Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccc(F)cc1F
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c(F)c1

Procedure:
To a solution of (E)-2,4-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,4-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,4-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1>O1CCCC1.CS(C)=O>[O:23]1[CH2:4][C:13]21[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH:16]=[CH:17][C:18]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]2=1
Reactant: C[S+](C)C
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C1=Cc2ccccc2C2(CO2)c2ccccc21
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 4.6 g. of sodium hydride (57%) and 100 ml. of dimethylsulfoxide is heated under nitrogen at 75° C. for 50 minutes and the resulting mixture treated by addition of 40 ml. tetrahydrofuran and then cooled to 0° C. Over a period of 3 minutes there is then added 10.2 g. of trimethylsulfonium iodide in 100 ml. of dimethylsulfoxide, the resulting mixture stirred for one minute and there is then added over a period of 10 minutes a solution of 16.4 g. of dibenzo[a,d]cyclo-hepten-5-one in 40 ml. of tetrahydrofuran. The resulting mixture is kept overnight at temperature of 5° C. and then stirred for 3 hours at room temperature (20° C.). The mixture is then poured onto 3 times its volume of ice water, extracted twice each with 600 ml. of pentane, the organic phases combined, washed four times with water, dried over anhydrous sodium sulfate and evaporated in vacuo to crystallize spiro[dibenzo[ a,d] cycloheptene-5,2'-oxirane], m.p. 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:24]3[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Reactant: CC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
A mixture of 1.989 (7.50 mmole) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 1.169 (9.05 mmole) of N-acetylpiperazine, and 2.0 mL of triethylamine in 20 mL of dry THF was refluxed under a nitro9en atmosphere for 16 hr. It was then poured into 5% aqueous sodium hydroxide and extracted three times with methylene chloride. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo to yield a product which was purified by flash chromatography (5% CH3OH in CHCl3) to afford 1.71g of the title compound as a glass.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:15]([C:17]1[CH:29]=[CH:28][C:20]([CH2:21][NH:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])=[CH:19][CH:18]=1)#[N:16].Cl.[NH2:31][OH:32].CN1CCOCC1>CO>[CH2:1]([S:5]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4].[OH:32][NH:31][C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])=[CH:28][CH:29]=1)=[NH:16]
Reactant: NO
Reactant: C[C@H](N)C(=O)NCc1ccc(C#N)cc1
Agent: CCCCS(=O)(=O)N[C@H](CO)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Product: C[C@H](N)C(=O)NCc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product in Example 7 (117 mg, 0.285 mmol) in 1.14 ml methanol was added hydroxylamine hydrochloride (33.7 mg, 0.485 mmol), followed by N-methylmorpholine (53 μl, 0.485 mmol). The reaction mixture was stirred overnight at ambient temperature and then at 50° C. for six hours. The reaction mixture was concentrated in vacuo. The crude product was taken to the next step (Example 9) without further purification. The product eluted at 6.5 minutes by reverse phase (C18) HPLC at 0.1% trifluoroacetic acid in 5-50% aqueous acetonitrile over 20 minutes.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:33][S:30]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:22]=1[CH:4]1[N:3]([S:37]([CH3:36])(=[O:39])=[O:38])[C:2](=[O:1])[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]1=2)[C:26]#[N:27])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2ccnc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.6, 150 mg, 0.32 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 35 mg, 0.88 mmol) in tetrahydrofuran (8.0 mL). After 10 min methanesulfonyl chloride (49 μL, 0.63 mmol) is added and the mixture is heated at 50° C. for 1.5 h. The mixture is cooled at room temperature and treated with water (1 mL). The mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (first purification: Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]+=555; Retention time HPLC: 0.90 min (Z011_S03).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]#[N:14].[OH-:15].[Na+].OO>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[CH2:12][C:13]([NH2:14])=[O:15]
Reactant: [OH-]
Reactant: N#CCc1c(F)cccc1C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)Cc1c(F)cccc1C(F)(F)F
Temperature: 40 °C

Procedure:
20 g (98.5 mmol) of 2-fluoro-6-trifluoromethyl-phenyl-acetonitrile is dissolved in 150 ml of methanol. It is adjusted to pH 10 with sodium hydroxide solution and heated to 40° C. Then, 15 ml (132.3 mmol) of hydrogen peroxide (30%) is instilled, diluted with 25 ml of water, and the pH is kept between 9-10 by simultaneous addition of sodium hydroxide solution. A solid precipitates with foaming. After completion of the addition, it is stirred for 30 more minutes, allowed to cool off, suctioned off from the solid, washed with water and dried in a vacuum. The title compound is obtained in crystalline form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:26])[C:15]=3[N:14]=[C:13]2[CH2:27][O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20]([C:39]5[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=5)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:26])[C:15]=3[N:14]=[C:13]2[CH2:27][O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Reactant: OB(O)c1cccnc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Yield: 53.9 %

