Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=[O:34])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]([C:7]2[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=2[O:18][CH3:19])[OH:34])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)C2CCN(Cc3ccccc3)CC2)c1C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
n-Butyllithium (1.6 M, 19.5 mL, 31.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (8.00 g, 30.87 mmol) in tetrahydrofuran (80 mL) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 1-benzyl-4-formylpiperidine (6.23 g, 30.65 mmol). The mixture was stirred for 30 minutes at room temperature, then poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to obtain the title compound (6.17 g, yield 52%). This was oily.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:14]1[S:13][C:12]([C:10]2[S:28][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)CCC(=O)c2ccccc2)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(-c3ccccc3)s2)s1
Yield: 131.6 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 3.0 grams (0.012 mole) of 1-phenyl-4-(5-methyl-2-thienyl)-1,4-butanedione and 3.0 grams (0.008 mole) of Lawesson's reagent in 100 ml of toluene was heated under reflux for one hour. The reaction mixture was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel using 15% methylene chloride-hexane as eluent. The appropriate fractions were combined and concentrated under reduced pressure to give 2.7 grams of 5'-methyl-5-phenyl[2,2'-bithienyl]; m.p. 102° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].[CH3:26][N:27]1[CH:31]=[N:30][N:29]=[C:28]1[SH:32].CC(C)([O-])C.[K+]>CN(C=O)C>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][S:32][C:28]4[N:27]([CH3:26])[CH:31]=[N:30][N:29]=4)=[C:6]([O:24][CH3:25])[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[C:17]([F:23])[CH:18]=1
Reactant: Cn1cnnc1S
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1nncn1C
Product: Cl
Temperature: 40 °C
Yield: 157.3 %

Procedure:
7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (98 mg, 0.23 mmol) was added to a solution of 4-methyl-4H-1,2,4-triazole-3-thiol (40 mg, 0.34 mmol) and potassium-t-butoxide (36 mg, 0.32 mmol) in DMF (1 ml) and the mixture heated at 40° C. for 30 minutes. The reaction mixture was allowed to cool and was partitioned between ammonium chloride and ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with a gradient of methylene chloride/methanol (95/50 to 80/20). The purified solid product was triturated with ether and collected by filtration. The solid was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation and the residue was crystallised from methylene chloride and ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-methyl-4H-1,2,4-triazol-3-ylthio)ethoxy)-quinazoline hydrochloride (90 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=O)[CH:3]=1.C(O)C.[NH3:13].C(Cl)(Cl)Cl>CCOCC>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:13][C:4](=[O:5])[CH:3]=1
Reactant: N
Reactant: Cc1cc(O)cc(=O)o1
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)cc(=O)[nH]1
Temperature: 25 °C
Yield: 88 %

