Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1.C(OCC)(=O)C>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
1.83 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 50 ml of tetrahydrofuran and combined at -50° with 7.3 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran; the mixture is stirred for 0.5 hour, further stirred with 1.05 g of cyclohexanone for 1 hour at -60°, and heated to 25°. Then water is added, the mixture is diluted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 2.7 g of crude 4-[1-hydroxycyclohex-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F>>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
N-Methylpiperazine (30 mL, 27.1 g, 0.268 mol) was cooled in ice/water while adding 3,4-difluoronitrobenzene (2.0 g, 0.0126 mol) with stirring. The mixture was then heated at 100° C. overnight, evaporated to remove all excess N-methylpiperazine and the residue dissolved in 1M—hydrochloric acid (30 mL). After washing twice with 20 mL portions of DCM the solution was basified with 5 M—sodium hydroxide (10 mL). The product was extracted into DCM (twice with 20 mL), dried over sodium sulphate and evaporated giving 1.50 g yellow oil which solidified on standing
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O-])([O-])=O.[K+].[K+].CI.Cl>CC(C)=O.O>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:17])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1oc2cccc(OC)c2c1C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-methyl-4-hydroxybenzofuran-2-carboxylate 20 (5.02 g, 22.8 mmol) in acetone (85 mL) was added sequentially K2CO3 (6.3 g, 45.6 mmol) and methyl iodide (6.47 g, 45.6 mmol). The resulting suspension was heated to reflux with stirring for 15 hours, allowed to cool, diluted with water (125 mL), and acidified with 2N HCl (50 mL). The resulting mixture was extracted with ethyl acetate (1×100 mL then 2×50 mL) and the combined extracts were dried and concentrated to a brown oil. Chromatographic purification (Preparative HPLC, 5% ethyl acetate in hexane as eluant) afforded pure ethyl 3-methyl-4-methoxybenzofuran-2-carboxylate as a colorless oil which crystallized on standing. mp 67°-69° C.; 1H NMR d 1.47 (3H, t, J=6 Hz), 2.78 (3H, s), 3.96 (3H, s), 4.48 (2H, q, J=6 Hz), 6.66 (1H, d, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.36 (1H, t, J=8 Hz).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
A mixture containing 2-(chloromethyl)-quinoline hydrochloride (100.0 g), 4-acetamidophenol (70.69 g) and milled anhydrous potassium carbonate (194 g) was stirred in DMF (1.2 L) using a mechanical stirrer for 48 hours. The mixture was carefully poured onto ice/water (3 L) with vigourous stirring. After the ice had melted, the solid was filtered and rinsed thoroughly with water. It was recrystallized from 95% ethanol and filtered to give the title compound in three crops.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][NH:8]O)[CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(C(C)C)CC)(C)C.NN>C1COCC1.C(OCC)(=O)C>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:8][O:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: ONOC1CCOCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NOC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
4-tetrahydropyranoxyhydroxylamine (33.2 mmol, 3.77 g) and 4-nitrobenzenesulfonylchloride (38.6 mmol, 8.56 g) were combined in anhydrous THF (100 mL) with diisopropylethylamine (69.3 mmol, 11.2 mL). The reaction was stirred at room temperature for 48 hours. Hydrazine (2 mL) was injected to the stirring solution to break-up the bisarylsulfonamide dimer biproduct. The reaction was stirred for an additional 24 hours. The reaction was diluted in ethyl acetate, washed in brine, filtered to remove insoluble solids and concentrated. The crude was purified by crystallization from hot ethyl acetate to provide 3.5 g (36%) of white crystals. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 8.42 (2H,d), 8.13 (2H,d), 6.93 (1H,s), 4.27 (1H,m), 3.91 (2H,m), 3.45 (2H,m), 2.02 (2H,m), 1.61 (2H,m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[NH2:49])[C:42]([O:44][CH3:45])=[O:43]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[C:41]1[CH:46]=[CH:47][C:48]([NH2:49])=[C:39]([NH:38][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:40]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N)c(NC(=O)CCCCNC(=O)OC(C)(C)C)c1
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
