Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:12]=1[C:13]([N:66]1[CH2:65][CH2:64][N:63]([C:46](=[O:45])[CH2:47][NH:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:53][CH:52]=2)=[O:50])[CH2:68][CH2:67]1)=[O:15]
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(F)cccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50.8 %

Procedure:
DIPEA (118 mg, 0.16 mL, 0.92 mmol) was added to a stirred solution of 2-fluoro-6-trifluoromethyl-benzoic acid (48 mg, 0.23 mmol) in DMF (2 mL). HOBT (46 mg, 0.35 mmol) and EDCI (100 mg, 0.57 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (75 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 60 mg (50.8% yield) of biphenyl-4-carboxylic acid {2-[4-(2-fluoro-6-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.5%. 1H NMR (CDCl3): δ 7.9 (m, 2H), 7.6 (m, 6H), 7.4 (m, 4H), 4.3 (m, 2H), 3.8 (m, 3H), 3.8 (m, 3H), 3.6-(m, 2H), 3.5 (m, 1H) 3.3 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([C@@H:10]([CH3:29])[CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:31])[C:9](=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]2)[C@@H:10]([CH3:29])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:34])[CH3:33]
Reactant: CCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 1, 1.0 g of 11β,21-dihydroxy-6α-methyl-17-propionyloxy-1,4-pregnadiene-3,20-dione is stirred in 10 ml of pyridine with 5 ml of acetic anhydride for one hour at room temperature and then worked up, thus isolating 790 mg of 21-acetoxy-11β-hydroxy-6α-methyl-17-propionyloxy-1,4-pregnadiene-3,20-dione, mp 138° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][N:8]1[C:12](C=O)=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[CH:9]1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:7][N:8]1[C:12]([C:1]([OH:2])=[O:4])=[C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:9]1
Reactant: Cn1cnc(-c2ccccc2)c1C=O
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cnc(-c2ccccc2)c1C(=O)O
Reaction time: 24 h
Yield: 68.8 %

Procedure:
Potassium carbonate (3.13 g) was added to 1-methyl-4-phenyl-1H-imidazole-5-carbaldehyde (intermediate 2) (2.33 g) dissolved in acetone (125 mL) and water (25 mL). Once dissolved, potassium permanganate (4.23 g) was added and the mixture stirred for 24 hours. The mixture was filtered through diatomaceous earth and the cake washed with water (2×20 mL). Acetone was evaporated from the filtrate which was extracted with EtOAc (50 mL). The aqueous layer was acidified with acetic acid to pH 5, reduced to half volume and a cream precipitate filtered and dried at 60° C. in vacuo to give the title compound as a cream solid (1.74 g, 69%);
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2[nH]ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]ccc12
Yield: 70 %

Procedure:
3,7-Dihydro-pyrrolo[2,3-d]pyrimidin-4-one (60 mg, 0.45 mmol) was reacted with 3.0 mL of phosphorus oxychloride to give 49 mg (70%) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.57 (s, br, 1H, NH), 8.58 (s, 1H), 7.68 (dd, J=2.53, 3.36 Hz, 1H), and 6.59 (dd, J=1.86, 3.36 Hz, 1H). MS m/e 153 [M−1]+.
Reaction SMILES: [H-].[K+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[C:6]([CH3:15])([CH2:11][CH2:12][CH2:13][OH:14])[CH:5]1[CH3:16].[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1>CCCCCC.C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[CH:17]1([CH2:20][O:14][CH2:13][CH2:12][CH2:11][C:6]2([CH3:15])[CH:7]([CH3:10])[CH2:8][CH2:9][N:4]([CH3:3])[CH:5]2[CH3:16])[CH2:19][CH2:18]1
Reactant: CC1CCN(C)C(C)C1(C)CCCO
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCN(C)C(C)C1(C)CCCOCC1CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45.4 %

