Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[C:25](O)(=[O:27])[CH3:26]>>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@@H:2]([NH:1][C:25](=[O:27])[CH3:26])[CH3:24])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: C[C@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: CC(=O)O
Product: CC(=O)N[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 4-[(5-{[(2S)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol (obtained as described in Example 59, preparation of starting materials) to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]acetamide in >100% yield; Mass spectrum MH+ 387.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[C:64]([CH:69]=[C:70]([O:72][CH3:73])[CH:71]=1)[C:65]([O:67][CH3:68])=[O:66]>ClCCl>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:60][CH2:61][C:62]3[CH:63]=[C:64]([CH:69]=[C:70]([O:72][CH3:73])[CH:71]=3)[C:65]([O:67][CH3:68])=[O:66])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1cc(CN)cc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)OC)c3)cn2)C1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (50 mg, 0.14 mmol) and HATU (63 mg, 0.17 mmol) in dry dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.075 mL, 0.42 mmol) at 20-25° C. The mixture was stirred for 10 min, then methyl 3-(aminomethyl)-5-methoxybenzoate hydrochloride was added (33 mg, 0.14 mmol) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 1 hour. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (10 mL), washed with water (2 times with 10 mL), and dried over NaSO4. The organics were concentrated under reduced pressure to obtain methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoate (65 mg, 87%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11]CC)=[O:10])[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([OH:11])=[O:10])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)c1cccc(-n2cnnn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine ethyl 3-(1H-tetrazol-1-yl)benzoate (4.93 g, 22.6 mmol) and tetrahydrofuran/water (100 mL/25 mL). Add lithium hydroxide (1.9 g, 45.2 mmol) and heat to reflux. After 2 hours, cool to ambient temperature and extract the reaction mixture five times with a 1 M aqueous sodium hydroxide solution. Combine the aqueous layers and extract with ethyl acetate. Acidify the aqueous layers with a 1 M aqueous hydrochloric acid solution (pH about 1) to give a solid. Collect the solid by filtration to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc(Br)n1
Solvent: CC#N
Product: Nc1ccc(Cl)c(Br)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopyridin-2-amine (1 g, 5.78 mmol) in acetonitrile (10 mL) was added N-chlorosuccinimide (0.849 g, 6.36 mmol) and the mixture was heated at 80° C. for 12 hours. The mixture was filtered through diatomaceous earth and concentrated and the residue was dissolved in ethyl acetate and washed with water and brine. Drying over anhydrous sodium sulfate, filtration, concentration and purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound. LCMS: 209.1 (M+2)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][Si:13]([CH2:16][Mg]Cl)([CH3:15])[CH3:14].Cl>C(OCC)C>[Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([OH:4])[CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)(CCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
8.63 g (0.05 mole) of 2-chloro-4'-fluoroacetophenone were dissolved in 60 ml of diethyl ether. The solution was stirred under a stream of nitrogen, and 200 ml (0.057 mole) of a diethyl ether solution of trimethylsilylmethylmagnesium chloride were added dropwise at such a rate that the temperature of the reaction mixture did not rise above 15° C.-20° C. The reaction mixture was then stirred for a further 1 hour at room temperature, after which it was poured into 200 ml of ice water, and its pH was adjusted to a value of 6-7 by the addition of 5% w/v aqueous hydrochloric acid. It was then extracted with 100 ml of ethyl acetate. The organic extract was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride It was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to afford a crude oily product. This crude oily product was purified by silica gel column chromatography, using mixtures of ethyl acetate and hexane ranging from 1:10 to 1:5 by volume, to give 8.8 g (yield 67.7%) of the title compound as an oily substance.
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH2:6]1>CCOCC>[O:4]=[C:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:3])=[O:12])[CH:8]=[CH:7][CH2:6]1
Reactant: C=[N+]=[N-]
Reactant: O=C1CC=CC(C(=O)O)C1
Solvent: CCOCC
Product: COC(=O)C1C=CCC(=O)C1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 0.7M diazomethane in ether was slowly added to a solution of 6.0 g (42.8 mmol) of 5-oxocyclohex-2-ene-1-carboxylic acid in 100 mL of ether at 0 degrees centigrade, with swirling. The addition of diazomethane was continued until the bubbling ceased and a yellow color persisted. The solution was treated with a rapid stream of nitrogen until the yellow color was discharged. The solvent was removed by evaporation. Benzene (100 mL) was added and evaporated at room temperature using an aspirator. The residue was placed on a vacuum line for 2 hours to produce 6.5 g (42.4 mmol, 99 percent) of methyl 5-oxocyclohex-2-ene-1-carboxylate (oil).
Reaction SMILES: [NH2:1][C:2]1[C:44]([N+:45]([O-])=O)=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 362.7 %

