Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH:7]2[CH2:8][C:9]([CH2:11][CH:3]1[CH2:4][CH2:5][CH2:6]2)=[O:10].[Cl:12][C:13]([Cl:20])([Cl:19])[CH2:14][O:15][C:16](Cl)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>[Cl:12][C:13]([Cl:20])([Cl:19])[CH2:14][O:15][C:16]([N:2]1[CH:7]2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:11][C:9](=[O:10])[CH2:8]2)=[O:17]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1C2CCCC1CC(=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CC2CCCC(C1)N2C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of pseudopelletierine (52 g, 0.34 mol) in toluene (220 mL) at 50° C. was added anhydrous potassium carbonate (1.0 g), followed by the slow addition of trichloroethylchloroformate (79 g, 0.37 mol). After addition was completed (30 minutes), triethylamine (10 mL) was added. The reaction was allowed to cool to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and 1N hydrochloric acid (200 mL). After the organic layer was washed with 1N hydrochloric acid (100 mL), it was washed with aqueous 10% sodium hydroxide (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford a beige solid which was triturated with hexane (300 mL) to afford 81.4 g of crystalline solid (76% yield); mp 95°-96° C. after recrystallization from ethyl acetate-hexane. Anal. (C11H14C13NO3).
Reaction SMILES: C([Li])CCC.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[I:15]CCI.[NH4+].[Cl-]>C1COCC1.O>[I:15][C:7]1[NH:6][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: ICCI
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1cc2ccccc2[nH]1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2-iodoindole is prepared according to the following procedure: n-butyllithium (4.2 mL, 2.5 M in solution in hexane) is added, dropwise, to a solution of indole (1.17 g, 10 mmol) in 20 mL of anhydrous THF at −70° C. The resulting suspension is left under stiffing at this temperature for 30 minutes then gaseous CO2 is bubbled through for 10 minutes. The solution which has become clear is then left under stirring for 10 minutes. The solvent and the excess CO2 are evaporated off under vacuum then the resulting solid residue is put into solution in 20 mL of anhydrous THF and cooled down to −70° C. t-butyllithium (6.2 mL; 1.7 M in solution in pentane) is then added dropwise then the resulting solution is left under stirring for 1 hour. 1,2-diiodoethane (2.82 g; 10 mmol) is then added. The reaction mixture is left at −78° C. for 1 hour then treated with 1 mL of water. The resulting solution is left to return to ambient temperature then it is treated with a saturated aqueous solution of NH4Cl. It is extracted with ether. The organic phase obtained is washed with a saturated aqueous solution of NaCl, dried over anhydrous MgSO4 and evaporated under vacuum. The solid residue obtained is purified by flash chromatography on silica gel (hexane/ether, 4/1) producing 2-iodoindole (2.19 g; 9 mmol) with a yield of 90%. The physical and spectral data are described in the article.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.23 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Yield: 82.7 %

Procedure:
A stirring suspension of 3-hydroxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-chromen-4-one (0.257 g, 0.6mmol), potassium carbonate (1.48 g, 11 mmol, 19 equ), potassium iodide (0.06 g, 0.3 mmol, 0.6 equ) and benzyl chloride (0.16 ml, 1.3 mmol, 2.3 equ) in acetone (12 ml) under nitrogen was heated to reflux for one hour. The reaction was filtered and the filtrate concentrated in vacuo to give an orange solid. This solid was recrystallised from isopropanol to give 34 (0.270 g, 88%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])[CH:6]=1.C=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:48](N(CC)CC)C.[C:55](Cl)(=[O:57])[CH3:56]>ClCCCl>[C:55]([N:1]1[CH2:2][CH2:3][N:4]([C:5]2[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]3[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=3)([CH3:15])[CH3:14])=[C:7]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH3:39])[CH:6]=2)[CH2:48]1)(=[O:57])[CH3:56]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1cc(F)ccc1-c1cc(NCCN)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: CC(=O)N1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Temperature: 85 °C
Yield: 72.8 %

