Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:5][O:6][C:7]1[C:8]([CH2:9][Cl:3])=[CH:11][CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1c(CO)cccc1Oc1ccccc1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1c(CCl)cccc1Oc1ccccc1C

Procedure:
Thionyl chloride (30 ml) and pyridine (1 drop) were added to a solution of 2-methoxy-3-(o-tolyloxy)benzyl alcohol (44.0 g) in benzene (150 ml). The mixture was refluxed under heating for 40 minutes and then evaporated. The residue was dissolved in diethyl ether, washed with aqueous sodium bicarbonate and water successively, dried over magnesium sulfate and then evaporated to give oily o-tolyl 2-methoxy-3-chloromethylphenyl ether (47.50 g).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)([OH:18])[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O.O>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=2)([O:18][CH3:34])[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:20][CH:21]=1
Reactant: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C(C)n1ncnn1
Reaction time: 20 h

Procedure:
1,1-bis(4-trifluoromethoxyphenyl)-2-(2H-tetrazol-2-yl)propanol (220 g) was added to a stirred suspension of sodium hydride (24 mg of a 50% dispension in oil) in dry dimethylformamide (6.0 cm3) at the ambient temperature under a nitrogen atmosphere, and the mixture stirred for a further 2 hours after which methyl iodide (71 mg) was added and the resultant mixtures stirred for a further 20 hours. After diluting with water the mixture was extracted with diethyl ether (3×15 cm3), the extracts were combined, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual yellow oil was subjected to h.p.l.c using a silica gel column eluted with a mixture of n-hexane and ethyl acetate (5:1 by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-1-methoxy-2-(2H-tetrazol-2-yl)propane.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=O)[CH2:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].CC[O-].[Na+]>C(O)C>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]1[C:8]([C:9]#[N:10])=[CH:7][NH:6][CH:5]=1
Reactant: N#CC=CNCC(=O)c1cccc(Cl)c1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl

Procedure:
4.2 g of the 3-(2,3-dichlorophenacylamino)acrylonitrile obtained in (a) are reacted in 50 ml of ethanol with 0.5 g of sodium ethylate as described in Example P5 (b), affording the title compound in quantitative yield. Melting point: 150°-152° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:27]1[C:35]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[CH:29]=[CH:28]1>>[CH3:19][N:18]([CH3:20])[CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:3][C:2]([N:27]4[C:35]5[CH:34]=[CH:33][N:32]=[CH:31][C:30]=5[CH:29]=[CH:28]4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5cnccc54)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine and 1H-pyrrolo[3,2-c]pyridine were reacted to give 149. MS m/e 478.6 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1)=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCN(c2ccccc2)CC1
Reaction time: 1 h
Yield: 134.2 %

Procedure:
19.7 g of N-(tert-butoxycarbonyl)tyrosine, 12.5 g of N-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were dissolved in 100 ml of tetrahydrofuran, and to the solution was added dropwise a solution of 18.7 g of DCC in 50 ml of tetrahydrofuran for 20 minutes with ice cooling, and the mixture was stirred for one hour. The reaction mixture was filtered to remove insoluble matter, which was then washed with 300 ml of ethyl acetate, and the filtrates were combined and concentrated under a reduced pressure. The resulting residue was dissolved in 500 ml of ethyl acetate, and the solution was washed three times with saturated sodium bicarbonate aqueous solution and once with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with ethyl acetate/hexane (1:2 to 1:1) to collect desired fractions, which were then combined and concentrated under a reduced pressure. Resulting residue was dissolved in 100 ml of ethyl acetate, and the solution was allowed to stand overnight&. in a refrigerator and then filtered to remove insoluble matter. The filtrate was concentrated under a reduced pressure, subjected to azeatropic distillation with benzene and dried under a reduced pressure to obtain 40.0 g of the title compound in a colorless amorphous form.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: COC1(c2cc(F)cc(F)c2)CCNC1
Yield: 35.5 %

Procedure:
Preparation according to Example 1. (+)-1-benzyl-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.35 g, 1.15 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.50 ml, 4.6 mmol) refluxed for 2 h, and methanol (10 ml) reflux 1 h Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.087 g, 35%). [a]D=+2.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 185-187° C. MS m/z (rel. intensity, 70 eV) 213 (M+, 1), 198 (54), 183 (bp), 171 (85), 141 (47).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15]3[C:14](=[O:22])[CH:13]=[CH:12][N:11]([CH3:23])[C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O>[Br:27][C:13]1[C:14](=[O:22])[C:15]2[C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=3)[C:9](=[O:24])[C:10]=2[N:11]([CH3:23])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CN2C(=O)c3c(c(=O)ccn3C)C23CCCCC3)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CN2C(=O)c3c(c(=O)c(Br)cn3C)C23CCCCC3)cc1
Temperature: 90 °C

