Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH:15][NH3+:16])=[O:14])[C:8](=[O:23])[C:7]1=[O:24])[CH2:3][CH2:4][CH3:5].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]1[C:44](O)=[O:45])=[O:31])([CH3:28])([CH3:27])[CH3:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:2]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:15][NH:16][C:44]([CH:33]2[CH:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35][CH2:36][CH2:37][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:45])=[O:14])[C:8](=[O:23])[C:7]1=[O:24])[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Reactant: CCCCN1CCN(C(C(=O)N[NH3+])c2ccccc2)C(=O)C1=O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCN1CCN(C(C(=O)NNC(=O)C2C(c3ccccc3)CCCN2C(=O)OC(C)(C)C)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
To a solution of 2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazinium chloride (94.0 mg, 0.27 mmol) in 1,2-dichloroethane (2 ml) were added 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (71.0 mg, 0.23 mmol), 1-hydroxybenzotriazole (44.5 mg, 0.26 mmol), diisopropylethylamine (0.050 ml, 0.27 mmol), and polystyrene bound carbodiimide (353 mg, 0.46 mmol, 1.34 mmol/g). The reaction was allowed to stir gently at room temperature for 24 h. The reaction was filtered, concentrated, and purified via reverse phase HPLC to yield tert-butyl 2-({2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazino}carbonyl)-3-phenylpiperidine-1-carboxylate (11%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=O.[CH3:28][NH2:29]>CCO>[CH3:28][NH:29][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=[O:2]
Reactant: COC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Temperature: 80 °C

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-5,6,7,8-tetrahydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.040 mmol) and methylamine (0.8 mL, 2M in THF) in EtOH (2 mL) was heated at 80° C. in a sealed tube for 4 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 372.27 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([OH:31])([CH3:30])[CH3:29])[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>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>[NH2:25][C:22]1[O:23][CH2:24][C@:20]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([CH3:30])([OH:31])[CH3:29])[CH:18]=3)[O:13][C:10]3[C:9]2=[CH:8][C:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:12][CH:11]=3)[N:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3ccccc3)ccc1O2

Procedure:
A 0.5-2 mL vial was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (72.4 mg, 0.150 mmol), phenylboronic acid (54.8 mg, 0.449 mmol), potassium carbonate (103 mg, 0.748 mmol), and tetrakis(triphenylphosphine)palladium (8.64 mg, 7.48 μmol). The vial was purged with Ar(g), then Dioxane (748 μL) and water (0.37 mL) were added in sequence. The vial was sealed and placed in a 90° C. oil bath for 1 hour. The mixture was diluted with water (15 mL), and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column eluting with 0-6% MeOH/DCM to give (S)-4-(2′-amino-7-phenyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a slightly tan solid
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:28])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([CH2:28][Br:29])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2c(C(C)=O)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 67 %

Procedure:
A mixture of 3-acetyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline (8.5 g), N-bromosuccinimide (5. mg) , 2,2'-azobis(isobutyronitrile) (1.46 g) and carbon tetrachloride (500 ml) was stirred under reflux for 40 minutes. The reaction mixture was cooled, and then the insoluble material was filtered off. The filtrate was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (20:1, v/v) gave 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (6.85 g, 67%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 181°-182° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[CH:12]=[N:11][C:10]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]2=3)[CH2:4][O:3]1.Cl>C1COCC1>[OH:3][CH2:4][CH:5]([N:8]1[C:13](=[O:14])[CH:12]=[N:11][C:10]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]1=2)[CH2:6][OH:7]
Reactant: COc1ccc2ncc(=O)n(C3COC(C)(C)OC3)c2n1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(C(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
4-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (17.40 g, 59.7 mmol) was dissolved in THF (220 ml) to give a dark yellow solution. 1M HCl aq. (200 ml) was added (transient blue and green colours appeared in the solution) and the now light yellow solution was stirred at room temperature for 1 h. The mixture was concentrated to ca. 300 ml on a rotary evaporator using a cold water bath (some solid was precipitated during this procedure) then was stirred vigorously while solid sodium hydrogen carbonate was added in portions (caution: effervescence) until the mixture was ca. pH 8. The resulting yellow solid was collected by filtration with suction, washed with water (2×20 ml) and air-dried to give the title compound as an amorphous yellow solid (13.805 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[OH-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21

