Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([OH:30])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)(OC)[O:19]C)[CH2:11][C@H:10]2[O:31][CH3:32])=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.Cl.N>O>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([OH:30])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])[CH2:11][C@H:10]2[O:31][CH3:32])=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC(O)C(OC)(OC)c2ccc(F)cc2)C[C@H]1OC
Agent: Cl
Agent: N
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC(O)C(=O)c2ccc(F)cc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 2.88 parts of cis-4-amino-5-chloro-N-[1-[4-(4-fluorophenyl)-3-hydroxy-4,4-dimethoxybutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, 30 parts of concentrate hydrochloric acid and 25 parts of water was stirred for 18 hours at room temperature. 100 Parts of water were added and the whole was alkalized with ammonia. The precipitated product was filtered off and taken up in trichloromethane. The organic phase was separated, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in benzene. Upon the addition of petroleumether, the product was precipitated. It was filtered off the dried, yielding 0.47 parts (16%) of cis-4-amino-5-chloro-N-[1-[4-(4-fluorophenyl)-3-hydroxy-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 146.4° C. (compound 238).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].C(O)C.[H][H]>[Pd].O>[NH2:1][C@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 7.1 %

Procedure:
Z-Glu(Nle-OBzl)-OBzl (4.05 g) and 5% palladium on carbon (5% palladium/carbon, 0.40 g) were added to a mixed solution of ethanol (50 mL) and water (10 mL), and a catalytic reducing reaction was carried out at 50° C. overnight (14 hours) in a hydrogen gas atmosphere. Water (10 mL) was added to the reaction system in small portions during the reaction. The palladium/carbon was removed from the reaction system through filtration and the resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from a small amount of water and ethanol to thus give γ-Glu-Nle (0.29 g) as hygroscopic crystals. Furthermore, the crystals were dissolved in water (30 mL) followed by the lyophilization of the solution to give γ-Glu-Nle (0.13 g, 0.50 mM) as a white powder. The characteristic values thereof will be given below:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@@H]1C)CO2

Procedure:
A solution of 3-(7-isopropyl-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 11) Rt=4.715 min, 0.32 g, 0.75 mmol) in DCM (8 mL) and TFA (2 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-7-isopropyl-4(S)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoacetic acid as a pale yellow solid (Example #57-2, Enantiomer 2, SFC (Table 1, Method 11) Rt=4.92 min, 0.31 g, 92%). LC/MS (Table 1, Method 5) Rt=1.688 min.; MS m/z: 330 [M+H]+.
Reaction SMILES: O=S(Cl)Cl.[N:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[O:18]1[C:14]2([CH2:19][CH2:20][C:11]([C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)=[CH:12][CH2:13]2)[O:15][CH2:16][CH2:17]1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccncc2)CCC2(C1)OCCO2
Reaction time: 0.25 h
Yield: 63 %