Procedure:
4-Hydroxy-6-methyl-2H-pyran-2-one (11.1 g, 88.0 mmol) was suspended into ethanol (5.0 mL), added with 28% aqueous ammonia (55 mL), and the resultant mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled down to room temperature, added with chloroform (25 mL) and ether (25 mL) to extract solid substance which was then washed sequentially with chloroform (10 mL), ether (10 mL) and tetrahydrofuran (30 mL), and concentrated in vacuo. Then, the obtained residue was further washed sequentially with chloroform (10 mL), ether (10 mL) and tetrahydrofuran (30 mL). 4-Hydroxy-6-methylpyridin-2(1H)-one (9.70 g, yield 88%) was obtained as a pale yellow crystal.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([Cl:19])=[N:9][C:8]=1[CH3:20].CN([CH:24]=[O:25])C>C1COCC1>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7]([CH:24]=[O:25])=[C:8]([CH3:20])[N:9]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(Cl)nc(C)c(Br)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(Cl)nc(C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
n-BuLi (12 ml of 1.6 M in hexane) is added dropwise to a solution of 4-bromo-1-chloro-6-methoxy-3-methyl-isoquinoline (4.8 g, 17 mmol) in THF (60 ml) at −78° C. After stirring for 40 min, DMF (4 ml, 51 mmol) is added slowly. The reaction is allowed to warm to 0° C. and the stirring is continued for 1 h. The mixture is then quenched with 1N—HCl (30 ml) and extracted with EtOAc. The combined extracts are dried over Na2SO4 and evaporated. The residue is chromatographed on silica gel eluting with EtOAc/hexane (1:4) to give 2.9 g of 1-chloro-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.8 (s, 1H), 8.61 (s, 1H), 8.24 (d, 1H), 7.29 (d, 1H), 4.01 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:19](OC(=O)C)(=O)C.C(OCC)(OCC)OCC.[NH2:36][C:37]1([CH2:42][OH:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:43][CH2:42][C:37]1([NH:36][CH:19]=[C:3]([C:2](=[O:1])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=2[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1(CO)CCCC1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C(=CNC1(CO)CCCC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (3.17 g, 12 mmol), acetic anhydride (3.34 mL, 3.6 g, 30 mmol) and triethyl orthoformate (3.00 mL, 2.6 g, 18 mmol) was heated at 130° C. for 1.5 h. The mixture was concentrated in vacuo and dried under high vacuum for 3 hours. The crude product was dissolved in EtOH (15 mL) and cooled to 0° C. and then 1-amino-1-cyclopentanemethanol (1.01 g, 8.8 mmol) was added very slowly. After 1.5 h, the solvent was removed by evaporation to yield the title compound as yellow oil (3.1 g crude) that was used in the next step without further purification.
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].[NH:4]([C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[C@@H:5]([C:13]([NH:15][C@H:16]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:54]([NH:56][C@H:57]([C:65](OC)=[O:66])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:39][C:40](=[O:42])[NH2:41])=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:17][S:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O>[NH:4]([C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[C@@H:5]([C:13]([NH:15][C@H:16]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:54]([NH:56][C@H:57]([C:65]([NH:2][NH2:3])=[O:66])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:39][C:40](=[O:42])[NH2:41])=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:17][S:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)=[O:1])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC[C@H](NC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reactant: NN
Reactant: O
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 48 h

Procedure:
5 ml of hydrazine-hydrate are added to 5 g of Z-(D)Phe-Cys(MBzl)-Nle-Asn-Phe-Phe-OMe in 80 ml dimethylformamide and the mixture allowed to stand for 2 days at room temperature. The title compound is obtained after precipitation with methanol, filtration, washing with methanol and drying: [α]D20 =-32° (c=1.0 in dimethylformamide); decomposition at 248° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:2]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].C1C[O:25]CC1>O.C(Cl)Cl>[OH:25][CH:2]([CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: N#CCCCCCCCC1OC1CCCCCCCC#N
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: N#CCCCCCCCC(O)C(O)CCCCCCCC#N
Reaction time: 24 h

Procedure:
To a solution of 0.10 g like-8,8′-(oxirane-2,3-diyl)dioctanenitrile in 5.0 g THF was added 0.50 mL of a solution of 0.0988 g 70% HClO4 in 1.9104 g water. After standing for 24 h at room temperature, the mixture was diluted with 250 mL CH2Cl2, which resulted in the separation of aqueous droplets. The mixture was dried over Na2CO3 and evaporated to afford 0.10 g of product as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]([C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36]([CH:37]=O)[C:31]2=[CH:30][CH:29]=1)#[CH:27]>CO.N1CCCCC1>[C:26]([C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36](/[CH:37]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])[C:31]2=[CH:30][CH:29]=1)#[CH:27]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: C#Cc1ccc2c(C=O)c[nH]c2n1
Solvent: CO
Solvent: C1CCNCC1
Product: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.017 g, 0.049 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.007 g, 0.041 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and then the residue was washed with methylene chloride to obtain tert-butyl (Z)-4-({2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=2[C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:22][C:21]=2[C:27]([F:30])([F:28])[F:29])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.9 %

