Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2I)=[CH:7][CH:6]=1>C(O)CC.C(Cl)Cl.CCCCCCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[C:2]#[N:3])=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: Fc1cc(I)c(N=Nc2ccc(Cl)cc2)cc1F
Solvent: CCCCCCC
Solvent: CCCO
Solvent: ClCCl
Product: N#Cc1cc(F)c(F)cc1N=Nc1ccc(Cl)cc1
Yield: 75 %

Procedure:
Copper (I) cyanide (9.76 g, 109 mmol) was added to a solution of (4-chloro-phenyl)-(4,5-difluoro-2-iodo-phenyl)-diazene (5.89 g, 16 mmol) in 1-propanol (95 ml) under an argon atmosphere. The reaction mixture was heated under reflux conditions for 14 h and diluted with CH2Cl2/heptane 1/1 (70 ml). The suspension was filtered and the filtrate was evaporated to dryness to give the title compound (3.3 g, 12 mmol; 77%) as brown solid which was used in the next step without further purification. MS: m/e=278.0 [M+H+].
Reaction SMILES: [F:1][C:2]([P:8](Cl)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:17]([OH:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(OCC)C>[F:1][C:2]([P:8]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[O:19][CH2:17][CH3:18])([F:7])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CCOP(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F

Procedure:
Bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, obtainable in accordance with Example 2, is added to a mixture of ethanol and 4-dimethylaminopyridine in diethyl ether at room temperature. The precipitated product 4-dimethylaminopyridinium chloride is separated off, and the solution comprises ethyl bis(pentafluoroethyl)phosphinite, (C2F5)2POC2H5.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[C:15]3[N:14]=[C:13]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=3)[CH:12]=2)[CH:5]=1.[OH-].[Na+]>CO>[NH2:35][C:31]1[CH:30]=[C:29]([NH:28][C:13]2[CH:12]=[C:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:36])=[O:2])[N:16]3[N:17]=[CH:18][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:15]3[N:14]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)CCCCc1cnn2c(Nc3cccc(C(=O)OC)c3)cc(Nc3cccc(N)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc(Nc2cc(Nc3cccc(C(=O)O)c3)n3ncc(CCCCC(=O)O)c3n2)c1
Yield: 53.5 %

Procedure:
To a solution of compound (16a) (102.1 mg, 0.203 mmol) in 5 mL of MeOH was added 1 M NaOH (0.41 mL, 0.407 mmol). The reaction mixture was refluxed for 1 h, and concentrated. HPLC purification gave 3-[5-(3-amino-phenylamino)-3-(4-carboxy-butyl)-pyrazolo[1,5-a]pyrimidin-7-ylamino]-benzoic acid (17a) (50 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.C([C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O>O1CCCC1>[OH:3][N:2]=[C:12]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:14]([CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13]1
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1=CC=C(CN2C(=O)c3ccccc3C2=O)CC1=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
5.2 g of hydroxylamine hydrochloride, 12.2 g of sodium acetate, and 50 ml water were added to a mixture of 20 g N-(3-formyl-4-methoxybenzyl)phthalimide and 200 ml tetrahydrofuran, and stirred at room temperature for 1 hr. It was stirred at 60° C. for 1 hr, and then evaporated. Water was added to the resulting residue, and the insoluble matters were collected by filtration. These were washed with diethyl ether to give 20 g of N-(3-hydroxyimino-4-methoxybenzyl)phthalimide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13]/[C:14](/[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[CH:15]\[CH:16]1[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13]/[C:14](/[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:15]\[CH:16]2[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC/C(=C\C1CC=CCC1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC/C(=C\C2CC=CCC2)c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 87.9 %

