Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH3:17][O:18][C:19](=[O:49])[N:20]=[C:21]([S:47][CH3:48])[C:22]([C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([OH:46])[CH:37]=1)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:49])[N:20]=[C:21]([S:47][CH3:48])[CH:22]([C:36]1[CH:37]=[C:38]([O:46][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)c(OC)c(OC)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N=C(SC)C(Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After adding 300 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 100 mg of {2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give (2-{3,4-dimethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]-1-methylsulfanylethylidene)carbamic acid methyl ester (80 mg) as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:31])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]4[N:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][N:27]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]2=[O:31])=[CH:7][CH:8]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(SC)cc4)c(=O)c3)CC2)nc1
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
To a stirring solution of 1-(4-(methylthio)phenyl)-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (51.4 mg, 0.118 mmol) in CH2Cl2 (15 mL) at 0° C. was added a solution of 3-Chloroperoxybenzoic acid (26.4 mg, 0.118 mmol) in 5 mL CH2Cl2. The reaction was stirred at 0° C. for 15 min and then quenched with Na2SO3 (sat. solution in H2O). The organic layer was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0 to 10% MeOH in CH2Cl2) to yield 50 mg of desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (s, 2 H), 7.77 (d, J=8.31 Hz, 2 H), 7.57 (d, J=8.31 Hz, 2 H), 7.23 (d, J=7.34 Hz, 1 H), 5.94-6.11 (m, 2 H), 4.44-4.64 (m, 1 H), 4.07-4.31 (m, 2 H), 3.50-3.74 (m, 2 H), 2.77 (s, 3 H), 2.40 (t, J=7.58 Hz, 2 H), 1.98-2.17 (m, 2 H), 1.73-1.93 (m, 2 H), 1.50-1.64 (m, 2 H), 0.93 (tr=7.34 Hz, 3 H). MS (ESI) 453 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1>[C:36]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])(=[O:38])[CH3:37]
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCCC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)CN1C(=O)N(C)C
Reaction time: 8 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in THF was added 21 μL (0.15 mmol) of triethylamine and 7 μL (0.10 mmol) of acetyl chloride. After stirring overnight the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 20-3 as a white solid. Data for 20-3: 1HNMR (500 MHz, d6-DMSO) δ 7.8 (m, 1H), 7.6 (m, 1H), 7.4-7.2 (m, 7H), 6.2 (s, 1H), 4.9 (m, 1H), 4.7 (m, 1H), 3.05 (m, 2H), 2.7 (s, 6H), 2.05 (m, 1H), 1.8 (s, 3H), 1.2-1.1 (m, 3H) ppm. HRMS (ES) calc'd M+H for C24H27ClFN3O2: 444.1849. Found: 444.1847.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])(=[O:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:38][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)[CH:39]=[CH:40][CH:41]=1)(=[O:33])[CH3:32]
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(Nc3cccc4c3ccn4C)n2)c1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsOH.H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (20 mg). MS found for C22H21N7O2 as (M+H)+ 416.3. λ=211.3, 250.9.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.O>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:5][C:4]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=2[Cl:2])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cl)c(NC(=O)Cc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.8 g (30 mmol) of 2-chloro-5-methoxyaniline-hydrochloride are dissolved with 7.08 g (70 mmol) of triethylamine in 100 ml methylene chloride and whilst cooling with ice 5.86 g (31 mmol) of 4-chlorophenylacetyl chloride are added dropwise. After 2 hours' stirring the mixture is added to water and extracted with methylene chloride. The extracts are dried and evaporated down. The evaporation residue is recrystallised from ether/petroleum ether. Melting point: 149-151° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:22][C:23]1[CH:24]=[C:25]([S:30][C:31]2[CH:32]=[C:33]3[C:39]([NH2:40])=[N:38][NH:37][C:34]3=[N:35][CH:36]=2)[CH:26]=[C:27]([F:29])[CH:28]=1.[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43]1>O1CCCC1.ClCCl>[F:22][C:23]1[CH:24]=[C:25]([S:30][C:31]2[CH:32]=[C:33]3[C:39]([NH:40][CH2:52][C:51]4[CH:50]=[CH:49][C:48]([N:45]5[CH2:44][CH2:43][N:42]([CH3:41])[CH2:47][CH2:46]5)=[CH:55][CH:54]=4)=[N:38][NH:37][C:34]3=[N:35][CH:36]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(CNc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
41.5 μl of trifluoroacetic acid (0.539 mmol) and, in small fractions, 129 mg (0.611 mmol) of sodium triacetoxyborohydride are added to a solution of 100 mg (0.35 mmol) of 5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine and 81 mg (0.395 mmol) of 4-(4-methylpiperazin-1-yl)benzaldehyde in 20 ml of a 1:1 mixture of dichloromethane and tetrahydrofuran. The reaction medium is stirred for 16 hours at room temperature. An additional fraction of 125 μl of trifluoroacetic acid and 388 mg of sodium triacetoxyborohydride are added and the reaction medium is stirred for an additional 24 hours. The solvent is then concentrated and the reaction medium extracted with ethyl acetate and washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnesium sulfate and then concentrated to yield a yellow oil. A trituration of this oil in methanol leads to the isolation of 135 mg of a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH2:7](N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:14]([O:1][CH2:2][CH:3]1[CH2:5][O:6][CH2:7][O:4]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCC(O)CO
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(OCC1COCO1)c1ccccc1
Reaction time: 1 h

