Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[C:12]1[N:13]([CH3:31])[C:14](=[O:30])[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:17]=1[C:18]([O-:20])=O.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CCN(C(C)C)C(C)C>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:16]1[C:17]([C:18]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:20])=[CH:12][N:13]([CH3:31])[C:14](=[O:30])[CH:15]=1
Reactant: Cn1c(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 95 %

Procedure:
2,3,4,5,6-Pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with 3-aminopropanol in THF in the presence of DIEA as for example 4, step B. The reaction solvent was removed under reduced pressure and the resulting oil purified by chromatography on silica gel (50% acetone/CH2Cl2) to give 4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (95%), m.p. (Et2O) 81-86° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.11 (s, 1H), 8.40 (br s, 1H), 8.24 (s, 1H), 7.74 (d, J=9.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 5.59 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.48 (q, J=5.7 Hz, 2H), 3.37 (s, 3H), 3.30-3.24 (m, 2H), 1.67 (pentet, J=6.7 Hz, 2H). Anal. Calcd for C16H17FIN3O3.0.5H2O: C, 42.3; H, 4.0; N, 9.3. Found: C, 42.2; H, 3.8; N, 9.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]#[N:14].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]#[N:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCOc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 41.7 grams (g) of 3-nitrophenol, 24 g of chloroacetonitrile and 58.8 g of anhydrous K2CO3 in 60 milliliters (ml) of DMSO was heated with stirring in a round-bottomed three-necked flask at 70°-80° C. for 3 hours. The reaction mixture was then poured into 1200 ml of ice and water, which resulted in crystal formation. When all of the ice had melted, the solids were filtered, washed well with water and dried overnight in a vacuum oven. The solids were then put in solution in 400 ml of boiling absolute ethanol, treated with activated charcoal and then filtered. The filtrate was cooled to 0° C. and the resulting solids removed by filtration. Drying in a vacuum oven gave 47 g of 3-nitrophenoxyacetonitrile as a pale tan solid having a melting point (m.p.) of 93°-95° C.
Reaction SMILES: [CH2:1]([N:8]([C@H:20]([CH2:41][OH:42])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=2)=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]([C@H:20]([CH2:41][OH:42])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)N(Cc3ccccc3)C[C@H](O)COc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)N(Cc3ccccc3)C[C@H](O)COc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To a solution of methyl 4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoate (93.6 mg) in methanol (2.0 ml) was added 1N sodium hydroxide solution (329 μl) and the solution was refluxed for 2.5 hours. After cooling to room temperature, the mixture was neutralized by the addition of 1N hydrochloric acid (329 μl). The solvent was removed by evaporation and the residual solid was suspended in water (2.0 ml). The solid was collected by filtration, washed with water, and dried under reduced pressure to give 4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]benzoic acid (80.2 mg) as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6](Cl)=[O:7])=[C:2]=[O:3].C[Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][Si](C)(C)C)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[N:1]([CH2:4][CH2:5][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:6](=[O:7])[CH2:5][CH2:4][N:1]=[C:2]=[O:3])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])=[C:2]=[O:3]
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(O[Si](C)(C)C)cc2)cc1
Reactant: O=C=NCCC(=O)Cl
Product: O=C=NCCC(=O)Oc1ccc(-c2ccc(OC(=O)CCN=C=O)cc2)cc1

Procedure:
From 35 g (0.26 mol) of 3-isocyanatopropanoic acid chloride and 30 g (0.09 mol) of 4,4'-bis(trimethylsiloxy)biphenyl.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:33])[N:21]=1>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]4[CH:25]=[C:24]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[N:23]=[C:22]([NH2:33])[N:21]=4)=[CH:13][C:12]=3[F:18])=[C:4]2[CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: Nc1ccc(Oc2ccnc3c2CCN3)c(F)c1
Product: Nc1nc(Nc2ccc(Oc3ccnc4c3CCN4)c(F)c2)cc(-c2ccc(F)cc2)n1