Procedure:
4-Methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.16 g, 2.0 mmol) and pyridine-3-boronic acid (0.30 g, 2.4 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, at which time additional pyridine-3-boronic acid (0.3 equivalent) was added and the reaction was heated for an additional five hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with methanol, isolated by filtration, and dried for 20 hours under high vacuum at 140° C. to provide 0.62 g of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a beige powder, mp 230-231.5° C.
Reaction SMILES: [C:1](=[O:4])([O-])O.[K+].[CH3:6][S:7][C:8]1[S:9][CH2:10][CH2:11][N:12]=1>>[OH:4][CH2:1][C@@H:11]1[CH2:10][S:9][C:8]([S:7][CH3:6])=[N:12]1
Reactant: O=C([O-])O
Reactant: CSC1=NCCS1
Agent: [K+]
Product: CSC1=N[C@H](CO)CS1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a 73 ml solution of methanol anhydride containing 7.95 g of 3-hydroxyazetidine hydrochloride (5) obtained in the above Example 3, there was added 5.09 g of potassium hydrogencarbonate at a room temperature, and, then, there was added 9.67 g of 2-(methylthio)-1,3-thiazoline dropwise, and, then, the resultant solution was subjected to heating and reflux for 20 hours. After the reaction liquid was left still until it had a room temperature, 3.63 g of potassium hydrogencarbonate was further added, and the liquid was stirred for one hour at the same temperature. After the reaction was over, precipitate was removed by filtration, and the solvent was evaporated in a vacuum, and, to the obtained residue, there was added 100 ml of tetrahydrofuran, and the resulting mixture was stirred for one hour at a room temperature. Insoluble matters were removed by filtration, and the solvent was evaporated in a vacuum, and, then, the residue was subjected to silica gel column chromatography (eluent: chloroform-methanol), and, thus, there was obtained 8.23 g (yield: 71.5%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless crystal.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromobenzene-1-sulfonamide [CAS 89599-01-9; commercially available] (236 mg, 1.0 mmol) according to
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[NH:11][CH2:10]1)=[O:8].C(O[CH2:35][CH:36]=[CH2:37])(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:37]([N:11]1[C@H:12]2[C@@H:22]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:24]=3[C:14]([CH2:13]2)=[CH:15][NH:16]4)[CH2:23][C@@H:9]([C:7]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])[C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[O:8])[CH2:10]1)[CH:36]=[CH2:35]
Reactant: CCNC(=O)N(CCCN(C)C)C(=O)[C@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Reactant: C=CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCN1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a suspension of 9.0 g (21.87 mmol) N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl)-ergoline-8β-carboxamide (XIX) in 250 ml of toluene 0.5 g of tetrakis(triphenylphosphine)palladium(0) and 5 ml of allyl acetate was added, and the reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was washed with 100 ml of water. The organic layer was dried over anhydrous sodium sulphate. The dried solution was concentrated in vacuum and the product was purified on a silica plug to give 9.1 g (92.3%) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].N[C:28]1[CH:29]=C2C(=C[CH:37]=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CCCCC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:29][CH2:28][CH2:37][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: O=C(O)C(=O)CC1(c2ccccc2)CCCCC1
Product: O=C(CC1(c2ccccc2)CCCCC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclohexyl)-2-oxo-propionic acid, melting point 120-123° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[C:11]([CH2:28][N:29]([CH3:31])[CH3:30])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](S(C1C=CC=CC=1)(=O)=O)[CH:14]=[CH:13]2.[OH-].[Na+]>CCO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[C:11]([CH2:28][N:29]([CH3:30])[CH3:31])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]ccc2c1CN(C)C

Procedure:
{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine trifluoroacetate (127 mg, 0.278 mmol) was refluxed in EtOH (2 ml) and 1 M NaOH (2 ml) for 3 h. The mixture was extracted with DCM The product was purified on Gilson HPLC using 20-40% MeCN in 0.1% TFA. Yield: 54.6 mg (62%); colourless oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[ClH:9].[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([CH2:5][N:3]([CH3:4])[CH3:2])[S:7][CH:12]=1
Reactant: CN(C)CC(N)=S
Reactant: O=C(CCl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)Cc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a 1000 ml. flask were added 77 g. of dimethylaminothioacetamide, hydrochloride, 70 g. of 1,3-dichloropropanone, 92.4 g. of sodium bicarbonate and 350 ml. of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 26 hours and filtered, and the filter cake was washed with 118 ml. of 1,2-dichloroethane. The filtrates were combined and cooled in an acetone-ice bath. To the filtrate was added, dropwise, 39.5 ml. of thionyl chloride at a temperature between 13° and 18°. The mixture was stirred at 20° for 30 minutes, then heated to 50°. An additional 100 ml. of 1,2-dichloroethane was added, and the mixture was stirred for 30 minutes at 60°. It was then cooled to ambient temperature, and 82 ml. of deionized water was added. The layers were separated, and the organic layer was extracted with 28 ml. and 14 ml. portions of deionized water. The aqueous layers were combined, and it was confirmed by tlc that the desired product had been collected in the aqueous layers.
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][CH2:13][O:14][C:15](=[O:25])[CH2:16][O:17]CC1C=CC=CC=1)=[O:11])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][CH2:9][C:10]([O:12][CH2:13][O:14][C:15](=[O:25])[CH2:16][OH:17])=[O:11]
Reactant: O=C(COCc1ccccc1)OCOC(=O)COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CO)OCOC(=O)CO
Reaction time: 16 h
Yield: 93.4 %