Procedure:
According to the method of the present invention, 1-(1-benzoyloxymethyl-2-hydroxyethyl)oxymethyl-2-nitroimidazole was produced. That is, 9.2 g of glycerin was dissolved in 100 ml of chloroform, 50 ml of triethylamine was added, and under ice cooling, 14 g of benzoyl chloride was dissolved in 50 ml of chloroform and added dropwise to the above-obtained mixture while stirring. After completion of the dropwise addition, the mixture was returned to room temperature, and stirring was continued for one hour at room temperature. 100 ml of water was added to wash the mixture with water, and then the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent; isopropyl ether:methanol 10:0→7:3) (yield; 14.1 g). To 9 g of this product, 100 ml of dimethoxymethane was added, and 1 g of phosphorus pentoxide was slowly added at room temperature while stirring. The mixture was allowed to react continuously for 16 hours. After completion of the reaction, 200 ml of water and 100 ml of ethyl acetate were added thereto, and liquid-liquid extraction was performed. The ethyl acetate layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resultant concentrate was purified by silica gel column chromatography (elution solvent; normal hexane: isopropyl ether 10:0→5:5), to obtain 9.8 g of 4-benzoyloxymethyl-1,3-dioxolane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]3)=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)[C@H]3CC[C@H](C(=O)O)CC3)CC2)CC1

Procedure:
Prepared from ethyl trans-4-[[-4-[1-(tert-butyloxycarbonyl)-piperidin-4-yl]-piperazin-1-yl]-carbonyl]-cyclohexane-carboxylate by hydrolysis with lithium hydroxide analogously to Example 24. Mass spectrum: (M+H)+ =424; Rf value: 0.24 (silica gel; methylene chloride/methanol/concentrated ammonia=4:1:0.2)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[NH:14][C:15]3[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:19]([F:28])=[CH:18][C:16]=3[N:17]=2)=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[C:32](Cl)=[O:33])[CH3:30].C(N(CC)C(C)C)(C)C.O>O1CCCC1>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][NH:22][C:20]1[C:19]([F:28])=[CH:18][C:16]2[N:17]=[C:13]([C:3]3[C:2]([NH:1][C:32](=[O:33])[N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[CH:6][N:5]([CH:7]4[CH2:12][CH2:11][CH2:10][CH2:9][O:8]4)[N:4]=3)[NH:14][C:15]=2[CH:21]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: CN(C)CCNc1cc2[nH]c(-c3nn(C4CCCCO4)cc3N)nc2cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(NCCN(C)C)cc2[nH]1

