:12])([CH3:8])[C:6]([OH:5])=[O:23]
Reactant: FC(F)(F)c1ccc(CBr)nc1
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1O
Product: CC(C)(NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cn1)C(=O)O

Procedure:
2-Methyl-2-{[4-(5-trifluoromethyl-pyridin-2-ylmethoxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid was prepared in analogy to example 13 via a sequence of an alkylation reaction of 2-[(4-Hydroxy-benzo[b]thiophene-5-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester using 2-bromomethyl-5-trifluoromethyl-pyridine and an acidic hydrolysis of the amino acid ester to the free amino acid