In DMF (20 ml), 5-t-butoxycarbonylamino valeric acid (manufactured by Aldrich Corporation) (1.45 g), WSCI hydrochloride (1.74 g), and HOBt (1.25 g) were dissolved and the whole was stirred for 15 minutes. Then, the solution was added with methyl 3,4-diaminobenzoate (1.00 g) and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and then washed with a saturated aqueous ammonium chloride solution and a 1 mol/l sodium hydroxide aqueous solution. Subsequently, the resultant was subjected to extraction with chloroform and the extract was then washed with a saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1[CH:23]=O)([CH3:15])([CH3:14])[CH3:13].N1CCCCC1>CO>[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1/[CH:23]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:14])([CH3:13])[CH3:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 92.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2.37 g, 12.7 mmol) was reacted with 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde prepared in Example 18 (4 g, 12.7 mmol) and piperidine (1.25 mL, 12.7 mmol) in methanol to give E/Z-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzylidene}-6-chloro-1,3-dihydro-indol-2-one as a yellow solid (Yield 5.46 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH2:22][O:23][CH3:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate in dry DMF (1.0 M) was treated with NaH (1.2 eq of a 60% dispersion in mineral oil) and the mixture was stirred at RT for 30 min. Chloromethyl methyl ether (1.2 eq) was then added dropwise and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and the organic phase washed with 1 N HCl and brine before drying (Na2SO4), filtering and concentrating in vacuo. The crude was purified by FC (PE/EtOAc 1/9) to afford the title compound (77%). (ES+) m/z 387, 389 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C@@H:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][C@H:13]1[OH:24].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][CH2:15][CH2:14][C@@H:13]([OH:24])[C@H:12]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[C:18]=2[CH:19]=1
Reactant: O[C@@H]1CCOc2ccc(Cl)cc2[C@H]1Br
Reactant: O=C1CCCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1CCCN1[C@@H]1c2cc(Cl)ccc2OCC[C@H]1O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
5 ml (5 mmol) of lithium bis-(trimethylsilyl)-amide (1M solution in THF) are added dropwise with stirring to 1.40 g (5 mmol) of trans-5-bromo-7-chloro-4-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin at 0° C. under argon. After stirring for 2 hours, 0.43 g (5 mmol) of 2-pyrrolidinone and subsequently a further 5 ml of lithium bis-(trimethylsilyl)-amide are added, and the mixture is heated at 110° C. for several hours (TLC check). The mixture is poured onto ice-water and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is triturated with hot methanol/ethyl acetate and filtered off with suction. Crystals of melting point 186°-188° C. are obtained.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:17]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([NH:6][C:7]3[O:11][N:10]=[C:9]([CH3:12])[C:8]=3[CH3:13])=[O:14])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3ccc(-c4ccccc4)cc3)CC2)c1C
Yield: 57 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (265 mg, 0.923 mmol), 1-biphenyl-4-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (180 mg, 57.1%) as solid product.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]([OH:17])=O)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C)C=O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15](=[O:17])[NH:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=3)=[O:53])[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)N1CC(=O)N2C(CCC2C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N1CC(=O)N2C(CCC2C(=O)NCC(=O)c2ccc(Br)cc2)C1
Yield: 75.8 %

Procedure:
A solution of 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester (81 mg, 0.33 mmol), HATU (152 mg, 0.40 mmol), and 4-methyl morpholine (146 μL, 1.33 mmol) in dimethylformamide (4 mL) was stirred at ambient temperature for 5 minutes. 2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (91 mg, 0.37 mmol) was added to the reaction mixture. After 1 hour the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was filtered. The solvent was removed under reduced pressure from the filtrate. The resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol, 75%). C18H20BrN3O5 calculated 437.1 observed [M+1]+ 438.1; rt=1.82 min.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:41])([CH2:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=3)=[CH:21][CH:22]=2)=[C:13]([CH3:40])[CH:12]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[CH3:3][C:4]([CH3:41])([CH2:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[N:27]=3)=[CH:21][CH:22]=2)=[C:13]([CH3:40])[CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)nc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Methanol (0.7 mL) and tetrahydrofuran (0.7 mL) were added to methyl 2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoate (99 mg), and after adding 2N aqueous sodium hydroxide solution (0.7 mL) to the mixture, the resulting mixture was stirred at 50° C. for 2 hours. To the reaction mixture was added ethyl acetate, and the mixture was neutralized by 2N hydrochloric acid. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=76:24 to 0:100) to obtain 2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoic acid (81 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1C2C(CCCC2)CCC1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 827 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added decalin (2.76 g) and 326 mg (5.53 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 348 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 69%) and 1.8 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24][C:23]=2[CH:31]=1>CO>[F:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24][C:23]=4[CH:31]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Fc1ccc(Nc2nc(Cl)ncc2F)cc1F
