Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CS(O[CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([O:1][C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
100 mg (0.38 mmol) of the compound of Example 24A and 104 mg (0.42 mmol) of tert-butyl 3-[(methylsulphonyl)oxy]azetidine-1-carboxylate together with 259 mg (0.80 mmol) of caesium carbonate were initially charged in 1 ml of DMF and stirred at 90° C. overnight. The mixture was then stirred into 10 ml of 0.1 M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 18). This gave 60 mg (88% pure, 33% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].O=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)[CH:10]=[O:11].C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:10]=2[OH:11])=[CH:13][CH:14]=1)[CH2:19][CH3:20]
Reactant: CNN=CC(C)=O
Reactant: CCCc1ccc(C(=O)C=O)cc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 6.2 %

Procedure:
2-Oxopropanal methylhydrazone (19.36 mmol, 1.94 g) and oxo(4-n-propylphenyl)acetaldehyde (19.0 mmol, 3.35 g) synthesized in Reference Synthetic Example 13 were dissolved in acetic acid (42 mL) and stirred at 100° C. for 6 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1), then by silica gel thin layer chromatography (chloroform) and by silica gel thin layer chromatography (n-hexane/ethyl acetate=7/2) to give the desired product as a brown solid (304 mg, yield 6%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO.C(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]2[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccccc2)CS(=O)(=O)CC1=Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3)CS(=O)(=O)CC2C1c1ccccc1
Yield: 48.7 %

Procedure:
A mixture of 3.24g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1,1-dioxide and 0.6g of n-propyl hydrazine in 100ml of absolute methanol is heated at reflux temperature for 2 hours. The mixture is allowed to cool, and is then filtered to give 2.8g of crude product. The crude material is stirred for about 16 hours in 200ml of carbon tetrachloride and filtered. The mother liquor is concentrated in vacuo and the residue is crystallized from methanol to give 1.5g of the title compound, melting point 197°-199°C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH:8]=O)=[CH:5][CH:4]=[CH:3]1.[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:14])[CH3:11].CC(O)=O.[BH3-]C#N.[Na+]>CCO>[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:8][C:6]1[NH:7][C:2](=[O:1])[CH:3]=[CH:4][CH:5]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1cccc(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1NCc1cccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84.8 %

Procedure:
6-Oxo-1,6-dihydropyridine-2-carbaldehyde (WO 2002/006272) (0.31 g, 2.5 mmol) was dissolved in EtOH (10 mL). 3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.19 g, 1.3 mmol) was added, followed by HOAc (0.14 mL, 2.5 mmol). The mixture was stirred for 75 minutes at r.t. and then NaCNBH3 (0.16 g, 2.5 mmol) was added. The reaction mixture was stirred at r.t. overnight. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 10% methanol), obtaining 0.288 g (85%) of the title product as an oil that crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Cl)cc(Br)c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Br)cc(Cl)cc1C(C)=O
Temperature: 60 °C
Yield: 96.8 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone (5.0 g, 20 mmol) in N,N-dimethylformamide (40 mL) was treated with potassium carbonate (5.5 g, 40 mmol) followed by methyl iodide (1.9 mL, 30 mmol) and heated at 60° C. overnight. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The organic layers were washed with water (3×100 mL) and brine, dried with sodium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography using ethyl acetate in hexanes (0%-5%-25%) gave the desired product (5.1 g, 96%). LCMS for C9H9BrClO2 (M+H)+: m/z=262.9, 264.9. Found: 262.9, 264.9.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1)#[N:2].Cl>O1CCCC1.[OH-].[Na+]>[C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCCC(=O)O)cc1
Yield: 98.2 %

Procedure:
A mixture of ethyl 4-(4-cyanophenoxy)butyrate (4.7 g) in tetrahydrofuran (23.5 ml) and 1N sodium hydroxide solution (40.2 ml) was refluxed for 2 hours under stirring. The reaction mixture was adjusted to pH≈2.0 with 10% hydrochloric acid, and the resulting precipitate was collected by filtration to give 4-(4-cyanophenoxy)butyric acid (4.06 g).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[C:11](=[O:19])[NH:10][C:9]2[CH:20]=[CH:21][CH:22]=[N:23][C:8]1=2)=[O:6].[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:25]>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11](=[O:19])[NH:10][C:9]3[CH:20]=[CH:21][CH:22]=[N:23][C:8]=3[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:24][CH3:25])[CH2:32][CH2:33]3)=[O:6])[C:13]=2[CH:14]=1
Reactant: CCN(CC)CCCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)NCCBr)c2cc(Cl)ccc21
Solvent: CN(C)C=O
Product: CCN(CC)CCCCC1CCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 19 %