Procedure:
A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide, and 1.0 ml (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was heated at reflux for 2 hr. The mixture was poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give off-white crystals, mp 122°-124° C.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)[CH:13]=1
Reactant: O=S(=O)(CC(NO)c1ccc(Cl)c(Cl)c1)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.23 ml) was added directly to formic acid (0.9 ml. The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1-yl]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.227 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was purified by chromatography using a 10 g silica isolute eluting with CH2Cl2-3% Methanol/CH12Cl2 to give N-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.178 g), 98-101° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[S:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:22]I>C1COCC1.CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19]([S:21][CH3:22])=[N:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: COCOc1cccc2oc(-c3n[nH]c(=S)o3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1cccc2oc(-c3nnc(SC)o3)cc12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension (40 ml) of sodium hydride (0.8 g) in THF was added dropwise a solution (30 ml) of 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazole-2-thione (4.6 g) in DMF at room temperature, and the mixture was stirred for 40 min. To this reaction mixture was added dropwise methyl iodide at room temperature, and the mixture was further stirred for 1 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated under reduced pressure to give the title compound (2.5 g) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C@H:10]1[C@H:15](O)[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1>>[C:20]([O:19][C:17]([N:12]1[CH2:13][CH2:14][C@H:15]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:10]([F:9])[CH2:11]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(Cl)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-1, using 6-chloropyridin-3-ol and trans(±)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.490 g, 48%); MS: 332.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[C:34]([O:36][CH2:37][CH3:38])[CH:33]=[CH:32][C:31]=4[O:39][CH2:40][CH3:41])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:42]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:42])=[O:26])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[C:34]([O:36][CH2:37][CH3:38])[CH:33]=[CH:32][C:31]=4[O:39][CH2:40][CH3:41])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: N
Reactant: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(=O)OC)c1
Solvent: CO
Product: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(N)=O)c1

Procedure:
In a similar manner as described for example A9, 1.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(2,5-diethoxybenzyl)oxy]thiophene-2-carboxylate and 250 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of N-(3,4-difluorophenyl)acetamide (48 g) in concentrated sulfuric acid (140 ml) was added dropwise concentrated nitric acid (d 1.42, 56 ml) at -1° to 3° C. during 50 minutes with stirring in an ice-salt bath. After stirring for 1.5 hours at 3° to 16° C., the reaction mixture was poured into ice water (560 ml). The resulting precipitate was collected by filtration, washed with chilled water sufficiently to give N-(4,5-difluoro-2-nitrophenyl)acetamide (55.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)CC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCOc2ccccc2)cc1O
Yield: 64 %