Procedure:
Analogously to example 25, the title compound is synthesized from 35 mg (0.14 mmol) of [4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluoro-phenyl]amine (from example XLVI) and 39 mg (0.15 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX). Purification by preparative HPLC gives the product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:12]1[CH:11]=[CH:10][C:15]([O:16][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 150 °C
Reaction time: 7.5 h
Yield: 98.8 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde (24.1 g) and p-cresol (21 g) in N,N-dimethylformamide (400 ml) was added powdered potassium carbonate (26.8 g) and the reaction mixture was stirred at 150° C. for 7.5 hours. After cooling, the reaction mixture was poured into ice water (1.4 kg). The mixture was extracted with ethyl acetate (1 l), washed with water (1 l×3), brine (1 l), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 4-(4-methylphenoxy)benzaldehyde (40.7 g) as a light yellow oil.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].C(Br)(Br)Br>CS(C)=O>[Cl:17][CH2:18][C:19]([NH:10][O:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: NOC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: BrC(Br)Br
Solvent: CS(C)=O
Product: O=C(CCl)NOC(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
This compound was prepared from diphenylmethoxyamine hydrochloride and chloroacetyl chloride by the method described in Preparation 1; m.p. 115°-117° νmax (CHBr3) include 3400 (NH), 1692 cm-1 (CO-N), τ(DMSO d6) 0.55 (NH), 2.60 (Ph) 4.01 (CHPh2), 6.02 (CH2). Yield 86%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH2:4]([NH:1][C:2]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=NCc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)NCc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using (isocyanatomethyl)benzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 437.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:5]2[C:10]([C:11]=1[CH:12]([OH:16])[C:13]([NH2:15])=[O:14])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C(O)C(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Reaction time: 20 h
Yield: 88 %

Procedure:
A mixture of 1 g (3 mmol) of 2-ethyl-4-methoxy-alpha-oxo-1-(phenylmethyl)-1H-indole-3-acetamide and 142 mg (3.75 mmol) of sodium borohydride and 100 mL of ethanol was stirred for 20 hours, and evaporated at reduced pressure. The residue was taken up in ethyl acetate and water, the ethyl acetate separated and washed with brine and dried (MgSO4). The solution was concentrated at reduced pressure and the residue stirred with ether. The insoluble material was filtered to give 893 mg (88%) of 2-ethyl-4-methoxy-alpha-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 160-162° C.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH:6]([CH3:8])[CH3:7].ClO[N:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>CCO>[CH2:14]([O:13][C:11]([C:10]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[N:18][O:9][C:5]=1[CH:6]([CH3:8])[CH3:7])=[O:12])[CH3:15]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Fc1cccc(C=NOCl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc(F)c2)noc1C(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3.39 g (53 mmol) of NaOEt in 30 mL of EtOH, at 0° C., was added dropwise 8.56 mL (53 mmol) of ethyl isobutyrylacetate (commercially available) in 10 mL of EtOH. The reaction mixture was stirred at room temperature for 40 minutes, and then 8.68 g (0.05 mol) solution of 3-fluoro-benzaldehyde-chloro-oxime (Prepared according to: J. Agric. Food Chem. 1995, 43, 219-228.) in 30 mL of EtOH was added dropwise in an ice-bath and the resulting suspension was stirred at room temperature for 2 h. The mixture was then evaporated and the residue partitioned between 200 mL of ethyl acetate and 100 mL of H2O. The aqueous phase was then separated and extracted with ethyl acetate (2×60 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and evaporated to give 15 g of crude product (purity ˜30%) as a yellow syrup. The crude product was used in the subsequent hydrolysis without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1>>[NH2:8][C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)=[N:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ncc(N)cn2)C1
Yield: 83.8 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyrimidine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-3-ylcarbamate (683 mg, 3.5 mmol) followed by reduction to afford the desired product (762 mg, 84%) as a purple solid: ESI MS m/z 294 [C14H23N5O2+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:11]\[OH:12]
Reactant: NO
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a suspension of 3-fluorobenzaldehyde (6.75 g, 54 mmol) and hydroxylamine hydrochloride (4.16 g, 60 mmol) in ethanol (4.3 mL) and water (13 mL) was added ice (25 g). Then a solution of sodium hydroxide (5.5 g, 138 mmol) in water (6.5 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (7.0 g, 93%) which was obtained as a white solid. MS m/e (EI): 139.1 [M].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:10][CH2:11]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCOC(=O)N1CCC(N(CCN)CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC(N(CCNC(=O)c2ccccc2)CCc2ccc(Cl)cc2)CC1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Allyl 4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate hydrochloride obtained in Step 2 was suspended in dichloromethane (4 mL/mmol), the suspension was cooled to −15° C. and DIPEA (2.2 equiv) followed by benzoyl chloride (1.05 equiv) were added dropwise over 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 2 h TLC revealed no presence of starting material. The reaction mixture was diluted with EtOAc (10 mL/mmol of starting material), washed with 1 M NaOH (2×), water (2×) and brine (2×) and dried over anhydrous MgSO4. After filtration of the drying agent the solvent was stripped off and the crude product was purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])ccc1F
Reaction time: 144 h

