Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>>[O:17]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Reaction time: 3 h
Yield: 98 %

Procedure:
The reaction was carried out completely in the same manner as in Example 21, except that p-fluoronitrobenzene was used instead of p-chloronitrobenzene and sodium phenolate was used instead of potassium fluoride in Example 21. Further, the reaction temperature was changed to 80° C. and the reaction time was changed to 3 hours without pursuing the reaction on halfway. Objective 4-phenoxynitrobenzene was produced in the yield of 98%.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].[NH2:16][OH:17].Cl.C(N(CC)CC)C.O>C(O)C>[NH2:2][C:1](=[N:16][OH:17])[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C#N
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(N)=NO
Temperature: 70 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
tert-Butyl [(1S,2R)-2-cyanocyclopentyl]carbamate (415 mg) and hydrochloric acid hydroxylamine (411 mg) were suspended in ethanol (6.2 ml), triethylamine (0.83 ml) was added thereto at room temperature, and the reaction mixture was then stirred at 70° C. for 24 hours. The reaction mixture was left to be cooled, and hydrochloric acid hydroxylamine (411 mg) and triethylamine (0.83 ml) were added thereto, followed by stirring at 75° C. for an additional 48 hours. The reaction mixture was left to be cooled, and water (30 ml) was added thereto, followed by extraction with ethyl acetate (40 ml). The organic layer was washed with a saturated sodium bicarbonate solution and saturated brine in this order and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (1.5% methanol-chloroform) to obtain tert-butyl {(1S,2R)-2-[amino(hydroxyimino)methyl]cyclopentyl}carbamate (315 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:26]([NH:19][S:16]([C:14]1[CH:13]=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[CH2:6][CH2:7][C:8]=2[CH:15]=1)(=[O:18])=[O:17])=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CCCCNC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2

Procedure:
By the reaction of 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with butylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-butyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) sulfonyl]urea, m.p. 93° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[H][H].C(Cl)(Cl)Cl>C(O)C.[Pd]=O>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: COc1ccc(CCNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNS(=O)(=O)c2ccc(N)cc2)cc1
Yield: 92.7 %

Procedure:
A solution of the product of stage (i) (4.5 g) in ethanol (150 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on charcoal (50% aq. paste, 0.5 g) for 2 h until hydrogen uptake ceased (1000 ml). Chloroform (150 ml) was added, and the mixture stirred until the product dissolved. The catalyst was filtered off, washed with ethanol, and the filtrate evaporated in vacuo to give a solid (3.8 g). A sample (0.2 g) was purified by flash chormatography eluted with chloroform:methanol (50:1) to give the title compound as a solid (0.11 g). m.p. 144°-146°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[CH:3]=[CH:2]1.I[C:21]1[CH:22]=[C:23]([O:27][CH3:28])[CH:24]=[CH:25][CH:26]=1.[OH-].[K+].N#N.[OH-].[Na+].Cl>CS(C)=O.O>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]4[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=4)[C:14]([OH:16])=[O:15])[CH:8]=3)[CH:3]=[CH:2]2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccc(Cc2ccc3cc[nH]c3c2)c1
Reactant: COc1cccc(I)c1
Agent: Cl
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(-n2ccc3ccc(Cc4cccc(C(=O)O)c4)cc32)c1
Temperature: 135 °C
Reaction time: 24 h