Procedure:
Methyl 2,4-dihydroxybenzoate (33.6g; 0.2 mole) and anhydrous sodium carbonate (34.8g; 0.3 mole) in dry butanone (300 ml) were stirred at reflux during the addition of 1-bromo-3-phenoxypropane (43.0g; 0.2 mole) in butanone (50 ml) and the mixture stirred at reflux for 24 hours. The mixture was cooled and filtered and the filtrate evaporated to a white solid. Recrystallisation from ethanol gave 38.7g (64%) of material of mp 90°-92°, νmax (mull) 1660, 1615, 1598, 1580 cm-1. (Found; C. 67.69; H, 6.22; C17H18O5 requires; C, 67.54; H, 6.00%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10]C(=O)[C:12](=[O:14])[N:13]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:13][C:12]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1)=[O:14])=[S:10]
Reactant: O=C1N=C(c2c(Cl)cccc2Cl)SC1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=S)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
26.0 g of 2-(2,6-dichlorophenyl)-thiazoline-4,5-dione are suspended in 250 ml of dry toluene and heated to 90° C. while stirring. Gas is evolved and a violet solution is obtained, to which is added 16.2 g of 3,4-dichloroaniline dissolved in 30 ml of toluene. After stirring for 15 minutes the solution is cooled and the precipitate obtained is drawn off. Yield 20.1 g. Melting point 168° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:29]2[CH:28]([C:27](=[O:32])[N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:34])[F:33])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCCN1c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2CCN1c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To N-benzyl(methoxy)-N-((trimethylsilyl)methyl)methanamine (1.7 g, 7.0 mmol) and 1-(4-trifluoromethoxy-phenyl)-5,6-dihydro-1H-pyridin-2-one (0.6 g, 2.3 mmol) in DCM (30 mL) was added a solution of trifluoroacetic acid (0.026 g, 0.23 mmol) in DCM (10 mL) at 4° C. After the mixture was stirred at 50° C. for 3 h, the solution was washed with saturated sodium bicarbonate and brine, then dried over anhydrous Na2SO4. After removal of the DCM, the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate P (10:1 to 5:1) to yield the title compound (0.19 g, 21%). 1H NMR (300 MHz, CDCl3): δ 7.34-7.20 (m, 9H), 3.77-3.55 (m, 4H), 3.18-3.01 (m, 2H), 2.93-3.83 (m, 3H), 2.43-2.41 (m, 1H), 2.07-2.05 (m, 1H), 1.80-1.75 (m, 1H); LC-MS: [M+1]+ 391.1.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].C(O)(=O)C.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:13])[CH2:10][O:11][C:12]=2[C:4]=1[CH:1]([N:29]1[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]1)[CH3:2]
Reactant: CC(=O)c1c(O)ccc2c1OCC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(c1c(O)ccc2c1OCC2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A solution of 7-acetyl-6-hydroxybenzofuran-3(2H)-one (0.60 g, 3.1 mmol) in methylene chloride (25 mL) was added with acetic acid (0.25 mL) and N-Boc-piperazine (0.64 g, 3.4 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.84 g, 4.1 mmol). After completion of the addition, the ice bath was removed to allow the reaction mixture to warm to room temperature, and the mixture was stirred at the same temperature for 20 hours. The reaction mixture was extracted with methylene chloride, and then the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→97:3)) to obtain tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.74 g, 90%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:31](=[O:33])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:29]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: O=C(NC1CC1)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 96.7 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].C(=O)([O-])O.[Na+].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1.S(=O)(=O)(O)O>O.C(OCC)(=O)C>[O:4]=[C:3]1[C:11]2[CH:10]=[CH:15][O:16][C:12]=2[CH2:13][CH2:14][CH2:2]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCc2occc21
Yield: 80 %

Procedure:
To a mixture of 10 ml of ethyl acetate, 2 ml of 40% aqueous solution of chloroacetaldehyde and about 3 ml of water was added 1.0 g (12 mmoles) of sodium hydrogencarbonate while cooling with ice, and then the resulting mixture was stirred. To the reaction mixture was added dropwise 5 ml of aqueous solution containing 1.12 g of 1,3-cyclohexanedione while cooling with ice at a rate of 0.05 ml/minute. The reaction mixture was maintained at a pH of from 6.2 to 8.7 throughout the reaction. After completing the dropping, the reaction mixture was stirred at a room temperature overnight, and then acidified with sulfuric acid. After stirring the mixture for one hour, the ethyl acetate layer was separated, washed with an aqueous solution of potassium carbonate for removing the unreacted 1,3-cyclohexanedione, and then dried on magnesium sulfate. After distilling away the solvent, the residue was applied to a column of silica gel and eluted with dichloromethane to give 1.09 g (yield: 80%) of 4-oxo-4,5,6,7-tetrahydrobenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[I-].[Li+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cnc(-c2cc(F)cc(F)c2)n(CCOC)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of ethyl ethyl 2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxyate (i.e. the product from Example 9, Step C) (1.14 g, 3.37 mmol) in ethyl acetate (10 mL) was added lithium iodide powder (1.35 g, 10.0 mmol). The reaction mixture was heated to reflux for 24 h, cooled, and then stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (10 mL), followed by 6 N hydrochloric acid until the pH was 2. The mixture was extracted with dichloromethane, and the organic layer was dried (MgSO4) and concentrated under reduced pressure to afford a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a white solid (700 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[C:8]([C:18]([NH2:20])=[O:19])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[C:10]2[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[C:8]([C:18]([NH2:20]=[O:29])=[O:19])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Oc1ccc(C(N)=O)c2c1oc1ccccc12
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(C(=O)[NH2+][O-])c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of N-pyrid-4-yl)-4-isopropyloxy dibenzo[b,d]furan-1-carboxamide (50 mg, 0.144 mmol) (example 34) and m-chloroperbenzoic acid (50-55%) (125 mg, 0.722 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 40% acetone-chloroform as the eluent to give 27 mg of N-pyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid, mp: 247-248° C. (dec)