Procedure:
To a solution of 6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (1.0 mmol, 1 eq) in carbon tetrachloride (25 mL), add N-bromosuccinimide and heat the mixture at 90° C. for 16 h. After completion the mixture was diluted with water and extracted with ethyl acetate. Remove the solvent under reduced pressure to get the crude. Purify the crude by column chromatography to afford 3′-bromo-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (7).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[C:8]([O:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=O)=[O:16])(=[O:10])[CH3:9]>>[C:8]([O:11][CH2:12][CH2:13][CH2:14][S:15]([Cl:2])(=[O:18])=[O:16])(=[O:10])[CH3:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)OCCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC(=O)OCCCS(=O)(=O)Cl
Reaction time: 2.5 h

Procedure:
A 100 g (0.48 mol) portion of phosphorus pentachloride is added to a flask containing 82.0 g (0.4 mol) of the above sulfonic acid salt. When the initial reaction subsides, the mixture is heated on the steam bath for 1 hr and 25 g of phosphorus pentachloride is added. Heating is continued for another 2.5 hr and another 10 g of phosphorus pentachloride is added and heating continued for 30 min. The dark reaction mixture is cooled and filtered and the filtrate distilled. The clear distillate is redistilled to give 42.3 g of 3-acetyloxy-1-propanesulfonyl chloride; bp 69°-81°/0.03 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.II.[Mg].[O:15]=[C:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc([Si](C)(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 2 L-3neck flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen inlet was charged with (4-bromophenyl)trimethylsilane (80.4 g, 0.35 mol), THF (600 mL), Mg (8.5 g), and I2 (catalytic amount). The suspension was refluxed at 68° C. for 1.5 hours until all magnesium disappeared. The solution was cooled to 0° C. in ice-bath. Then, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (Preparation 2, 30 g, 0.17 mol) in THF (200 mL) was added slowly via addition funnel. The solution was stirred at 0° C. for 3 hours. LC/MS indicated the formation of desired product. The reaction was quenched with brine at 0° C. The aqueous layer was extracted with EtOAc (2×800 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give the desired product (47.4 g, 84% yield). 1H NMR (CDCl3) δ 7.3 (d, 2H), 7.2 (d, 2H), 4.0 (d, 2H), 3.9 (d, 2H), 2.9 (s, 1H), 1.2 (s, 9H), 0.0 (s, 9H).
Reaction SMILES: [NH:1]1[C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=[N:2]1.[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=2)=[N:16]1>>[Cl:29][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[NH:6][C:5]4[NH:1][N:2]=[CH:3][C:4]=4[CH:8]=3)=[O:11])[CH3:30])[N:16]=2)[CH:27]=[C:26]([F:28])[C:23]=1[C:24]#[N:25]
Reactant: O=C(O)c1cc2cn[nH]c2[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc2cn[nH]c2[nH]1
Yield: 18.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h), starting from 1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid (0.280 mmol, 0.042 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.215 mmol, 0.080 g). The crude product was purified by preparative HPLC. 0.0164 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.29 (d, 3H), 4.27-4.34 (m, 1H), 4.36-4.43 (m, 1H), 4.50-4.60 (m, 1H), 6.75-6.79 (m, 2H), 7.58 (s, 1H), 7.60-7.65 (m, 1H), 7.69 (d, 1H), 7.79-7.82 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+:25]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([NH2:25])=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1noc2c1-c1ccnc(N)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 80 °C
Yield: 24.3 %

Procedure:
To a solution of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine (0.025 g, 0.076 mmol) in 1,4-dioxane (1 mL) was added concentrated ammonium hydroxide (2.00 mL, 51.4 mmol) at room temperature. The reaction was heated to 80° C. for 17 h before silica gel was added. The solvent was removed under vacuum, the dry silica gel was packed and the adsorbed product was purified by flash chromatography (hexane/EtOAc 6:4 to 0:10) to give 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine as an off-white solid (0.006 g). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=5.26 Hz, 1H), 7.38 (td, J=2.20, 8.93 Hz, 2H), 7.34 (td, J=2.20, 8.47 Hz, 2H), 6.94 (d, J=5.26 Hz, 1H), 5.91 (s, 2H), 5.21 (d, J=12.82 Hz, 1H), 4.04 (d, J=13.05 Hz, 1H), 2.50 (s, 3H); LC/MS m/z 325 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.C1C(=O)N([Br:24])C(=O)C1.O>FC(F)(F)C(O)=O>[Br:24][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7%) to get compound 0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+1]+, 1H NMR (400 MHz, DMSO-d6) 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15].[OH-].[Li+].O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15]
Reactant: COC(=O)c1ccc(Cl)c(C(F)F)c1SC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1c(C(=O)O)ccc(Cl)c1C(F)F
Yield: 93 %

