Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH3:34])=[C:32]([C:35](Cl)=[O:36])[CH:31]=[N:30]2)=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:35]([C:32]2[CH:31]=[N:30][N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:33]=2[CH3:34])=[O:36])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CCCC(N)c1cncc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(Br)c1
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of 1-(5-bromo-pyridin-3-yl)-butylamine (470 mg, 2.0 mmol), diisopropylethylamine (0.82 mL, 4.7 mmol) and DMAP (19 mg, 0.16 mmol) in CH2Cl2 (20 mL) is treated with 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl chloride (400 mg, 1.6 mmol) and stirred for 15 hours. The reaction mixture is then diluted with CH2Cl2 (50 mL), washed with saturated aqueous ammonium chloride (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 50% EtOAc/hexanes) to provide 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-bromo-pyridin-3-yl)-butyl]amide as a colorless foam-solid (540 mg, 78%).
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCCOCC(O)Cn1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-(pentoxy)propyl]-1H-imidazole (Example 29b; 2.12 g, 0.01 mol) was added to a stirred suspension of powdered potassium hydroxide (2.24 g, 0.040 mol) in dimethylsulphoxide (10 ml) at 18° C. and stirred for 0.5 hours. 4-Methoxybenzyl chloride was then added and stirring was continued for 2 hours. Ethyl acetate (350 ml) was added and the solution was washed with water and dried (MgSO4). Ths solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give 1-[2-[(4-methoxyphenyl)methoxy]-3-(pentoxy)propyl]-1H-imidazole as a pale-yellow oil.
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.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH:22]=O.N1CCCC1.ClC1C=C2C(/C(=C/C3C=C(Cl)C=CC=3O)/C(=O)N2)=CC=1>CO>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH:22]=[C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: COC(=O)c1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (1.2 g, 7 mmol) and 4-chloro-2-formyl-benzoic acid methyl ester (1.4 g, 7 mmol) in methanol (10 mL) was added pyrrolidine (490 mg, 7 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-2-hydroxy-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (500 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5](=O)[CH2:6][CH3:7])[CH3:4].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:6]([C:5]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][C:3]=1[CH3:4])[CH3:7]
Reactant: CCOC(=O)C(=N)SC
Reactant: CCC(=O)C(C)N
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)c1nc(C)c(CC)[nH]1
Yield: 60 %

Procedure:
The same operation as in Example (lb) was performed using 2-amino-pentan-3-one hydrochloride obtained in Example (15c) (about 10 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 10 mmol), to obtain 1.1 g of the title compound as a yellow solid (60%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:11]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]([O:10][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1)[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC(C)O
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)OC(C)COC(=O)CCC)cc2)cc1

Procedure:
0,75 g of optically active 1-butyryloxy-2-propanol [obtainable by esterification of (S)-1,2-propanediol], 1,7 g of p-(p-n-octylphenyl)-benzoic acid chloride, 20 ml of toluene and 2,1 ml of pyridine are boiled under reflux for 6 hours. The pyridinium chloride is filtered off hot with suction and the filtrate is worked up in the customary manner. Optically active 1-butyryloxy-2-[p-(p-n-octylphenyl)-benzoyloxy]-propane is obtained.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+]>CCO>[Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: NO
Reactant: O=Cc1c(O)ccc(O)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1c(O)ccc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a mixture of 2-bromo-3,6-dihydroxy-benzaldehyde (12A) (50 g, 0.23 mol) and hydroxylamine hydrochloride (19.2 g, 0.28 mol) was added 95% EtOH (500 mL), followed by NaOH (13.8 g, 0.345 mol). The reaction mixture was stirred at room temperature for 2 hours, then extracted with ethyl acetate and concentrated to give 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B) (45 g, 84.1% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]1.[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]=1.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO)c3)c(F)c2)C(=O)O1
Reactant: c1ccc2[nH]cnc2c1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(Cn4cnc5ccccc54)c3)c(F)c2)C(=O)O1
Yield: 37.3 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-hydroxymethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide (104 mg, 0.3 mM) and benzimidazole (71 mg, 0.6 mM) were suspended in dry acetonitrile (6 ml) under argon, and NAN-dimethylformamide dineopentyl acetal (208 mg, 0.9 mM) added. The mixture was refluxed for 8 hours. Solvent was evaporated, and the residue dissolved in dichloromethane and chrornatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 20% methanol in dichnoromethane. Relevant fractions were combined and evaporated to give the title product (50 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])[CH3:34]>C1COCC1>[C:33]([C:36]1[CH:37]=[CH:38][C:39]([S:42]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:23])[CH3:1])[CH:4]=2)[CH2:10][C:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])(=[O:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])[CH3:34]
Reactant: CCN(Cc1ccccn1)C(=O)CNc1cccc(N(C)C)c1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)=O)cc1
Reaction time: 2 h
Yield: 36.4 %