Procedure:
Potassium hydride (3.8 g, 33 mmol) was washed with dry hexane (2×10 mL) and suspended in THF (60 mL) under a nitrogen atmosphere and 1,2,3,4-tetramethyl-3-piperidinepropanol (6.0 g, 30 mole) in THF (50 mL) was added dropwise over 10 minutes. The mixture was stirred at room temperature for 45 minutes then approximately 5 mole percent of tetrabutylammonium iodide, followed by cyclopropylmethyl bromide (4.5 g, 33 mmol) in THF (20 mL) was added. The mixture was stirred for 24 hours, diluted with ether and washed with brine (3×50 mL]. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was combined with additional crude 3-[3-(cyclopropylmethoxy)propyl)1,2,3,4-tetramethylpiperidine which was obtained from a similar experimental run but starting with 1.0 g of 1,2,3,4-tetramethyl-3-piperidinepropanol, and the mixture was purified by column chromatography on silica eluting with 10% ether/hexanes to 1% isopropylamine/10% ether/hexanes to afford 3.8 g(50%) of 3-[3-(cyclopropylmethoxy)propyl]1,2,3,4-tetramethylpiperidine. The product was dissolved in ethanol, treated with 7.2 U ethereal·HCl and diluted with ether to afford 3.2 g of the hydrochloride salt as a cream colored solid. The salt was recrystallized from ethanol/ether and had a melting point of 127-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10](=O)[CH:11]=[CH:12][CH3:13].[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([CH3:13])[CH:11]=[C:10]2[CH3:9]
Reactant: CC=CC(C)=O
Reactant: Nc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c2cccc(Cl)c2n1
Yield: 42 %

Procedure:
To 4.0 g (0.03 mol) of o-chloroaniline in 50 ml of hydrochloric acid at 100° C. was added dropwise 3.4 g (0.04 mol) of 3-penten-2-one. The mixture was refluxed for 12 hours, then neutralised with 5N sodium hydroxide and extracted with dichloromethane. The organic extract was dried and concentrated to an oil. This was purified on a silica gel column to give 2.54 g (42% of the title product; m.p. 66°-68° C. Anal. Calcd. for C11H10NCl: C, 68.94; H, 5.26; N, 7.31; Cl, 18.50. Found C, 68.87; H, 5.27; N, 7.29; Cl, 18.48.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([OH:15])[C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
(S)-2-(6-Methoxy-pyridine-3-carbonyl)-morpholine-4-carboxylic acid tert-butyl ester (305 mg, 0.95 mmol) was dissolved in methanol (5 mL) and cooled to 0° C. Sodium borohydride (36 mg, 0.95 mmol) was added and the resulting reaction mixture was stirred for 2 h at room temperature before pouring onto NaHCO3 and extracting 3 times with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford (S)-2-[hydroxy-(6-methoxy-pyridin-3-yl)-methyl]-morpholine-4-carboxylic acid tert-butyl ester (295 mg, 96%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].Br[C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[N:18]3[C:25](=[O:35])[N:26]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:27]=[C:17]3[C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([N:26]2[C:25](=[O:35])[N:18]3[C:19](=[O:24])[NH:20][C:21]4[CH:22]=[CH:23][C:14](/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[O:4])=[CH:15][C:16]=4[C:17]3=[N:27]2)=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3c4cc(/C=C/C(=O)OCc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
To a stirred solution of benzyl acrylate (44 μg, 0.274 mmol) and 8a (50.6 mg, 0.137 mmol) in a mixture of 8 mL of DMF and 4 mL of NEt3, was added Pd(OAc)2 (3.06 mg, 13.7 mmol) and triphenylphosphine (7.14 mg, 27.4 μmol) in a seal tube. The tube was sealed under argon and the mixture was stirred at 120° C. for 15 h. The mixture was cooled and concentrated to dryness in vacuo and the crude product was precipitated from acetone to give 17 as a white solid (29 mg, 47%). mp: 242° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].[H][H]>N.C1(C)C=CC=CC=1.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N
Reactant: [H][H]
Agent: [Rh]
Agent: N
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(CCCCN)CCCc1cccnc1