Procedure:
To a solution of 4-(2-amino-3-nitrobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (3.88 g) in ethanol (40 ml) were added a solution of ammonium chloride (385 mg) in water (10 ml) and iron powder (2.01 g) and the mixture was stirred at 100° C. for 2 hours. The mixture was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate and the solution was washed with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and the solution was concentrated in vacuo to give 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide as a yellow powder 13.42 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:19]C3(CC(C(OC)=O)C3)[CH:10]=2)[O:3]1.[CH3:21][C:22]1[CH:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24]C=C(OS(C(F)(F)F)(=O)=O)C=1>>[CH3:21][C:22]1[CH:10]=[C:9]([B:4]2[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]2)[CH2:19][CH2:24][C:23]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Reactant: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)C=C1C
Product: CCOC(=O)C1=C(C)C=C(B2OC(C)(C)C(C)(C)O2)CC1
Yield: 57.8 %

Procedure:
The title compound was prepared following the method for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, Step 2 described above in page 65-67, using ethyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohexa-2,4-dienecarboxylate as the reactant. (57.8% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.64 (t, J=1.6 Hz, 1H), 4.28-4.15 (m, 2H), 2.46-2.32 (m, 2H), 2.29-2.19 (m, 2H), 2.18 (t, J=1.8 Hz, 3H), 1.38-1.25 (m, 15H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:27].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][C:16]([Br:27])=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Br-]
Reactant: Cc1ccc(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)c(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a stirred solution of (R)-2-benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (190 mg, 0.59 mmol) in dry CH2Cl2:methanol (4:2 mL), tetrabutylammonium tribromide (331 mg, 0.68 mmol) was added. The reaction was stirred for 1 h under Argon added more tetrabutylammonium tribromide (45 mg, 0.09 mmol). After 20 min removed solvent in rotavap and then diluted with dichloromethane (100 mL), washed with 5% Na2S2O3 (10 mL), saturated NaHCO3 (10 mL) and brine (15 mL). The organic layer was dried over MgSO4, and conc in vacuo and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to yield 86 mg (36%) of the product as a faint brown oil. MS (ESI) 401, 403 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.CON(C)[C:12](=[O:14])[CH3:13]>C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:12](=[O:14])[CH3:13])=[CH:3][CH:4]=1
Reactant: CON(C)C(C)=O
Reactant: Clc1ccc(Br)cn1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
A round bottomed flask was charged with 5-bromo-2-chloropyridine (5.30 g, 27.6 mmol) in THF under N2 and cooled at 0° C. A solution of 1 M iso-propylmagnesiumchloride-lithium chloride complex in THF (40 mL) was added drop wise over 15 min. After 70 min N-methoxy-N-methylacetamide (4.1 mL, 38 mmol) was added drop wise. After stirring for 5 min at 0° C. the cooling bath was removed. The mixture was left stirring overnight and was then quenched by the addition of 100 mL saturated aqueous NH4Cl solution. The mixture was extracted with 3×100 mL EtOAc. The combined organic layers were washed with water followed by brine and dried over MgSO4. Evaporation of the volatiles at 80° C. 10 mbar for 1 h gave the title compound (3.596 g, 84) sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.O>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]([CH3:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Solvent: O
Solvent: CC#N
Product: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reaction time: 4 h
Yield: 97 %

Procedure:
13.8 kg of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine and 11.5 kg of phosphorus oxychloride were refluxed in acetonitrile, and stirred for 4 hours. The reaction solution was combined with water, and the precipitated crystal was separated, and the resultant crystal was washed and dried to obtain 14.6 kg of the target compound as a pale yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].[H-].[Na+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 56.5 %

Procedure:
1.52 g (3.90 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 30 mL of dimethylformamide under argon atmosphere, 2.25 mL (19.5 mmol) of 1-bromo-4-chlorobutane and 470 mg (11.8 mmol) of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 1.3 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=100:1) to give 1.06 g of 5-(4-chlorobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 57%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:7]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(Cl)nc(NCCc2ccc(F)cc2)n1