Procedure:
Methylene bis(benzyloxyacetate) (0.52 g, 1.5 mmol) and Pd/C (100 mg, 10%) are added to dry ethanol (100 ml). Hydrogen (1 atm) is introduced and the reaction is complete after 16 hours at room temperature, whereupon the reaction mixture is filtered and the solvent is evaporated under reduced pressure (0.01 mmHg) to yield 0.23 g (95%) product. 1H NMR (200 MHz, MeOH): δ 4.2 (CH2, s), 4.9 (OH), 5.9 (OCH2O, s). The product may be used to form polyesters with di- or poly-acids and to form polyurethanes with isocyanates.
Reaction SMILES: O.[N:2]([CH:5]([C:7]1[S:11][C:10]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:9][C:8]=1[CH3:29])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:15]2([C:17]([F:18])([F:20])[F:19])[O:14][N:13]=[C:12]([C:10]3[S:11][C:7]([CH:5]([NH2:2])[CH3:6])=[C:8]([CH3:29])[CH:9]=3)[CH2:16]2)[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N
Reaction time: 18 h
Yield: 37.7 %

Procedure:
Water (2 ml) is added to a mixture of 3-[5-(1-azido-ethyl)-4-methyl-thiophen-2-yl]-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (0.80 g) and triphenylphosphine (0.93 g) in tetrahydrofuran (9 ml). After 18 hours at 50° C., the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethylamine (0.284 g) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([F:1])[CH:7]=1)[CH3:21]
Reactant: C=CC(=O)OCC
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-4-bromobiphenyl 12-1 (7.5 gm, 31.8 mmol), ethyl acrylate (4.3 mL), Pd(OAc)2 (0.714 gm, 3.2 mmol), tri-o-tolylphosphine (1.94 gm, 1.5 mmol), and triethylamine (12 mL) was heated to 100° C. in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (40 mL). The organic solution was washed with 10% aq. citric acid (20 mL), satd. aq. NaHCO3, and brine (20 mL). The organic solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (95:5 to 90:10 hexanes/EtOAc) to give the acrylate ester 12-2 as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pt+2].[OH-]>[CH3:26][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[NH:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Nc1cc(F)ccc1N(C)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pt+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Nc1cc(F)ccc1N(C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-methyl-N-(2-isopropylamino-4-fluorophenyl)amino]piperidine (EXAMPLE 170, 2.90 g, 8.16 mmol) and platinum hydroxide on carbon (1.0 g) in 50 ml ethanol is hydrogenated at 276 kPa (40 psi) hydrogen for 25 hrs. Filtration and evaporation of the solvent gives the tide compound, NMR (300 MHz, CD3OD) 7.02, 6.32, 6.24, 3.60, 3.15, 2.90, 2.75, 2.54, 1.8-2.0, 1.50 and 1.18δ.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].Cl>C1COCC1.CCO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: N#Cc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Yield: 36 %

Procedure:
Combine 4-(5-cyano-pyridin-2-yloxy)-benzamide (202 mg, 0.844 mmol), 5% Pd/C (80 mg) and conc. HCl (0.423 mL) in THF (4 mL) and EtOH (4 mL). Run the reaction under hydrogen atmosphere (1 atm) at rt overnight. Add NaOH (5 N, 2 mL) and filter the reaction mixture through Celite®. Concentrate the filtrate. Wash the residue with H2O (5 mL) and extract with CH2Cl2 (3×5 mL). Combine the organic layers and purify through an SCX column eluting with 2M ammonia in methanol. Concentrate the fractions to give the title compound (74 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:27]([O-])(=[O:29])C.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:15]=[CH:16][C:17]([CH:27]=[O:29])=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(Cc2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
In an argon atmosphere, N-(4-bromobenzyl)diphenylamine (169 mg, 0.500 mmol) obtained in Example 64 was dissolved in dimethylformamide (1.5 mL), and phosphorus oxychloride (0.116 mL, 1.25 mmol) was added thereto, followed by stirring at 100° C. for 30 minutes. The reaction liquid was cooled to room temperature, poured into saturated sodium acetate aqueous solution, and was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=4/1) to give 4-[N-(4-bromobenzyl)-N-phenylamino]-benzaldehyde (159 mg, 87%).