Procedure:
A solution of 132 mg of N1-{2-[4-amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}-N2,N2-dimethylethane-1,2-diamine in 8 mL of tetrahydrofuran with 428 μL of diethylcarbamoyl chloride and 560 μL of N,N-diisopropylethylamine is heated at 55° C. for 48 hours. 15 mL of water are added and then the aqueous phase is extracted with 3×15 mL of ethyl acetate. The organic phases are washed with 2×15 mL of distilled water, dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge, with a 95/5 dichloromethane/-methanol eluent. 18 mg of 3-[3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea are isolated in the form of a yellow resin. 1H NMR (400 MHz, DMSO-d6, δ in ppm), after addition of a drop of TFA-d1 (trifluoroacetic acid CF3COOD-d1) and of a drop of acetic acid-d4-(CD3OD-d4): 1.16 (t, J=7.5 Hz, 6H); 1.56 (m, 2H); 1.70 (m, 1H); 1.97 (m, 2H); 2.14 (m, 1H); 2.86 (s, 6H); 3.37 (m, 6H); 3.50 (t, J=6.5 Hz, 2H); 3.68 (m, 1H); 3.96 (m, 1H); 5.48 (broad d, J=10.0 Hz, 1H); 6.88 (d, J=7.5 Hz, 1H); 7.42 (d, J=11.0 Hz, 1H); 8.11 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:20]=3)=[N:11][C:12]([C:15](OC)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[ClH:1].[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH:20]=3)=[N:11][C:12]([C:15]([NH:33][C:34]3([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Product: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)CCCCC3)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Product: Cl
Yield: 96.3 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 1.8 g (3.62 mmol) of methyl 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate and 472 mg (3.3 mmol) of 2-aminocyclohexane-2-carboxylic acid, we obtain 1.12 g of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](=[O:22])[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([OH:22])([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: COc1cccc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 3-methoxyphenyl magnesium bromide in tetrahydrofuran (1.0 M, 25 mL, 25 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])[CH2:63][CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]5[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=5)=[O:68])[CH2:63][CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 76.3 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (270 mg, 0.46 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (216 mg, 0.40 mmol, compound of Reference Example 32) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (267 mg, yield: 65.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)=[O:24])[C:6]=2[CH:50]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:23](=[O:24])[N:25]3[CH2:26][CH2:27][N:28]([CH:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)[CH2:29][CH2:30]3)[C:6]=2[CH:50]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCNCC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
122 mg (0.17 mmol) of tert-butyl 4-(4-{2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenylacetyl}piperazin-1-yl)piperidine-1-carboxylate (Example 127) were dissolved in dichloromethane (3 ml) and while stirring at room temperature, trifluoroacetic acid (3 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. The residue was dissolved in 15 ml of dichloromethane/methanol (9:1), mixed with 4 eq. of Si-carbonate (Silicycle, 0.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. Yield: 105 mg (100%) of colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:10])[C@@H:4]1[CH:8](O)[CH2:7][CH2:6][NH:5]1.CCN(S(F)(F)[F:17])CC>C(Cl)Cl>[F:17][CH:8]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:3]([OH:2])=[O:10]
Reactant: COC(=O)[C@H]1NCCC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H]1NCCC1F
Temperature: 25 °C

Procedure:
To a solution of the 3-hydroxyproline methyl ester in DCM at −78° C., DAST (4 eq.) was added dropwise with stirring. The reaction was slowly warmed to rt. It was stirred at rt for 16 h, then diluted with more DCM and washed with cold saturated sodium bicarbonate, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (SiO2, 20-30% ethyl acetate/hexanes) to provide the desired 3-fluoroproline intermediate.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](C(C3(O)CCCCC3)CN3CCN(C)CC3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([CH:39](C2(O)CCCCC2)[CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:35][CH:34]=1.FC1C=CC(B(O)[OH:63])=CC=1.FC1C=CC(C2C=CC(C(C3(O)CCCCC3)CN3CCN(C)CC3)=CC=2)=CC=1.Cl>C(OCC)C.O1CCOCC1>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:37]3([OH:63])[CH2:38][CH2:33][CH2:34][CH2:35][CH:36]3[CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN1CCN(CC(c2ccc(-c3ccc(F)cc3)cc2)C2(O)CCCCC2)CC1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1CCN(CC(c2ccc(Br)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1CCN(CCC2CCCCC2(O)c2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 16 h

Procedure:
In an analogous manner to Example 135, step 3, 1-[1-(4′-fluoro-1,1′-biphenyl-4-yl)-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(4-bromophenyl)-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol using 4-fluorophenylboronic acid. Salt formation: A solution of 1-[1-(4′-fluoro-1,1′-biphenyl-4-yl)-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol, in diethyl ether (2 mL) was treated with a 4 N solution of hydrogen chloride in dioxane (1 mL) and stored in the refrigerator for 16 h. The resulting crystals were collected, washed with diethyl ether, and dried in vacuo to yield 1-[1-(4′-fluoro-1,1′-biphenyl-4-yl)-2-(4-methylpiperazin-1-ylethyl]cyclohexanol dihydrochloride. MS (ESI) m/z 397 ([M+H]+); HRMS: calcd for C25H33FN2O.2.00 HCl, 468.2110. found (ESI), 397.2639.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.[C-:15]#[N:16].[Na+].O>CS(C)=O>[C:15]([CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)#[N:16]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)C(CCBr)CC2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(CCC#N)CC2
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a solution of 1-(2-bromoethyl)-6-methoxyindan (1.75 g, 6.86 mmol) in dimethyl sulfoxide (80 ml) was added sodium cyanide (0.35 g, 7.20 mmol). This mixture was stirred for 40 minutes at 60° C. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 85:15) to give 1.28 g (yield 93%) of the above-titled compound as an oily-product.