Procedure:
32.5 g of 4-methylbenzenesulfonyl chloride are added, at room temperature, to a solution of 34 g of Z-1-hydroxymethyl-1-(4-fluorophenyl)-2-(3-cyclohexenyl)ethene in 200 ml of methylene chloride and 29 g of triethylamine. After 24 hours, the reaction mixture is washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. 49.7 g (95%) of Z-1-(4-methylphenylsulfonyloxymethyl)-1-(4-fluorophenyl)-2-(3-cyclohexenyl)-ethene are obtained from the residue.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18]1([CH3:19])[O:24][CH2:23][CH2:22][O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(CCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)OCCO1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-1 (45 g, 156 mmol) and ethylene glycol (13.0 mL, 223 mmol) in benzene (500 mL) was added catalytic p-toluenesulfonic acid (125 mg). The resulting mixture was heated at strong reflux with azeotropic removal of water for 4 h. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 2-2 as a yellow oil, which crystallized on standing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[C:9]([Cl:18])[CH:8]=1)[CH3:6])[CH3:2].[Cl:20]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([Cl:20])[CH:15]=[N:14]2)=[C:9]([Cl:18])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(-n2cccn2)c(Cl)c1
Reactant: ClCl
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 12 h

Procedure:
2.79 g (0.01 mole) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid ethyl ester are dissolved in 30 ml of methylene chloride, and 700 mg of chlorine (dissolved in 5 ml of methylene chloride) are added. Stirring is effected for 12 hours at room temperature, followed by washing of the reaction solution with sodium carbonate solution and water, drying, concentration and distillation. 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid ethyl ester is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35]1([N:41]=[C:42]=[S:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:42](=[S:43])[NH:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=S)Nc1ccccc1)C3
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.5 %

Procedure:
A mixture of the compound obtained in Example 5A (1.0 g), phenyl isothiocyanate (0.31 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 14 hours, after which it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-phenylthiocarbamoyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (1.03 g, 80%), which was then recrystallized from ethyl acetate-hexane to yield colorless crystals having a melting point of 104 to 106° C. ##STR51##
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-:36].[K+]>CS(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:36])[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Cl-]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCc1ccc(CN(CCCCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Yield: 64.7 %

Procedure:
A mixture of 1.9 g of 1-[(4-butylphenyl)methyl]-1-[6-[(methylsulfonyl)oxy]hexyl]-3-(2,4,6-trichlorophenyl)urea, 0.6 g of potassium chloride, and 3.0 ml of dried dimethyl sulfoxide was heated at an oil bath temperature of 60°-70° C. for 20 hours. The extraction and chromatography procedures of Example 521 were followed to give 1.1 g of the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([O:32]C)=[O:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)=[O:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH2:1]([C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)=[O:10])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(=O)CCc5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCc1ccccc1

Procedure:
A mixture of methyl 17β-(phenethylcarbonyl)-androsta-3,5-diene-3-carboxylate, K2CO3, water and methanol is heated at reflux for about 5 hours. Acidification followed by conventional workup yields title compound.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:6]=1.[H][H]>C(O)C.[Pt]=O>[N:14]1([C:7]2[CH:6]=[C:5]3[CH:4]=[CH:3][NH:11][C:10]3=[CH:9][N:8]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CN(C)C=Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: c1ncn(-c2cc3cc[nH]c3cn2)n1
Yield: 50.3 %