Procedure:
Prepared analogously to Example 109 from 11-[[[2-bromo-ethyl]amino]carbonyl]-9-chloro-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine, but using dimethylformamide instead of acetonitrile, in a yield of 19% of theory. Colourless crystals, m.p. 157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13]1[CH2:17][CH2:16][CH2:15][N:14]=1.[ClH:18].C(OCC)C>CO.C(O)(C)C>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13]1[CH2:17][CH2:16][CH2:15][N:14]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1NC1=NCCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cc(N)cc(C)c1NC1=NCCC1

Procedure:
The title compound was prepared by the method of Example 9 using 10.5 g of the product compound of Example 10, except that no hydrochloric acid was added during hydrogenation. The crude product was dissolved in methanol and acidified with HCl in isopropyl alcohol. Addition of diethyl ether induced precipitation of 11.6 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[C:52]([F:53])=[CH:51][C:48]([C:49]#[N:50])=[C:47]([F:54])[CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[C:52]([F:53])=[CH:51][C:48]([C:49]#[N:50])=[C:47]([F:54])[CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cc(F)c(C#N)cc3F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-2,5-difluoro-benzonitrile according to procedure A followed by deprotection yielded the title compound as a white foam. MS (ESI): m/z=416.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:61](=[NH:74])([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[Cl:8][C:7]1[C:2]([N:74]=[C:61]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Clc1cccnc1N=C(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
2,3-Dichloropyridine (105.00 g, 710 mmol), Pd(OAc)2 (3.98 g, 17.74 mmol), rac-BINAP (16.57 g, 26.61 mmol), cesium carbonate (346.76 g, 1065 mmol), THF (1.05 L), and benzophenone imine (124.67 mL, 745 mmol) were added to a 2 L CHEMGLASS® Reactor fitted with a mechanical stirrer and reflux condenser. The mixture was heated to reflux with stirring for 18 h. The material was filtered, washed with THF (100 mL). The resulting filtrate was concentrated in vacuo to ⅓ volume and used without further purification. 1H NMR (CDCl3) δ 6.79 (dd, 1H, J=4.6, 7.6 Hz), 7.19-7.60 (m, 9H), 7.79-7.95 (m, 2H), 8.16 (dd, 1H, J=1.5, 5.1 Hz); MS (ESI+) m/z 293.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[C:13]([CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[S:31]([CH3:30])(=[O:33])=[O:32])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN(CCN(C)C)S(C)(=O)=O)CCCN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (intermediate 199, 780 mg, 2.53 mmol) and NEt3 (0.705 mL, 5.06 mmol) in DCM (20 ml) at 0° C. was added dropwise methanesulfonyl chloride (0.215 ml, 2.78 mmol) and the solution was allowed to stir for 2 h at room temperature. The reaction mixture was quenched by the addition of NaHCO3 and diluted. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 6, H2O/MeCN 95:05 to 40:60 in 25 min). Fractions containing the product were collected, diluted with water and basified with NaHCO3. The mixture was concentrated and extracted with DCM, dried using Na2SO4, filtered and dried to yield the title compound as a colorless waxy solid. (UPLC-MS 3) tR 0.34 min, ESI-MS 387.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.26 (s, 1H), 6.56-6.52 (m, 1H), 5.01 (s, 1H), 4.33 (s, 2H), 3.32 (s, 6H), 3.28-3.23 (m, 2H), 3.11 (t, 2H), 3.06 (s, 3H), 2.66 (t, 2H), 2.24 (t, 2H), 2.08 (s, 6H), 1.80-1.73 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:11]=[C:10]([C:12](O)=[O:13])[O:9][N:8]=1)[CH3:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>ClCCl>[Cl:19][C:12]([C:10]1[O:9][N:8]=[C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:11]=1)=[O:13]
Reactant: CCOC(=O)COc1cc(C(=O)O)on1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)Cl)on1