Procedure:
A solution of 125 g of ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate in 825 ml of 9.53% ethanolic ammonia is added to a slurry of 62.5 g of 5% rhodium on carbon (50% water wet) in 300 ml of 9.53% ethanolic ammonia. The mixture is hydrogenated at about 3 atmospheres pressure (50 psi) until theoretical uptake of hydrogen (4 moles) for saturation of the nitrile and double bond is obtained (about 12 hours). The catalyst is then filtered off, washed with methylene chloride and ethanol, and the filtrate is evaporated to dryness to yield a residue which is redissolved in toluene. Evaporation to dryness yields ethyl 8-amino-4-[3-(3-pyridyl)-propyl]-octanoate.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([CH3:17])[CH:13]=[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]=2)=[O:7])C.Cl>C(O)C>[CH2:19]([O:18][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:8]([C:6]([OH:7])=[O:5])[NH:9]2)=[C:14]([CH3:17])[CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2c(C)cc(OCc3ccccc3)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)cc2[nH]c(C(=O)O)cc12
Yield: 100 %

Procedure:
A 2 M solution of potassium hydroxide in ethanol (0.48 ml, 0.97 mmol) was added to a solution of 6-benzyloxy-4-methyl-1H-indole-2-carboxylic acid ethyl ester (100 mg, 0.32 mmol; PCT Int. Appl. (2001), WO 2001044186 A1) in ethanol (1 ml). The mixture was heated at reflux for 1.5 h, acidified with 1 N HCl and extracted two times with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 90 mg (0.32 mmol, 99%) of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19](Cl)(=[O:21])=[O:20])=[N:17][CH:18]=1)([CH3:12])[CH3:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][N:17]=1)(=[O:20])=[O:21]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of 2-methoxy-phenylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[C:5](O)=[O:6].[BH4-].[Li+].C(O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cc(CO)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of 3-bromo-5-(methoxycarbonyl)benzoic acid prepared by the method in Preparation 2 (10.3 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) is added lithium borohydride (12 g, 550 mmol) portion-wise. The reaction is stirred 4 h at this temperature. Absolute ethanol (20 mL) is added dropwise, and the reaction is stirred 1.5 h. The reaction is slowly poured on ice, and 10% hydrochloric acid (aq) is added until gas evolution ceased. The aqueous layer is extracted with chloroform, and the organic layer is washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 229, 231 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[CH:10][C:11]([CH2:16]Br)=[C:12]([CH2:14]Br)[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH:19][C:20]1[CH:21]=[C:22]([C:29]#[N:30])[C:23](=[CH:26][C:27]=1[OH:28])[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]2[CH2:16][O:19][C:20]3[CH:21]=[C:22]([C:29]#[N:30])[C:23]([C:24]#[N:25])=[CH:26][C:27]=3[O:28][CH2:14][C:12]=2[CH:13]=1)=[O:18]
Reactant: COC(=O)c1cc(CBr)c(CBr)cc1C(=O)OC
Reactant: N#Cc1cc(O)c(O)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(cc1C(=O)OC)COc1cc(C#N)c(C#N)cc1OC2
Temperature: 25 °C