Procedure:
4-(4-Amino-2-trifluoromethyl-benzensulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.44 g, 0.11 mmol) was dissolved in THF (15 ml). To this solution was added diisopropylethylamine (0.52 ml, 0.33 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.09 ml, 0.11 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material, was purified by preparative HPLC to give the title compound (70 mg, 14% yield) as a white solid.
Reaction SMILES: C(OC)(=O)CC.[Cl:7][C:8]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1.[C:23]([CH2:25][C:26](=O)[CH2:27][CH3:28])#[N:24]>>[C:23]([C:25]1[CH:10]([C:9]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:8]=2[Cl:7])[C:22]2[C:18](=[N:19][NH:20][CH:21]=2)[NH:17][C:26]=1[CH2:27][CH3:28])#[N:24]
Reactant: CCC(=O)CC#N
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: Nc1cc[nH]n1
Solvent: CCC(=O)OC
Product: CCC1=C(C#N)C(c2cccc(Cl)c2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from methyl propionate, 2,3-dichlorobenzaldehyde, 3-aminopyrazole and 1-cyanobutan-2-one in the same manner as in Example 94.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8]O>CC(C)CC(=O)C>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:8])=[CH:3][CH:2]=1)[OH:7]
Reactant: OO
Reactant: Oc1ccccc1
Solvent: CC(=O)CC(C)C
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O
Reaction time: 0.5 h

Procedure:
To a mixture of 10 g. (106 m. moles) of phenol, 0.820 g. (8.20 m. moles) of 4-methyl-2-pentanone and 0.300 g. (5.29 m. moles) of 60 percent hydrogen peroxide was added the catalyst indicated in Table 4, and the reaction was effected at 100° C. for 30 minutes in the same manner as in Example 1. The reaction in Example 26 was effected at 160° C. for 1 hour. Yields of catechol and hydroquinone are shown in Table 4.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35]C)[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][OH:35])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 52.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide (prepared according to WO2002055517) as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide (52 mg, 52.7%) as a yellow solid.
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](=O)[CH3:19])=[CH:14][CH:13]=1)#[N:11]>CO>[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([NH2:7])[CH3:19])=[CH:14][CH:13]=1)#[N:11]
Reactant: [BH3-]C#N
Reactant: CC(=O)COc1ccc(C#N)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)COc1ccc(C#N)cc1
Yield: 27.8 %

Procedure:
293 g of ammonium acetate and 16.7 g of sodium cyanoborohydride were added to a solution containing 66.5 g of 4-cyanophenoxyacetone dissolved in 1500 ml of methanol, and the resultant mixture was stirred for 30 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and acidified with concentrated hydrochloric acid. 500 ml of diethyl ether and 300 ml of water were then added thereto. Subsequently, the resultant water layer was made basic with a 5% aqueous solution of sodium hydroxide, the solution was extracted with 1000 ml of diethyl ether, and then washed with water. The organic layer was then dried over anhydrous sodium sulfate, and the diethyl ether was removed under reduced pressure. The obtained residue was distilled under reduced pressure to yield 13.0 g of the desired product (19%). Boiling point: 132° C./0.26 mmHg.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S(Cl)(Cl)=O.[CH3:23]O>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:23])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CO
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3,5-Bis(trifluoromethyl)phenylacetic acid (10.0 ·, 36.7 mmol), was dissolved in methanol (150 ml). The solution was cooled to 4° C. under an atmosphere of dry nitrogen, and thionyl chloride (10 ml) was added dropwise with vigorous stirring over 30 minutes. The mixture was warmed to room temperature, and then stirred for 1 hour. The solvents were evaporated at reduced pressure, the residue dissolved in diethyl ether (150 ml), washed with saturated aqueous NaHCO3, dried (Na2 SO4), and evaporated to afford the title compound (10.5 g, 100%), as a colourless oil which was used without further purification.
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7][C:6]=3[CH:13]=2)[O:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]([CH2:35][Cl:36])[CH2:29]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[ClH:36].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]([CH2:35][N:9]3[C:8](=[O:12])[CH2:7][C:6]4[CH:13]=[C:14]5[O:15][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[CH2:11][CH2:10]3)[CH2:29]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CCN2CCCCC(CCl)C2)cc1OC
Reactant: O=C1Cc2cc3c(cc2CCN1)OCO3
Product: COc1ccc(CCN2CCCCC(CN3CCc4cc5c(cc4CC3=O)OCO5)C2)cc1OC
Product: Cl