Procedure:
A mixture of 2-fluoro-5-nitro-benzoyl chloride (1.1 g, 5.4 mmol) in 20 mL DCM was added dropwise to 4-bromoaniline (929 mg, 5.4 mmol), 0.905 mL TEA in 20 mL DCM. The mixture was stirred for 6 days, successively washed with satd. NaHCO3-solution and 2 M aq. HCl solution and dried with Na2SO4. After filtration and concentration i. vac. the subtitle compound was obtained. Yield: 1.57 g (86%). MS [M+H]+=339 (Br-isotope pattern); TLC: Rt=0.96 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].CN(C=O)C.Br[CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]2[CH2:25][CH:20]1[C:21]2([CH3:27])[CH3:26]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]3[CH2:25][CH:20]2[C:21]3([CH3:26])[CH3:27])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC1(C)C2CCC(CCBr)C1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C2CCC(CCOc3ccc(I)cc3)C1C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.4 %

Procedure:
To a stirred suspension of 4-iodophenol (0.5 g; 2.27 mmol) and 60% NaH (0.16 g, 2.3 mmol) in anhydrous DMF (5 ml) 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]heptane (0.5 g, 2.2 mmol) was added the and mixture was stirred for 3 h at room temperature. After addition of more of 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]heptane (0.2 g) the mixture was stirred for additional 2 h, quenched with NH4Cl solution and diluted to 20 ml with EtOAc. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.61 g, 73%), as a colourless paste. 1H-NMR (CDCl3) 7.51 (d, 2H, J=8.91 Hz); 6.64 (d, 2H, J=8.88 Hz); 3.88 (t, 2H, J=3.21 Hz); 2.34-1.84 (m, 10H); 1.17 (s, 3H); 1.01 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br>CN(C=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2CCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (302 mg, 1.65 mmol), and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×2) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure, hexane was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with hexane and was then dried under reduced pressure to obtain methyl 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (524 mg, 1.22 mmol, 81%).
Reaction SMILES: [C:1]1([CH3:42])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][O:31][C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36]C)=[O:35])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([CH3:42])[CH:2]=[CH:3][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][O:31][C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([OH:36])=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1OCCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCOc4ccccc4C(=O)O)CCCCC3)CC2)cc1
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a solution of methyl 2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzoate (synthesized in Example 39) (221 mg) in methanol (5 mL) was added a sodium hydroxide (77 mg) solution in water (3 mL) dropwise at room temperature. The solution was stirred for 18 hours. After neutralizing the reaction solution with 2N hydrochloric acid, silica gel was added to the solution. The solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give the title compound (172 mg).
Reaction SMILES: [I-].[CH3:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH2:5][CH2:6][N+](C)(C)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[S:24])[S-:23])=[N:19][CH:20]=1.C([NH+](CC)CC)C.O>C(#N)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[S:23])[S:24][CH2:6][CH2:5][C:4](=[O:11])[C:3]([CH3:2])([CH3:12])[CH3:13])=[N:19][CH:20]=1
Reactant: CC(C)(C)C(=O)CC[N+](C)(C)C
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Agent: CC[NH+](CC)CC
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 6 h
Yield: 60.1 %

Procedure:
4,4-Dimethyl-3-oxopentyltrimethylammonium iodide (6.0 g) is added, at 20° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (6.1 g) in anhydrous acetonitrile (25 cc). The reaction is allowed to proceed for 6 hours at 20° C. Distilled water (25 cc) is added. The crystals which appear are filtered off, washed three times with distilled water (total 30 cc) and dried in air at 20° C. The product obtained (5.1 g; m.p.=110° C.) is recrystallised from acetonitrile (15 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (3.8 g), which melts at 111° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:37])C.Cl>O.C(Cl)Cl>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH2:30])=[O:37])=[CH:27][CH:28]=2)=[O:31])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C#N)cc2)c2ccccc21
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(N)=O)cc2)c2ccccc21

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-cyanobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (143 mg, 0.33 mmol) and potassium hydroxide (55 mg, 1.00 mmol)) were dissolved in water (150 mL), ethanol (3 mL) and heated to 70° C. for 4 h. The slurry was portioned between 1N HCl (until acidic) and methylene chloride. The organic layer was collected, concentrated and subjected to flash chromatography (EtOAc to 20% MeOH, EtOAc) to afford the title compound as a white solid.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH:48]1[CH2:52][C:51](=[O:53])[NH:50][C:49]1=[O:54])=[O:41])[CH:37]=[CH2:38]>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH:48]1[CH2:52][C:51](=[O:53])[NH:50][C:49]1=[O:54])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C1CC(=O)NC1=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C3CC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 50.9 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (230 mg, 0.46 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)-4-mercaptopyrrolidine (130 mg, 0.46 mmol, compound of Reference Example 9) to obtain allyl (1R,5S,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (125 mg, yield: 50.9%).