Procedure:
The acid, 3-((1H-indol-6-yl)methyl)benzoic acid, 20 mg, was dissolved in 4 ml DMSO, and 18 mg 3-iodoanisole, 12 mg potassium hydroxide and 5 mg Cu2O catalyst were added. The mixture was protected by N2 and stirred for 24 hours at 135° C. After cooling to room temperature, 1 ml 25% NaOH in H2O was added, The mixture was stirred for 3 hours at room temperature, then adjusted to pH 3.0 using 2M HCl. The solution was extracted with CH2Cl2, 3×15 ml. The organic solvent was combined and dried with Na2SO4, then evaporated to dryness. The final product was purified by HPLC using acetonitrile/H2O as eluent. The acetonitrile was removed from the eluent, the eluent frozen and lyophilized. After lyophilization, 5.0 mg of the target compound was obtained as a grey powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[Cl:22][C:23]1[CH:38]=[CH:37][C:26]2[N:27]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:28](=[O:30])[NH:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[OH2:30].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]2[N:27]([CH:31]3[CH2:32][CH2:33][N:34]([CH2:2][CH2:3][CH2:4][CH:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:14])([F:15])[F:13])[CH:7]=4)[CH2:35][CH2:36]3)[C:28](=[O:30])[NH:29][C:25]=2[CH:24]=1
Reactant: FC(F)(F)c1cccc(C(CCCCl)c2ccccc2)c1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 9.35 parts of 1-chloro-4-phenyl-4-(3-trifluoromethylphenyl)butane, 6.3 parts of 5-chloro-1-(4-piperidyl)-2-benzimidazolinone, 6.35 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 5-chloro-1,3-dihydro-1-[1-{4-phenyl-4-[3-(trifluoromethyl)phenyl]butyl}4-piperidinyl]-2H-benzimidazol-2-one hydrate; mp. 114.9° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:14]([O-])=O)[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([OH:3])=[O:2].Cl[Sn]Cl>CO>[NH2:14][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2cccnc12
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1cc(C(=O)O)c2ncccc2c1
Temperature: 40 °C
Yield: 34.8 %

Procedure:
To a suspension of 8-carboxy-6-nitroquinoline (4 g; 18 mM) in methanol (70 ml) was added SnCl2 (20.4 g; 90 mM). The mixture was heated to, and maintained at 40° C. until dissolution of the insoluble. After evaporation of the :solvent, the residue was taken-up in a 2M aqueous solution of NaOH and purified by subjecting to chromatography on Dowex 1X2 Resin. After basification (pH3) with concentrated NH4OH the resulting solid was further purified by subjecting to chromatography on HP20SS resin, eluting with MeOH/H2O--AcOH 1% (30.70) to give 6-amino-8-carboxyquinoline (1.2 g, 35.5%)
Reaction SMILES: [ClH:1].Cl.C([O:5][C:6]([C:8]1([CH2:20][O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:32](=[NH:34])[NH2:33])[CH2:29]3)=[CH:24][CH:23]=2)[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C>Cl>[ClH:1].[ClH:1].[C:32]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:20][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][N:11]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[CH2:12][CH2:13]3)=[CH:23][CH:24]=2)[CH2:29]1)(=[NH:33])[NH2:34]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Agent: Cl
Product: N=C(N)N1CCc2ccc(OCC3(C(=O)O)CCN(c4ccncc4)CC3)cc2C1
Yield: 211.6 %

Procedure:
4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (9 g) was dissolved in conc. hydrochloric acid (50 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, insoluble material was filtered off and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (9.0 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:21])=[C:18]([O:19]C)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:19][C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:30])=[C:16]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]=1[CH3:21]
Reactant: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 78 %

Procedure:
Using N-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 36, the title compound was synthesized in the same manner as in Example 134. Yield: 78%. Melting point: 181-182° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH-:15].[K+].Cl>CO.[Cl-].C([N+](CC)(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:15])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
450 g of 2-chloro-5-nitro-benzotrifluoride in 1,250 ml of methanol and 35 g of tetraethylammonium chloride are initially introduced. 1,000 g of an aqueous, 50% strength potassium hydroxide solution are then added dropwise (1 hour), the temperature being kept at a maximum of 40° C. by cooling. About 30 minutes after the addition has ended, the mixture is heated to 80° C. for 6 hours, cooled and rendered acid with concentrated hydrochloric acid. The mixture is extracted several times with 300 ml of methylene chloride each time, and the organic phase is dried with sodium sulphate and freed from the solvent under reduced pressure. About 413 g of crude product, melting point: 90°-95° C., are obtained with a purity of about 95% according to analysis by gas chromatography. After recrystallisation from toluene, or distillation under 0.5 mm, pure 4-nitro-2-trifluoromethylphenol is obtained, melting point: 134° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]#[C:4][CH3:5].C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[CH3:6][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[C:11]([CH:12]=1)[CH:25]=[O:26])([CH3:1])[C:3]#[C:4][CH3:5]
Reactant: CC#CC(C)(C)c1ccc(OC)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: CC#CC(C)(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 54 in the same manner of Compound 2.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]=[CH:8][N:7]([CH2:10]Cl)[N:6]=1)([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:2]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ncn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 27.3 %