Procedure:
To a solution of 50 mg (0.090 mmol) N-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 2 ml 1,2-dichloroethane were added 3 mg (0.1 mmol) paraformaldehyde and 32 mg (0.27 mmol) magnesium sulfate. After stirring at room temperature over night another 3 mg (0.1 mmol) paraformaldehyde were added and the reaction mixture was heated to 85° C. After 1 h the reaction mixture was cooled to room temperature and treated with 14 mg (0.13 mmol) triethylamine and 11 mg (0.13 mmol) acetyl chloride. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 40 mg (73%) of the title compound as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Br[CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[OH:38][CH2:37][CH2:36][N:32]1[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CCO)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (300 mg), 2-bromoethanol (170 mg), sodium carbonate (280 mg) and ethanol (20 mL) was stirred at 80° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)] to give the title compound as a colorless amorphous compound (205 mg, 63%).
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[C:15]2=[O:35])=[CH:11][CH:10]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O.C1COCC1>[F:32][C:31]([F:33])([F:34])[O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([NH:8][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:37][CH:36]=3)[C:15]2=[O:35])=[CH:25][CH:26]=1
Reactant: Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.4 mL, 5.0 mmol) was added to a suspension of the hydrochloride of 1-(4-aminobenzyl)-3-(4-trifluoromethoxybenzyl)-1,3-dihydrobenzimidazol-2-one (U) (806 mg, 1.79 mmol) in abs. THF (40 mL). The reaction mixture was stirred at RT for 30 min, methanesulphonyl chloride (0.16 mL, 2.1 mmol, dissolved in abs. THF (1 mL)) was added within a period of 20 min, and the reaction mixture was again stirred at RT over a period of 18 h. To the reaction mixture there were then added H2O (150 mL) and aqueous 2N hydrochloric acid solution (5 mL). After 2 hours, the precipitated solid matter was separated by a frit and then dried in vacuo and recrystallized from ethanol (20 mL). The desired product N-{4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (70) was obtained in a yield of 505 mg (57% of theory, mp: 182-187° C.).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][N:13]([CH3:17])[SH:14](=[O:16])=[O:15].O>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2].[CH3:12][N:13]([CH3:17])[SH:14](=[O:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Agent: CN(C)[SH](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a gently stirring solution comprised of 1 molar equivalent of fuming nitric acid in excess concentrated sulfuric acid is added 1 molar equivalent of 4-methyl-benzene-N,N-dimethylsulfonamide in increments. The mixture is stirred for one hour and then poured over chilled water. The mixture is extracted with a suitable solvent like diethyl ether or dichloromethane. The organic phase is dried over a suitable drying agent like magnesium sulfate and concentrated in vacuo to afford a crude product which may be purified by normal methods such as chromatography or crystallization from a solvent like chloroform or heptane.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CO.C(Cl)Cl>[S:24]1[CH:25]=[N:26][N:27]=[C:23]1[NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([C:5]1[C:4]([O:28][CH3:29])=[CH:3][C:2]([C:33]3[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=3)=[C:7]([F:8])[CH:6]=1)=[N:10][CH:11]=[CH:12]2)(=[O:20])=[O:21]
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-c2cc(F)cc(F)c2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 30.5 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 88.75 mg, 0.197 mmol). (3,5-difluorophenyl)boronic acid (62.2 mg, 0.394 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.020 mg, 4.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.46 mg, 9.84 μmol), and potassium phosphate (125 mg, 0.590 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (895 μl) and water (89 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (4×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM, then with 4-10% MeOH/DCM) to give N-(1,3,4-thiadiazol-2-yl)-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonamide (31.54 mg, 0.060 mmol, 30.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.78 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.90 (dd, J=1.8, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.43-7.34 (m, 3H), 3.73 (s, 3H). m/z (ESI) 528.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[CH:2].[CH2:12]([SnH:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]=[CH:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:8])=[CH:5][CH:4]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#Cc1ccc(C(=O)O)cc1
Product: CCCC[Sn](C=Cc1ccc(C(=O)O[Sn](CCCC)(CCCC)CCCC)cc1)(CCCC)CCCC
Temperature: 60 °C