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Solvent: CO
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(F)c(F)c4)n3)ccc2O1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of equivalent amount of 2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine and (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran in MeOH was shaken in a seated tube at 80° C. for 48 h, cooled to room temperature and diluted with a mixture of n-hexanes:EtOAc (1:1; v/v). The resulting solid formed was filtered, washed with a mixture of EtOAc:n-hexanes (1:1; v/v), dried and analyzed to give (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.21 (bs, 1H), 9.80 (bs, 1H), 8.20 (d, 1H, J=4.8 Hz), 7.94 (bs, 1H), 7.43 (m, 3H0, 7.15 (bd, 1H, J=8.4 Hz), 6.81 (d, 1H, J=8.1 Hz), 5.35 (dd, 1H, J=6.0 and 6.3 Hz), 3.69 (s, 3H), 3.52 (dd, 1H, J=10.5), 3.22 (dd, 1H, J=9.0 and 6.0 Hz); LCMS: purity: 99%; MS (m/e): 417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[C:8]2=O)=[CH:4][C:3]=1[S:26]([NH2:29])(=[O:28])=[O:27].[Sn].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH2:8]2)=[CH:4][C:3]=1[S:26]([NH2:29])(=[O:28])=[O:27]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccccc3)CC1)C2=O
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: NS(=O)(=O)c1cc2c(cc1Cl)CN(C1CCN(Cc3ccccc3)CC1)C2=O

Procedure:
A mixture of the above part (a) 1,3-dioxoisoindole (4.4 g., 0.01 mole), and 30 mesh granulated tin (2.8 g., 0.024 mole) in 20 ml of methanol and 12 ml. of concentrated hydrochloric acid was heated at 75°-80° for a 8 hr. period. Additional 1 g. portions of tin were added at the end of 5 hr. and 6 hr., respectively. After cooling, the reaction mixture was diluted with 40 ml. of methanol, heated to reflux and filtered through infusorial earth to remove unreacted tin. The filter-cake was washed with methanol and combined filtrates concentrated under reduced pressure. Residual oil slurried with warm methanol provided 1 g. of solid and cooling of the methanol decant an additional 2.1 g. of solid. The combined crude product was further purified by stirring with 65 ml. of 0.077N hydrochloric acid while slowly introducing a gaseous stream of hydrogen sulfide (H2S) during a 2.0 hr. period. Excess H2S was removed under reduced pressure, the mixture filtered through infursorial earth and the filter-cake extracted with warm methanol. Cooling the methanol filtrates provided 2.2 g. of product which crystallized from methanol-water gave analytically pure 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide hydrochloride as the monohydrate, m.p. 282°-284°.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([OH:8])/[CH:5]=[CH:6]/[I:7].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([O:8][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:5]=[CH:6]/[I:7]
Reactant: CCCC(C)(C)CC(O)/C=C/I
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCC(C)(C)CC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 6.0 g. of 5,5-dimethyl-1-iodo-trans-1-octen-3-ol (Example 1000) with 6.9 g. of triphenylmethyl bromide in 30 ml. of pyridine and purification on Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([O-:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1
Reactant: O=C([O-])c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Reaction time: 0.5 h

Procedure:
To a 3 mL plastic tube fitted with a frit containing 50 mg of resin-bound 2-(3-indolyl)quinoline-4-carboxylate (0.035 mmol) was added I mL of a 50% mixture of TFA and DCM. The reaction mixture was agitated on an orbital shaker for 30 min. The mixture was filtered and the resin washed with DCM (3×3 mL). The organic solutions were combined and evaporated by a stream of nitrogen. The residual solid was lyophilized to give 2-(3-indolyl)quinoline-4-carboxylic acid or amide (80-100% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:29][C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:30][C:25]=2[N:26]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2cc(N)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3oc(C)nc3c2)cc1
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (93 mg, 0.43 mmol) in dichloromethane (2 mL) was added pyridine (80 μL, 1.0 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-2-methylbenzoxazole (60 mg, 0.40 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink oil (112 mg, 85%), single spot at Rf 0.53 (1:1 hexane:ethyl acetate). HPLC purity 99+% (tR 2.38 min in 10% water-acetonitrile) 1H NMR (CDCl3): δ 7.64 (2H, dt, J=8.1, 1.8 Hz), 7.31 (2H, m), 7.18 (2H, d, J=8.4 Hz), 7.06 (1H, dd, J=8.6, 2.4 Hz), 2.59 (5H, m), 1.58 (2H, sextet, J=7.3 Hz), 0.89 (3H, t, J=7.3 Hz). LCMS: 329.15 (M−). FAB-MS (MH+, C17H18N2O3S): calcd 331.1116, found 331.1118.