Procedure:
0.78 g of 3-i-propyl-1-(chloromethyl) -1H-1,2,4-triazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.10 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.31 g of [(3-i-propyl-1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (28), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:22])=[O:20])[C@@H:8]([O:10]C(C3C=CC=CC=3)=O)[CH2:9][C@@H:3]1[CH2:4][CH2:5]2>Cl>[CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:22])=[O:20])[C@@H:8]([OH:10])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Product: COC(=O)[C@@H]1[C@H]2CC[C@@H](C[C@@H]1O)N2C
Temperature: 25 °C

Procedure:
Cocaine (Merck) (3.91 g) was dissolved in 100 ml IN HCl and heated to reflux for 19 hours. After cooling to room temperature, the benzoic acid was filtered and washed with water. The water was washed with chloroform several times and the water was removed in vacuo. The residue was dissolved in 200 ml anhydrous methanol and the solution was saturated with HCl gas. The reaction mixture was refluxed for 17 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in water and basified with potassium carbonate to pH 9. The basic water was extracted with methylene chloride several times. After drying the organic layer over sodium sulfate, the solvent was removed in vacuo to yield ecgonine methyl ester as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[Cl:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:47]3[CH:48]=[CH:49][C:44]([Cl:43])=[CH:45][CH:46]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(Cl)cc2)c1
Yield: 90.3 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-(propane-1-sulfonyl)-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (220 mg, 0.33 mmol), 4-chloro-phenylboronic acid (108 mg, 0.66 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.049 mmol), and cesium carbonate (217 mg, 0.66 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-1-sulfonyl)-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (209 mg, 91%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C38H49ClO8S (M+Na)+ 723.2729, found 723.2729.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11]C)=[O:10].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nnc(Cl)cc1Cl

Procedure:
To a solution of methyl 4,6-dichloro-pyridazine-3-carboxylate (6.01 g, 29.03 mmol, WO 2004/031174) in THF (29 ml) at 0° C. is added 29 ml of aqueous 1.0 M LiOH with stirring. The resulted mixture is stirred continuously at 0° C. for 40 min and monitored by TLC. The reaction mixture is diluted with water, and acidified to pH 1-2 with aqueous 1.0 M HCl. The crude product is suspended between the organic and aqueous layers. After filtration and washed with water and hexane, and dried under vacuum, the product is obtained.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:8][C:9](=[O:23])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[C:20](=O)[CH3:21])=O)[CH3:7]>C(O)(=O)C>[Br:19][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[N:12]=[C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:23])[N:5]=[C:20]2[CH3:21]
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)cc1C(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(C)c2cc(Br)ccc2n1
Yield: 49.3 %

Procedure:
Ammonium acetate (400.0 mg, 5.19 mmol) was added to ethyl[(2-acetyl-4-bromophenyl)amino](oxo)acetate (163.0 mg, 518.9 μmol) in acetic acid (5.2 mL) at room temperature and the reaction was heated at reflux for 19 hours. The reaction mixture was concentrated, then water was added, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 75.5 mg (49%) of ethyl 6-bromo-4-methyl-2-quinazolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, J=2 Hz, 1H), 8.21 (dd, J=9, 2 Hz, 1H), 8.07 (d, J=9 Hz, 1H), 4.41 (q, J=7 Hz, 2H), 2.97 (s, 3H), 1.35 (t, J=7 Hz, 3H). ESI-LCMS m/z 295 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:14][C:15]1C(F)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[C:11]([N:10]2[CH2:9][CH2:8][N:7]([CH3:6])[CH2:13][CH2:12]2)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: CN1CCCNCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C