Procedure:
A solution of 2-(3-dimethylamino-phenylamino)-N-ethyl-N-pyridin-2-ylmethyl-acetamide (2.50 mmol) and of DIPEA (5.00 mmol) in THF (10 mL) was added to a solution of 4-acetyl-benzenesulfonyl chloride (2.50 mmol) in THF (10 mL). The reaction mixture was stirred for 2 h, the solvents were removed and the residue was purified by preparative HPLC chromatography to give 451 mg (0.91 mmol, 36%) product as a brownish foam.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[Cl:30])=[O:19])[CH3:16].[O:31]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:39]=2)=[CH:25][C:24]=1[Cl:30])=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Sodium triacetoxyborohydride (0.424 g, 2.00 mmol) was added to a solution of the enantiomerically enriched-(trans)-ethyl-2-(4-amino-2-chlorophenyl)cyclopropanecarboxylate (III-1d) (0.191 g, 0.80 mmol) and 3-phenoxybenzaldehyde (0.160 g, 0.80 mmol) in 8 mL of dichloroethane. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned between chloroform and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by chromatography on silica gel with hexane:ethyl acetate to give 0.269 g (80% yield) of the title compound as a colorless oil. NMR (400 MHz, CDCl3) δ 7.32 (t, J=7.51 Hz, 2H), 7.28 (t, J=8.42 Hz, 1H), 7.10 (t, J=8.24 Hz, 1H), 7.06 (d, J=8.24 Hz, 1H), 6.99 (d, J=7.69 Hz, 2H), 6.98 (m, 1H), 6.90 (dd, J=8.06 Hz, 2.38 Hz, 1H) 6.79 (d, J=8.42 Hz, 1H), 6.61 (d, J=2.38 Hz, 1H), 6.40 (dd, J=8.42 Hz, 2.38 Hz, 1H), 4.25 (d, J=5.49 Hz, 2H), 4.19 (q, J=7.14 Hz, 2H), 4.12 (br s, 1H), 2.60 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H), 1.28 (t, J=7.14 Hz, 3H), 1.25 (m, 1H). ES-MS m/z 422 (MH)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[C:3]([OH:5])=[O:4].[CH3:13]O>S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[C:3]([O:5][CH3:13])=[O:4]
Reactant: Cc1ccccc1C(O)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccccc1C

Procedure:
A solution of (RS)-a-hydroxy-(2-methylphenyl)acetic acid (3.6 g) in methanol (80 ml) containing 2 drops of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was concentrated and the residual oil partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulphate and evaporated to give the title compound (2.5 g) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:25])[NH:9][N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[OH-].[Na+].Cl[CH2:34][CH2:35][OH:36]>O>[OH:36][CH2:35][CH2:34][N:9]1[C:8](=[O:25])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:10]1
Reactant: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)nn1CCO
Temperature: 25 °C
Yield: 25 %

Procedure:
To 4,5,6-triphenyl-2H-pyridazin-3-one (6.0 g) were added 50 ml of dimethylformamide and a solution of sodium hydroxide pellets (0.7 g) dissolved in 5 ml of water. The resultant slurry was stirred at room temperature, while adding dropwise, 1.5 g of 2-chloroethanol. The mixture was heated to 110° C. for 1 hour and then allowed to heat for 16 hours at 90° C., after which time, the dimethylformamide was removed by evacuation. The residue was redissolved in methanol from which the compound was triturated, filtered and washed with petroleum ether to obtain the title compound (25 percent yield), m.p. 189° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:12][C@@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M-(CH2═CMe2)-CO2]H+ 236.3, no molecular ion.
Reaction SMILES: [NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Br:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C(OCC)C>C(Cl)Cl>[Br:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][O:22][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1
Reactant: C1=COCCC1
Reactant: C[C@@H](CO)CBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](CBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.7 %

Procedure:
Pyridinium-4-toluenesulfonate (PPTs) (0.18g, 0.072 mmol) was dissolved in dry CH2Cl2 (30 mL), (S)-(+)-3-bromo-2-methyl-1-propanol (1.1 g, 7.2 mmol) and 2,3-dihydro-4H-pyran (DHP) (0.60 g, 7.2 mmol) were added. The mixture was stirred under a N2 atmosphere at room temperature for 5 h. Diethylether (20 mL) was added and the resulting mixture was washed with brine (820 mL), dried (MgSO4) and the solvents were removed In vacuo. This afforded a crude product which on ball-tube-distillation (90° C./0.1 mmHg) gave the title compound 1.07 g (63%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([N:21](S(C)(=O)=O)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:15]=2)=[N:6][N:7]([CH3:13])[C:8]=1[O:9][CH:10]([F:12])[F:11]>O.CO>[Cl:3][C:4]1[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[CH:15]=2)=[N:6][N:7]([CH3:13])[C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: Cn1nc(-c2ccc(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c2)c(Cl)c1OC(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
0.3 g (4.7 mmol) of potassium hydroxide (dissolved in a little water) was added to a solution of 0.9 g (2.3 mmol) of 4-chloro-3-(4-chloro-3-[di-(methylsulfonyl)-amino]-phenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of methanol. The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was taken up in 1N hydrochloric acid and then extracted with ethyl acetate. Drying of the organic phase with magnesium sulfate followed by concentration gave 0.7 g of the target product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl.N>O=P(Cl)(Cl)Cl.C(O)(C)C>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([Br:19])[CH:21]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
A solution of 7-acetamido-6-nitro-3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl3 (250 mL) is heated under reflux for 2 h, the excess of POCl3 is removed under vacuum, and the residue is dissolved in CH2Cl2 and washed with aqueous Na2CO3 solution. Workup gives the crude 4-chloro derivative, which is coupled directly with 3-bromoaniline in isopropanol as above, and the resulting hydrochloride is converted directly to the free base, by treatment with aqueous NH3, to give 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (3.60 g, 45%). 1H NMR (DMSO) δ10.56 (1H, s), 10.29 (1H, s), 9.34 (1H, s), 8.70 (1H, s), 8.19 (1H, brs), 7.97 (1H, s), 7.88 (1H, d, J=6.0 Hz), 7.43-7.35 (2H, m), 2.13 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]([CH3:30])([CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)[C:15]#[N:16]>C1COCC1>[C:15]([C:14]([NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:30])[CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)#[N:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-nitrobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6.7 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=452, RT=0.69 min.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.COCCOC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[NH:12][N:13]=[CH:14][N:15]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:45][CH:44]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 60 °C
Yield: 11.3 %