Procedure:
N,N-Dimethyl-2-(5-nitro-2-(1,2,4-triazol-1-yl)pyridin-4-yl)ethenamine (8 g, 31 mmol) was hydrogenated over platinum oxide (1.6 g) in ethanol (150 mL) at 30 psi of hydrogen for 1 hour. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on silica eluting with ethyl acetate to afford an orange/brown solid. This was triturated with ether and the precipitate collected by filtration to give the title compound (2.89 g, 51%) as a pink solid. mp 203°-205° C. 1H NMR (360 MHz, d6 -DMSO)δ6.67 (1H, d, J=3.0 Hz), 7.76 (1H, d, J=2.9 Hz), 8.01 (1H, s), 8.23 (1H, s), 8.70 (1H, s), 9.25 (1H, s) and 11.86 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:31]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:18]=[C:19]([S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[N:32]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(OCC)(=O)C.[Cu]I>[C:27]([NH:26][S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:11]3[N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([O:39][CH2:38][CH2:37][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:3][CH:4]=4)[N:31]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH:18]=1)(=[O:25])=[O:24])([CH3:30])([CH3:29])[CH3:28]
Reactant: OCCN1CCCC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(Br)cc4)nn23)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
A solution of 3-(2-(4-bromophenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-tert-butylbenzenesulfonamide (150 mg, 0.3 mmol) and copper (I) iodide (57 mg, 0.3 mmol) in 2-(pyrrolidin-1-yl)ethanol (2 mL) was heated at 140° C. under a nitrogen atmosphere. After 18 hr, the reaction mixture was cooled to 20° C. and diluted with ethyl acetate (100 mL). The solution was washed with water. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative thin layer chromatography afforded the desired product (58.5 mg, 36% yield). LCMS (ESI) m/z: 535.3. 1H NMR (400 MHz, DMSO-d6), δ: 9.44 (s, 1H), 8.64 (s, 1H), 8.21-8.19 (d, J=8 Hz, 1H), 8.10-7.99 (d, J=8 Hz, 1H), 7.78 (m, 1H), 7.66-7.57 (m, 5H), 7.24-7.22 (d, J=8 Hz, 1H), 6.90-6.88 (d, J=8 Hz, 2H), 4.15-4.10 (m, 2H), 3.20-3.10 (m, 3H), 2.89-3.05 (m, 3H), 1.83-1.79 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>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>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc([N+](=O)[O-])c(C#N)n2)cc1OC
Yield: 79.3 %

Procedure:
To a degassed suspension of 6-chloro-2-cyano-3-nitropyridine (5.51 g, 30 mmol), 3,4-dimethoxyphenyl boronic acid (6.55 g, 36 mmole) and potassium carbonate (16.59 g, 120 mmol) in dry toluene (300 ml), was added a catalytic amount of tetrakis(triphenylphosphine)palladium (3.47 g, 3 mmol). The mixture was refluxed for 24 hours and after cooling, the volatiles were evaporated to dryness. The crude mixture was purified by silica gel column chromatography, the mobile phase consisting of hexane/CH2Cl2 mixtures (in a ratio gradually ranging from 15:85 to 0:100). The appropriated fractions were collected, evaporated to dryness and the residue was suspended in ether. The orange precipitate was filtered off, washed with ether and dried, resulting in the pure title compound (6.79 g, yield 79%).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[C:20](/[CH3:25])=[CH:21]\[C:22]([OH:24])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOC[CH2:27]1>[Ni]>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:25])[CH2:21][C:22]([O:24][CH3:27])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCO1
Reactant: C/C(=C/C(=O)O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Agent: [Ni]
Product: COC(=O)CC(C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 8 h

Procedure:
3.2 g (8.95 mmol) of 3-(2-benzenesulphonamido-indan-5-yl)-crotonic acid in 50 ml of dioxan are hydrogenated in the presence of Raney nickel at room temperature under a hydrogen pressure of 3.5 bar. The mixture is filtered, the filtrate is evaporated, the residue is dissolved in 20 ml of methanol, and 1.5 ml of thionyl chloride are added dropwise at -50° C. The mixture is allowed to stand overnight at room temperature and is evaporated again, and the residue is chromatographed over silica gel using ethylene chloride. The fractions having an Rf-value of 0.6 are combined and evaporated. This gives a colourless oil.
Reaction SMILES: [C:1]([C:14]1[C:18]([CH3:19])=[C:17]([CH2:20][C:21]([O:23]CC)=[O:22])[N:16]([CH2:26][C:27]2[CH:39]=[CH:38][C:30](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])=[CH:29][CH:28]=2)[C:15]=1[CH3:40])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CO>[C:21]([CH2:20][C:17]1[N:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)[C:15]([CH3:40])=[C:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:18]=1[CH3:19])([OH:23])=[O:22]
Reactant: CCCCCCCCCCCC(=O)c1c(C)c(CC(=O)OCC)n(Cc2ccc(/C=C/C(=O)OCC)cc2)c1C
Solvent: CO
Product: CCCCCCCCCCCC(=O)c1c(C)c(CC(=O)O)n(Cc2ccc(/C=C/C(=O)O)cc2)c1C