Procedure:
Prepared from 7,8-methylenedioxy-1,3,4,5-tetrahydro-2-oxo-3-benzazepine and N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH:8][C:9]([C:11]1([NH:16][C:17]([C:19]2([SH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])CCC.[OH-].[Na+]>CO>[SH:24][C:19]1([C:17]([NH:16][C:11]2([C:9]([NH:8][C@H:7]([C:6]([OH:33])=[O:5])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Reaction time: 17 h

Procedure:
To a stirred solution of N-[[1-[[(1-mercapto-1-cyclopentyl)carbonyl]amino]-1-cyclopentyl]carbonyl]-L-tyrosine butyl ester (0.47 g, 0.99 mmol) in degassed methanol is added 1N sodium hydroxide (3.00 mL, 3.00 mmol). The mixture is stirred for 17 hours. The solvent is removed in vacuo and water (30 mL) is added to the residue. The aqueous phase is washed with ethyl acetate (10 mL) and then acidified to pH 1 with 1N hydrochloric acid. The aqueous phase is extracted with ethyl acetate (3×50 mL), washed with brine and dried over magnesium sulfate. The solvent is removed in vacuo to afford a foam which is crystallized from hexane/ethyl acetate to give N-[[1-[[(1-mercapto-1-cyclopentyl)carbonyl]amino]-1-cyclopentyl]carbonyl]-L-tyrosine, m.p. 90° C.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O[Li].O.[O:20]=[C:21]1[O:25][C@H:24]2[CH2:26][C@@H:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:28]([CH:29]=O)[C@H:23]2[CH2:22]1.[NH4+].[Cl-]>CC(OC)(C)C.ClCCl.O>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:29]/[C@@H:28]1[C@@H:23]2[C@@H:24]([O:25][C:21](=[O:20])[CH2:22]2)[CH2:26][C@H:27]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (6.9 g, 26.5 mmoL) in MTBE (30 mL) was added LiOH.H2O (1.11 g, 26.5 mmoL) and the mixture was stirred under nitrogen for 1 h. A solution of (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde (6, R1 is phenyl, and R2 and R3 are H, 6 g, 23.1 mmoL) in dichloromethane (30 mL) was added followed by NH4Cl (370 mg, 6.93 mmoL), 0.2 mL water and then the mixture was stirred for 12 h. After completion of the reaction, the reaction was then quenched with a saturated NH4Cl solution (12 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness under vacuum. The crude material was further purified by column chromatography [25% ethyl acetate in heptanes] to yield (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan (7, R1 is phenyl, and R2 and R3 are H) in 56% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([OH:29])[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33](S(C)(=O)=O)[N:32]=1.O>C1COCC1>[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:29][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][C:7]3[N:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[N:8]=3)[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])[N:32]=1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2C(=O)OCC[Si](C)(C)C)n1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.4 g, purity: 60%) was suspended in 50 ml of THF. To this suspension, trimethylsilylethyl 6-(4,6-dimethoxypyrimidin-2-yl)oxysalicylate (3.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, 4-chloro-6-methoxy-2-methylsulfonylpyrimidine (1.8 g) was added, and the mixture was stirred at room temperature for further 12 hours. After completion of the reaction, water was added thereto, and the mixture was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The crude extract thus obtained was purified by silica gel column chromatography to obtain the above identified compound as a slightly yellow liquid (4.0 g).