Procedure:
Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl {[15-chlorocarbonyl)isoxazol-3-yl]oxy}acetate was prepared in 4 steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (3.00 mL) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT/US03/03224). Methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate was further treated with aqueous 5% sodium hydroxide in methanol to yield 3-(carboxymethoxy)isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid (90%). 3-(2-Ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate). Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was treated with a solution of lithium hydroxide monohydrate (aq) in methanol at room temperature overnight to afford [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid in 60% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Yield: 47.4 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (241 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 148 mg (47.5%) of the desired product as a solid.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[C:11]([O-])(=[O:13])[CH3:12].[Na+]>C(OC(=O)C)(=O)C>[OH:10][C:7]1[C:8]([C:11](=[O:13])[CH3:12])=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cc2c(cc1O)OCO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of sesamol (5.6 g, 40 mmol) in acetic anhydride (20 mL) was cooled to 0° C. under an argon atmosphere. The solution was slowly added with boron trifluoride/diethyl ether complex (10 mL), and then the mixture was stirred at 90° C. for 2 hours. The reaction mixture was added to saturated aqueous sodium acetate (50 mL), and the mixture was stirred at room temperature. The solid formed was removed by filtration, and then the reaction mixture was extracted with ethyl acetate, and the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residual solid was suspended in methanol, thereby washed, then collected by filtration and dried to obtain 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)ethanone (5.9 g, 82%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[S:26][C:27]([C:31](O)=[O:32])=[C:28]([CH3:30])[N:29]=2)[C:21](=[O:34])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[S:26][C:27]([C:31]([NH:10][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)=[O:32])=[C:28]([CH3:30])[N:29]=2)[C:21](=[O:34])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NC1Cc2ccccc2C1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NC1Cc2ccccc2C1
Yield: 27 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use 2,3-dihydro-1H-inden-2-amine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J=8.1 Hz, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.50-7.31 (m, 5H), 7.20-7.09 (m, 4H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.66-4.58 (m, 1H), 3.24-3.11 (m, 2H), 2.95-2.84 (m, 2H), 2.52 (s, 3H); MS (ES+) m/z 458.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])[CH3:2].C(N(CC)CC)C.Cl.[NH2:37][OH:38]>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:37][OH:38])=[CH:22][CH:21]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester (136 mg) described in example 2.2 was dissolved in ethanol. Triethylamine (712 mg) and hydroxylamine hydrochloride (245 mg) were added and the mixture was stirred for 18 h at room temperature. The mixture was concentrated; the residue was dissolved in CH2Cl2 and washed with water. The product was purified by column chromatography (CH2Cl2/MeOH) to give 87 mg of (RS)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester as a colorless foam. MS: 420 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]1=[O:34]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[C:29]([CH3:33])([CH3:32])[C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:34])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)nc3)CC2)c(C)c1
Yield: 63.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 145 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) m described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (115 mg) was obtained.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][NH:3]1.CI.[C:11](O)(=O)C>[OH-].[Na+]>[CH3:11][S:1][C:2]1[NH:3][N:4]=[CH:5][C:6](=[O:8])[N:7]=1
Reactant: CC(=O)O
Reactant: O=c1cn[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nc(=O)cn[nH]1
Reaction time: 2 h

Procedure:
Compound 14a (62 g) dissolved in 2N sodium hydroxide (480 ml) is treated with a solution of methyl iodide (30 ml). After 2 hours at room temperature with agitation, the acetic acid (36 ml) is added drop by drop and the mixture set aside overnight at 0° C. The precipitate formed is filtered, centrifuged, and dried under vacuum at 60° C. in the presence of P2O5 in order to obtain the compound 14b (56.4 g).
Reaction SMILES: [C:1]([C:5]1[C:13]([OH:14])=[CH:12][C:8]2[CH:9]=[CH:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([C:5]1[C:13]([OH:14])=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2occc2cc1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(cc1O)CCO2
Reaction time: 6 h
Yield: 70.7 %

Procedure:
0.07 g of 6-t-butyl-5-hydroxybenzofuran was dissolved in 5 ml of acetic acid and a catalytic amount of 10% palladium on carbon was added. The mixture was stirred under a hydrogen pressure (3.5 kg/cm2) for 6 hours. After the palladium on carbon was filtered off, the solution was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 9% ethyl acetate) to give 0.05 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran as a white solid (yield 71%).