Procedure:
A mixture of 4-ethynylbenzoic acid (1.0 equiv.) and tri-n-butyltinhydride (1.0 equiv.) (Aldrich) is warmed to 60° C. for six hours. Kugelrohr distillation of the crude product gives tri-n-butylstannyl 4-[2'-(tri-n-butylstannyl)ethenyl]benzoate.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1I.C([Li])CCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH:24]=[O:25])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(I)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)nc1C=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 4,5-diiodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (8.86 g, 19.68 mmol) in anhydrous THF (110 ml) under argon was cooled to −78° C. and was treated dropwise with n-butyllithium (13.5 ml, 21.65 mmol, 1.6M in hexane). After 10 minutes stirring at −78° C. and 30 minutes at −45° C., the reaction mixture was cooled to −78° C. and treated at once with DMF (10 ml). The mixture was allowed to warm to room temperature and saturated NH4Cl (150 ml) was added. The aqueous layer was extracted 2 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution with hexane/AcOEt=98:2) to provide the title compound (5.18 g, 75%) as a light yellow oil. MS: m/e 352.1 (M+).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH3:39])[C:35](=[O:40])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:31])[CH3:32])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH2:38][CH3:39])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)CN
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3C)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Product: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2C)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
10 mg of 2-hydroxypyridine (0.11 mmol) was added to a solution of 100 mg of {(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (110b) (0.21 mmol) in (2,2-dimethylpropyl)amine (0.5 ml), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate) to obtain 105 mg of the title compound (yield: 89%).
Reaction SMILES: SCCO.[CH3:5][N:6]([C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25]2)[CH2:21][CH2:20]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:5][NH:6][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25]2)[CH2:21][CH2:20]1
Reactant: CN([C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: OCCS
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reaction time: 0.5 h

Procedure:
2-Mercaptoethanol (0.056 mL, 0.793 mmol) was added dropwise to a mixture of N-methyl-2-nitro-N-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-yl)benzenesulfonamide (235 mg, 0.440 mmol) from Example 300 and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.166 mL, 1.101 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was stirred for 30 minutes, and 1 N NaHCO3 solution was added, The mixture was extracted with dichloromethane, and the separated the organic layer was concentrated. The resultant crude material was purified using a SF15-12g cartridge (Analogix®, Burlington, Wis.) with a gradient of 0-5.5% methanol (2 N NH3)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.17 (d, J=8.1, 2H), 7.94 (d, J=8.2, 2H), 4.93-4.86 (m, 1H), 3.34 (dd, J=9.8, 3.3, 1H), 3.14 (dd, J=9.7, 3.2, 1H), 3.06 (dd, J=9.7, 8.2, 1H), 2.65 (q, J=5.7, 1H), 2.57-2.46 (m, 1H), 2.29 (s, 3H), 2.25 (ddd, J=8.6, 5.0, 2.5, 1H), 1.86 (ddd, J=12.0, 8.6, 6.1, 1H), 1.80-1.72 (m, 1H), 1.61-1.32 (m, 1H), 1.32-1.19 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:33]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:33][C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[CH:10][CH:9]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2nccs2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ccc(-c3nccs3)[nH]2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
To a solution (5 mL) of 6-cyclopentyl-5-[4-(methylsulfonyl)phenyl]-1-(1,3-thiazol-2-yl)hexane-1,4-dione (300 mg) in N,N-dimethylformamide was added ammonium acetate (310 mg), and the mixture was stirred at 100° C. for 1.5 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (150 mg, yield 53%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 401 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
tert-Butyl 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (3.65 g, 10.9 mmol) was taken into methanol (40 mL) followed by addition of 1M aqueous sodium hydroxide (15 mL) and THF (15 mL), and the mixture was heated at 50° C. for one hour. An additional portion of 1 M aqueous sodium hydroxide (10 mL) was then added and heating was continued an additional two hours. The mixture was then cooled to room temperature and concentrated to remove organic solvents. The aqueous residue was partitioned with ethyl ether and the organic layer was discarded. The aqueous phase has carefully brought to pH 5-6 by addition of 1M aqueous hydrochloric acid to give a thick white suspension. The solid was collected by filtration and dried to give 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g). 1H NMR (400 MHz, DMSO-d6): 12.57 (br s, 1H), 8.64 (s, 1H), 7.95 (d, 1H), 6.86 (d, 1H), 3.67-3.62 (m, 4H), 3.45-3.40 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[O:15][CH3:16].S(Cl)([Cl:19])=O>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:19])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(=O)O)ccc1OCCCCl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1OCCCCl
Yield: 60.8 %

Procedure:
To a mixture of 4-(3-chloropropoxy)-3-methoxybenzoic acid (2.4 g, 10 mmol) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 12 mmol) dissolved in dichloromethane (5 ml). The reaction was stirred and refluxed for 1 hour, and then the dichloromethane was removed in vacuo to leave a dark oil. The oil was triturated with hexane and the solid that formed while scratching with a glass rod was collected to afford 1.6 g of 4-(3-chloropropoxy)-3-methoxybenzoyl chloride, m.p.=60°-63° C.