Procedure:
Methyl 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoate (9.1 g) and lithium hydroxide (2.2 g) were dissolved in methanol and water and the mixture stirred overnight at room temperature. The mixture was then evaporated and the residue dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 2 M HCl and extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoic acid (8.02 g) as a beige solid NMR (CDCl3) 2.5(s,3H), 7.5(d,1H), 7.65(t,1H), 7.8(d,1H). By proceeding in a similar manner 4-chloro-3-(N,N-dimethylcarboxamido)-2-methylsulphenylbenzoic acid was prepared from the appropriately substituted starting material as a yellow solid, NMR (CDCl3) 2.5(s,3H), 2.8(s,3H), 3.2(s,3H), 7.4(d,1H), 7.9(d,1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C.Cl>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:31])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)CCNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c2c1OC
Temperature: 100 °C
Reaction time: 10 h
Yield: 70.1 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.50 g, 5.39 mmol), β-alanine ethyl ester hydrochloride (2.48 g, 16.1 mmol) and triethylamine (4.50 mL, 32.3 mmol) in anhydrous DMSO (30 mL) was stirred at 100° C. for 10 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and acidified with 1M HCl. The product was extracted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Trituration of the residue with MeOH (30 mL) gave 5-amino-1-cyclopropyl-7-[2-(ethoxycarbonyl)ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.54 g, 70%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-bromo-2,4-dimethylbenzene (1.85 g), 1-Boc-[1,4]diazepane (2 g), palladium(II) acetate (0.12 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.31 g) and sodium tert-butoxide (1.34 g) was added toluene (35 mL), and the mixture was stirred with heating under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g). The obtained 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g) was dissolved in chloroform (17 mL), 4N hydrogen chloride/ethyl acetate solution (6.9 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture to give the title compound (1.74 g).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>CO>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[CH:1]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)c2cc3ccccc3o2)cc1

Procedure:
To 11.0 g. (0.09 mol.) of salicylaldehyde in 30 ml. of dry methanol was added 5.1 g. (0.09 mol.) of potassium hydroxide dissolved in 50 ml. of methanol. The solution was refluxed for 10 minutes and 20.5 g. (0.09 mol.) of α-bromo-p-methoxyacetophenone dissolved in 50 ml. of warm methanol was added dropwise but rapidly over a 10 minute interval. The resulting solution was refluxed for one hour, then filtered and concentrated. The residue was dissolved in ether and the ether solution was washed with water. The aqueous washings were extracted twice with ether and the ethereal extracts were combined, reduced in volume, refluxed with decolorizing carbon, filtered, dried (MgSO4) and concentrated to give 2-(4'-methoxybenzoyl)benzofuran which was recrystallized from isopropanol, m.p. 93°-94°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[CH:20]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[CH3:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:9][C:2]=1[O:1][CH:20]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[CH3:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:5]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1O
Reactant: CCOC(=O)CCC(Cl)c1cc(C)ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
2-Hydroxy-4-(3-thienylmethoxy)benzonitrile (1.5 g) is added portionwise to a stirred suspension of sodium hydride (440 mg, 60% dispersion in mineral oil) in dry DMF(50 mL). After stirring at ambient temperature for 30 minutes, ethyl (RS)-4-chloro-4-(2,5-dimethylphenyl)butanoate (2.5 g) is added in one portion and the reaction stirred for 48 hours at 90° C. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer is extracted twice with ethyl acetate (50 mL). The combined organic phases are dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)-4-(2,5-dimethylphenyl)butanoate (500 mg) as a pale brown oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:11](I)[CH3:12]>CN(C)C=O.O>[CH2:11]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[CH3:12]
Reactant: CCI
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 16.6 g sodium hydride in 500 ml dry dimethylformamide (DMF) under nitrogen at 0° C. is added 90 g 5-hydroxy-2-methylpyridine at such a rate that the temperature remains between 0°-5° C. When gas evolution ceases, 73.8 ml ethyl iodide in 100 ml DMF is added dropwise. After stirring at room temperature overnight, the mixture is diluted with water and extracted with ether. The ether extracts are washed with brine, dried and concentrated. This oil is distilled to give 62.5 g of 5-ethoxy-2-methylpyridine, bp 89°-91° C. at 12 mm.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@](C(C)(C)C)=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl>C(Cl)Cl>[NH2:12][C@@H:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1)[CH2:2][NH:1][C:20](=[O:21])[O:22][CH3:23]
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.297 mmol) in DCM (988 μl) was added TEA (124 μl, 0.890 mmol) and methyl chloroformate (24.12 μl, 0.311 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted by EtOAc and the organics were washed with water and brine, dried over sodium sulfate, filtered off, and concentrated in vacuo. The residue was dissolved in Et2O (1 mL), then HCl (4M in dioxane) (148 μl, 0.593 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. After the solvent was decant out, the residue solid was used in next step without further purification. LCMS (m/z): 291.2/293 (MH+), 0.49 min.