Procedure:
A solution of 10 g of 2,4-dichloro-6-methoxy-1,3,5-triazine in 200 ml of acetonitrile is cooled on an ice bath, 8.73 ml of DIPEA and then 6.56 ml of 2-(4-fluorophenyl)ethanamine are added and the mixture is stirred. The precipitate formed is drained by suction, washed with EtOAc and dried. 13.7 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:5][CH:4]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:4][CH:5]=1)[CH3:23]
Reactant: CCS(=O)(=O)Cl
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CCNc1ccc(CNS(=O)(=O)CC)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of 2.5 g of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) in 30 mL of pyridine was cooled in an ice bath for 15 min and 0.95 g of ethanesulfonyl chloride in 5 mL of pyridine was added rapidly dropwise and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into 75 mL of water containing 0.75 g of NaOH, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over sodium sulfate. The mixture was concentrated in vacuo and the residue was stirred in ether and dried (40° C./0.1 mm) to afford 1.7 g of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]ethanesulfonamide, amide, m.p. 105° C. (dec.). The sulfonamide was dissolved in methanol and treated with methanesulfonic acid in methanol to afford 1.61 g (42%) of the methanesulfonate salt, m.p. 135° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[N:8]=1>C(O)C.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[O:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Reaction time: 6 h
Yield: 25 %

Procedure:
A mixture of 5-(3-chloro-thiophen-2-yl)-3-(4-nitro-phenyl)-[1,2,4]-oxadiazole and Pd/C (30 mg) in ethanol (30 mL) under hydrogen (46 psi) was shaken for 6 h. After filtration, the filtrate was concentrated and applied to small column chromatography (hexane:ethyl acetate, 5:1) to yield 18 mg (25%) of the title compound. 1H NMR (CDCl3): 7.98 (d, J=8.7 Hz, 2H), 7.60 (d, J=5.1 Hz, 1H), 7.14 (d, J=5.1 Hz, 2H), 6.78 (d, J=8.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]C)=[CH:6][C:5]([B:10]2[O:14]C(C)(C)C(C)(C)O2)=[C:4]([C:19]([O:22]COCC)([CH3:21])[CH3:20])[CH:3]=1.Cl.O>C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[B:10]([OH:14])[O:22][C:19]([CH3:20])([CH3:21])[C:4]=2[CH:3]=1
Reactant: CCOCOC(C)(C)c1cc(Cl)c(CC)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cl)C(C)(C)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of 2-(4-chloro-2-(2-(ethoxymethoxy)propan 2-yl)-5-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.77 g, 4.8 mmol) in THF (24 mL) was added 6N HCl (24 mL). The reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with EA. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE-EA (20:1) to give 5-chloro-3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (540 mg; yield 53.6% over 2 steps) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 2.36 (s, 3H), 1.46 (s, 6H) ppm; MS: m/z=210.9 (M+1, ESI+).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][CH:6]=[C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[OH-].[Na+]>CO>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C=CC=C(c1ccccc1OC)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(=C/C=C/C(=O)O)c1ccccc1OC
Yield: 84.6 %

Procedure:
In the manner described in Example 99, 5,5-bis(2-methoxyphenyl) -2,4-pentadienoic acid methyl ester (6.3 g) was saponified in a refluxing mixture of methanol (50 mL) and 1N NaOH (50 mL). After 45 minutes the crude acid was isolated in the normal manner and the crystallized from 2-propanol to yield 5.1 g of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid, mp 96°-197° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:8][CH2:7]1
Reactant: COCCOCCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COCCOCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.66 g) in 2-propanol (20 mL) were added 4-{[2-(2-methoxyethoxy)ethyl]amino}-1,3-thiazol-2(5H)-one (1.60 g) and piperidinium acetate (0.710 g). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.88 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH3:2].[Br:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([NH2:24])=[CH:17][C:16]=1[CH3:25]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:24][C:18]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:15]([Br:14])=[C:16]([CH3:25])[CH:17]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCN=C=O
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(Br)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 36 %

Procedure:
6-Isocyanato-hexanoic acid ethyl ester (370 μL, 2.16 mmol) was added to a solution of 4-bromo-3-methyl-5-nitro-phenylamine (250 mg, 1.08 mmol, Example 135: step a) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture was stirred overnight, then diluted in EtOAc and washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by flash chromatography (50–75% EtOAc/hexanes) to afford the title compound as a brown oil (162 mg, 36%). 1H-NMR (CDCl3): δ 7.59 (d, 1H, J=2.56 Hz), 7.42–7.48 (m, 1H), 4.10–4.17 (m, 2H), 3.20–3.28 (m, 2H), 2.39 (s, 3H), 2.29–2.35 (m, 2H), 1.47–1.68 (m, 4H), 1.23–1.41 (m, 5H).