Procedure:
A slurry of 4,5-bis-bromomethyl-phthalic acid dimethyl ester (1.57 g, 4.12 mmol), 4,5-dihydroxy-phthalonitrile (660 mg, 4.12 mmol) and potassium carbonate (1.1 g, 8.24 mmol) in DMF (20 mL) was heated to 60° C. for 1 h under an atmosphere of argon. The resulting slurry was cooled to room temperature and diluted with water. A white precipitate was collected via filtration and re-crystallized from EtOAc to yield 2,3-dicyano-6,11-dihydro-5,12-dioxa-dibenzo[a,e]cyclooctene-8,9-dicarboxylic acid dimethyl ester as a white solid. C20H14N2O6; MS (ESI) m/z 378.9 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:15]2[C:14]3[C:9](=[C:10]([CH3:17])[CH:11]=[CH:12][C:13]=3[CH3:16])[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:28]#[N:29].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:28]([CH2:2][C:3]1[C:15]2[C:14]3[C:9](=[C:10]([CH3:17])[CH:11]=[CH:12][C:13]=3[CH3:16])[N:8]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:29]
Reactant: Cc1ccc(S(=O)(=O)n2c3cccc(CCl)c3c3c(C)ccc(C)c32)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2c3cccc(CC#N)c3c3c(C)ccc(C)c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 5.39 g of 4-chloromethyl-5,8-dimethyl-9-p-toluenesulfonylcarbazole obtained in Example 1(3), 1.82 g of potassium cyanide and 1.79 g of 18-crown-6 in 80 ml of acetonitrile was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate, and the organic layer was washed, in turn, with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chlorided solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 5.21 g of 4-cyanomethyl-5,8-dimethyl-9-p-toluenesulfonylcarbazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89]O>O1CCCC1>[CH3:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:40][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COCCOCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCCOCCOC(=O)COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetic acid (Example 69, 150 mg, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (1 mL) to give a light brown suspension at room temperature. It was stirred for 30 min and the solution became clear. Triethylene glycol monomethyl ether (76.9 mg, 73.4 μL, 445 μmol) was added drop wise to the mixture. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with ethyl acetate gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxycarbonylmethyl ester as an off-white solid (65 mg, 35% yield). LCMS (ES+) m/z calcd. for C40H46Cl2F2N3O9 [(M+H)+]: 820. found: 820.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C(F)(F)F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-trifluoromethyl-phenylboronic acid to give [1-(3-trifluoromethyl-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 399(MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CS(N)(=O)=[O:29].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[OH:29][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH:4]=[CH:3][S:2](=[O:1])(=[O:26])[CH2:7][CH2:6]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(O)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
A solution of (S)-N-[[3-[4-(3,6-dihydro-1,1-dioxido-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.415 g, 1.08 mmol; prepared as described in U.S. Pat. No. 5,968,962) in 1:1 t-butanol-water (4 mL) is added to a solution of the standard reagent AD mix-β (1.51 g; available from Aldrich Co.) and methanesulfonamide (0.103 g, 1.08 mmol) in 1:1 t-butanol-water (10 mL) cooled at 0° C. The reaction mixture is stirred 5 days at 4° C. and then treated with sodium sulfite (1.5 g) and stirred 30 minutes. The solution is then extracted with four 10 mL portions of ethyl acetate and the combined organic phases dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-5% MeOH-DCM) provided the title compound as a mixture of diastereomers. Yield 0.29 g (64%). 1H NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Cc2cccc(O)c2O1
Solvent: CCOCC
Product: CC1(C)Cc2c([N+](=O)[O-])ccc(O)c2O1
Reaction time: 0.33 h

Procedure:
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (16.4 g, 0.1 mol) in 150 ml of ether, 70% nitric acid (9.0 g, 0.1 mol) was slowly dropwise added at room temperature. The reaction solution was stirred for further 20 minutes, then washed with water, dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained, was repeatedly recrystallized from hexane-ethyl acetate, whereby 6.2 g of 2,3-dihydro-2,2-dimethyl-4-nitro-7-benzofuranol and 6.0 g of 2,3-dihydro-2,2-dimethyl-6-nitro-7-benzofuranol as its 6-nitro isomer, were obtained. The melting points of these products were 164°-165° C. and 125°-126° C., respectively. Further, the structures of these intermediate phenols were confirmed by 1H-NMR spectra. 2,3-Dihydro-2,2-dimethyl-4-nitro-7-benzofuranol thus obtained, was reacted with O-ethyl-S-n-propylthiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 6) identified in Table 1 was obtained.