Procedure:
36.2 g of sodium bicarbonate and 28.7 mL of N-methylhomopiperazine are added to a solution of 15 g of 4,5-difluoro-2-nitroaniline in 120 mL of anhydrous DMF. The reaction medium is heated to 80° C. using an oil bath for 2H30. The reaction medium is cooled to ambient temperature, then poured into 500 mL of water. The mixture is cooled using an ice bath and stirred, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with water. The solid is dried in an oven at 40° C. 21.2 g of 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrophenylamine are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 2.22 (s, 3H); 2.45 (m, 4H); 3.17 (m, 4H); 6.42 (d, J=8.0 Hz, 1H); 7.34 (broad s, 2H); 7.63 (d, J=14.5 Hz, 1H). EI mass spectrum: m/z=254: M+. (base peak)—m/z=239: (M−CH3)+—m/z=234: (M−HF)+.−m/z=183: (M−C4H9N)+—m/z=70: C4H8N+—m/z=43: C2H5N+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1(=[O:19])[O:14][C:12](=O)[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>>[CH:16]1[CH:17]=[CH:18][C:10]([C:9]([OH:14])=[O:19])=[C:11]([C:12]2[C:6]3[CH:4]=[CH:3][C:1]([OH:2])=[CH:8][C:7]=3[O:5][C:4]3[C:6]=2[CH:7]=[CH:8][C:1]([CH:3]=3)=[O:2])[CH:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1cccc(O)c1
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Yield: 89.9 %

Procedure:
Resorcinol (470 g, technical grade 99.4%, white flakes) was added to a one-liter jacketed glass vessel and heated to 135 C. in order to melt the resorcinol. Once melted, phthalic anhydride (124 g, technical grade 99.7%, white flakes) was added to the vessel, and the reaction mixture was blanketed with nitrogen, mixed and heated to 200 C. The reaction mixture was held at 200-215 C. for approximately 2 hours while the water (24 g) was removed by distillation. Upon completion, the reaction mixture was cooled to 185 C. and quenched with water by transferring the reaction mixture under nitrogen to a stirred vessel containing water (approximately 500 ml). The vessel was then rinsed with water to transfer all of the precipitated product. The combined product slurry in water was digested at 75 C. (to dissolve any unreacted intermediates) and cooled to 35 C. The product was recovered by vacuum filtration in the form of a filter cake. This filter cake was washed free of dissolved impurities, such as resorcinol, by mixing and heating with fresh water (approximately 1L), filtering and rinsing with about 800 ml boiling hot water. This cake upon drying yielded fluorescein (250.1 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23](O)=[O:24])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[N:7][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O.[CH2:37]([NH2:40])[C:38]#[CH:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1(C)C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([NH:40][CH2:37][C:38]#[CH:39])=[O:24])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)O)ccc23)nc1
Reactant: C#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(C=Cc3ccc(CC)cn3)n[nH]c2c1
Yield: 65.5 %

Procedure:
To 2-{3-[2-(5-Ethyl-pyridin-2-yl)-vinyl]-1H-indazol-6-ylamino}-benzoic acid (49 mg, 0.105 mmol) was added 2 mL of a 90:10:1 mixture of CH2Cl2:TFA:TES. The reaction was stirred at reflux for 1 hour, and then diluted with toluene (20 mL). The solvent was removed by rotary evaporation to yield a thick oil. The oil was dissolved in DMF (1 mL) and to this solution was added TEA (0.072 mL, 0.52 mmol), propargyl amine (0.014 mL, 0.208 mmol), and HATU (59 mg, 0.156 mmol). The reaction was stirred for 3 hours, and then purified by preparatory HPLC to yield the desired product (29 mg, 66%). 1H NMR (CDCL3-d): δ 9.83 (1H, s), 8.63 (2H, s), 8.04 (2H, m), 7.68 (2H, s), 7.47 (1H, m), 7.32 (1H, d, J=1.51 Hz), 7.10 (1H, dd, J1=8.67 Hz, J2=1.88 Hz), 6.93 (1H, m), 6.07 (2H, dd, J1=5.09 Hz, J2=2.26 Hz), 3.15 (1H, t, J=2.35 Hz), 2.97 (2H, s), 2.74 (1H, s), 2.29 (1H, s), 1.27 (3H, t, J=7.44 Hz)