Procedure:
Preparation as in Example 2E with ethyl (E)-4-({3-dodecanoyl-5-[(ethoxycarbonyl)methyl]-2,4-dimethyl-pyrrol-1-yl}methyl)cinnamate in place of ethyl (E)-3-({3-dodecanoyl-5-[(ethoxycarbonyl)methyl]-2,4-dimethyl-pyrrol-1-yl}methyl)cinnamate. The product is recrystal-lized from methanol.
Reaction SMILES: C(P(=CC#N)(CCCC)CCCC)CCC.C([O:21][C:22](=[O:34])[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(C)(C)C.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][CH:38]=1.FC(F)(F)C(O)=O>ClCCl.O.C1(C)C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][O:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]([NH:24][CH2:23][C:22]([OH:21])=[O:34])=[O:33])=[CH:31][CH:30]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 71.7 %

Procedure:
(Tributyl phosphoranylidene)acetonitrile (428 μL, 1.50 mmol) was added to a solution of toluene (7 mL) containing N-(4-hydroxybenzoyl)glycine tert-butyl ester (264 mg, 1.05 mmol) prepared in Example 1 (1a) and 2-(4-methoxyphenyl)ethanol (176 mg, 1.16 mmol). The mixture was stirred at 100° C. for 3.5 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate, 6:1, 4:1, and 3:1, v/v) to give an oily substance (358 mg). To a solution of dichloromethane (1 mL) containing this oily substance (358 mg, 0.929 mmol), trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. Diisopropyl ether was added to the resulting residue to suspend it. The produced precipitate was collected by filtration and was washed with diisopropyl ether to give 248 mg of the title compound (colorless crystalline solid, yield: 72%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[F:17])(=O)=O.[CH3:20][N:21](C=O)C>C(OCC)(=O)C.[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N>[F:17][C:8]1[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:7]=1[C:20]#[N:21]
Reactant: CS(=O)(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C#N)c(F)c1
Temperature: 80 °C

Procedure:
To a stirred solution of the product from Step D (662 mg, 2.06 mmol) in DMF (8 mL) was added zinc cyanide (951 mg, 8.1 mmol), and the reaction was then heated at 80° C. for 12 h. The reaction mixture was diluted with ethyl acetate and poured into brine. The organic phase was separated, and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (50:50 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC(C)=CC=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([CH3:24])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccc(N)cc1
Solvent: CC(=O)O
Product: Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 68 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (80 mg, 0.34 mmol), triethyl orthoformate (0.65 ml), p-toluidine (67.5 mg, 0.63 mmol), and acetic acid (0.08 ml) were used to give 73.8 mg (0.23 mmol, 68% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)Cc1cc(Cl)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cl)cc1CC(CNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of methyl 3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoate (500 mg) in methanol (5 ml), 5N aqueous sodium hydroxide solution (0.84 ml) was added under ice cooling and the mixture was stirred at that temperature for 16 hours. The reaction solution was concentrated in vacuo, then 6N hydrochloric acid was added to make the pH4, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off in vacuo to obtain the title compound (457.1 mg) as a colorless crystal. The 1H-NMR spectral data matched those of Example 312.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]([CH2:22][C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)[N:9]=1)=[O:7])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([CH2:22][N:10]2[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[N:9]2)=[O:32])=[N:26][CH:27]=1
Reactant: COCCOCCOCc1cc(C(=O)OC(C)(C)C)nn1CC(=O)Nc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCOCCOCc1cc(C(=O)O)nn1CC(=O)Nc1ccc(Cl)cn1

Procedure:
To a solution of 400 mg 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid tert-butyl ester in 5 ml DCM, 15 ml TFA were added at RT. After 3 h 30 ml toluene were added and the solvents were removed under reduced pressure. The residue was then three times codistillied with toluene and subjected to the next reaction step without further purification.