Procedure:
A mixture of 2-{3-bromo-5[-1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazolyl}perhydro-2H-pyran (300 mg, 0.508 mmol), 4-trifluoromethylphenylboronic acid (144 mg, 0.758 mmol, 1.49 equiv.), [1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladium (II) complex with dichloromethane (Aldrich), 41.5 mg (0.0508 mmol, 0.100 equiv.), 2.53 mL of anhydrous DME, and powdered potassium phosphate (K3PO4, 535 mg, 2.52 mmol, 4.96 equiv.) were refluxed for 5 days. The reaction was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel using 30–40% EtOAc in hexanes. To the purified material was added 5.00 mL of MeOH, and 5.00 mL of 6.0 N aq. HCl. The mixture was heated at 60° C. for 24 h. The reaction mixture was filtered. The solid was further purified by silica gel chromatography using EtOAc affording the title compound (69.3 mg). Further purification by prep HPLC afforded the title compound (18.9 mg, 11.3% yield): 1H NMR (CDCl3/CD3OD) δ 8.74 (s, 1H), 8.41–7.97 (m, 4H), 7.78 (d, 2H), 7.66 (d, 1H); ES-MS (m/z) 330 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6](=[O:18])[C:5]2=[O:19].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C1COCC1>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:6](=[O:18])[C:5]([C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:8]=1[NH:7][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:19]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)N1C(=O)C(=O)c2cc(I)ccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1C(=O)C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
62.41 g of tert-butyl 5-iodo-2,3-dioxo-2,3-dihydroindole-1-carboxylate are dissolved in dried THF, and 18.98 ml of isoindoline are added. The mixture is stirred at 25° C. for 30 min, evaporated to dryness in vacuo, and the residue is triturated with petroleum ether, filtration gives 82.3 g of tert-butyl {2-[2-(1,3-dihydroisoindol-2-yl)-2-oxoacetyl]-4-iodophenyl}carbamate (beige solid);
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C1NCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1NCc2ccc(OCc3cccc(F)c3)cc21
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of 6-hydroxy-2,3-dihydro-isoindol-1-one (125.0 mg, 0.84 mmol) and 3-fluorobenzylbromide (174.3 mg, 0.92 mmol) in acetone (5 mL) containing potassium carbonate (276.4 mg, 2.0 mmol) was heated under reflux for 17 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 90:10) to afford the title product (180 mg, 83%) as a white solid. MS m/e=258.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[Br:14][CH:7]1[C:6](=[O:13])[C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][CH2:8]1
Reactant: [Br-]
Reactant: O=C1CCOc2c1ccc(Cl)c2Cl
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(Cl)c(Cl)c2OCC1Br
Reaction time: 0.5 h

Procedure:
A mixture of 100 mg. (0.46 mmol) 7,8-dichlorochroman-4-one was dissolved in anhydrous ethanol (5 ml) and Chloroform (5 ml). To this solution was added pyridinium tribromide (0.442 g, 1.38 mmol, 3 equiv). The reddish brown mixture was heated with stirring at 50 C for 30 min. The reaction mixture was then cooled and the solvent was evaporated. Then water (20 ml) was added to the residue and it was then extracted with 20 ml of dichloromethane. The dichloromethane layer was then washed with 5% sodium bicarbonate solution followed by water (20 ml). The organic layer was then dried and the solvent was evaporated in vacuum to yield the crude product which was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC1(O)OC(=O)C(c2cccs2)=C1c1ccc(Cl)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2cccs2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 3.35 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-thienyl)-2(5H)-furanone, 0.70 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 7 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 1.46 g of 5-(4-chloro-phenyl)-6-methyl-4-(2-thienyl)-2H-pyridazin-3-one.