Procedure:
SOCl2(10.5 ml) was added dropwise at −10° C. to a solution of 8-(pyridin-4-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (6.0 g, 25.5 mmol, 1 eq) in pyridine (50 ml), and stirring was carried out for 15 min. After monitoring by thin-layer chromatography, the reaction mixture was poured carefully onto ice (100 g), neutralized with sat. sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (2×150 ml). The combined organic phases were washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH in dichloromethane). Yield: 63% (3.5 g, 16.1 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=O)[NH:7]2.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:21]=[CH:20][C:18]=1[NH2:19].C(N=C=NCCCN(C)C)C.Cl.ON1C2N=CC=CC=2N=N1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([B:24]3[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28]3)=[CH:23][C:17]=1[O:16][CH3:15])=[O:14])[NH:7]2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To 4-methoxy-1H-indole-2-carboxylic acid (0.844 g, 4.42 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.01 mmol) in dichloromethane (20 ml) at 0° C. under a nitrogen atmosphere were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (0.846 g, 4.42 mmol) and 1-hydroxy-7-azabenzotriazole (0.546 g, 4.01 mmol). The resulting brown solution was stirred at room temperature overnight. The reaction mixture was poured in water, the solids were collected by filtration and washed with some water. The solid was dried in a vacuum oven at 40° C. The solids were suspended in acetonitril (50 ml) and methanol (10 ml) and heated at 60° C. for 1 hour. The solids were collected by filtration and washed with hot acetonitril. Then the solids were stirred over night in dichloromethane. The mixture was filtered over a filter. The filtrate was concentrated in vacuo and gave 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indole-2-carboxamide (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])O.[Na+].[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>C(Cl)(Cl)Cl.O1CCCC1>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([NH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]([C:12]([F:13])([F:14])[F:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:25]
Reactant: COC(=O)c1cc(N)c(O)cc1C(F)(F)F
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)C(C)(C)Br)c(O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
Methyl 5-amino-4-hydroxy-2-(trifluoromethyl)benzoate (53.0 g) was dissolved in chloroform (200 ml) and tetrahydrofuran (200 ml), and thereto was added an aqueous sodium hydrogen carbonate solution (27.60 g/240 ml), and the mixture was vigorously stirred. The mixture was cooled in an ice-bath, and thereto was slowly added dropwise 2-bromoisobutyryl bromide (65.5 g), and the mixture was stirred for 30 minutes. The mixture was warmed to room temperature, and further stirred for 2.5 hours. After the reaction was complete, the mixture was extracted twice with chloroform (300 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 5-[(2-bromo-2-methylpropanoyl)amino]-4-hydroxy-2-(trifluoromethyl)benzoate. This crude product was diluted in N,N-dimethylformamide (500 ml), and thereto was added potassium carbonate (60.53 g), and the mixture was stirred at 50° C. for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and the obtained solid was removed by filtration. To the filtrate was added ethyl acetate (500 ml), and the mixture was washed with a 1N hydrochloric acid (500 ml) and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was crystallized from ethyl acetate/hexane (5/1, 200 ml) to give the title compound (48.5 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]([C:8]1[C:12](Cl)=[C:11]([CH3:14])[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Br:19]C1C(C(OCC)=O)=NNC=1C>>[Br:19][C:12]1[C:8]([C:6]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])=[N:9][NH:10][C:11]=1[CH3:14]
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Reactant: CCOC(=O)c1n[nH]c(C)c1Br
Product: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Br
Yield: 75 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1B, ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate (Tabrizi, M. A. et al., Bioorg. Med. Chem., 16:2419-2430 (2008)) (5.68 g, 24.4 mmol) was converted to the title compound (5.79 g, 75%). 1H NMR (CDCl3) δ 3.51 (t, J=7.4 Hz, 2H), 3.38-3.26 (m, 2H), 2.34 (s, 3H), 1.73-1.34 (m, 6H), 1.22-1.13 (m, 2H), 1.03-0.75 (m, 6H); MS(ESI+) m/z 316.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:20][C:34]([NH:33][S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:36])=[CH:25][CH:26]=4)(=[O:32])=[O:31])=[O:35])=[O:19])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(=O)NC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetamide (step 5, 105 mg, 0.30 mmol), p-toluenesulfonyl isocyanate (0.07 mL, 0.45 mmol), toluene (10 mL) and THF (5 mL) was heated at reflux temperature. After 6 h, an additional 0.1 mL of p-toluenesulfonyl isocyanate was added and the mixture was heated for 3 h. The mixture was cooled and left at room temperature for 2 days. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to afford 150 mg (92%) of the title compound as colorless amorphous solids: 1H-NMR (CDCl3) δ 9.78 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.84 (1H, s), 7.54 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.78 (2H, s), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.35 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:29](Cl)[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH:26]=[N:25][C:24]=2[CH:35]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]([C:13]3[CH:12]=[CH:11][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:15][CH:14]=3)=[N:25][C:24]=2[CH:35]=1
Reactant: CCCCCCCCCc1ccc(B(O)O)cc1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Product: CCCCCCCCCc1ccc(C2=Nc3cc(Cl)ccc3Nc3ccccc32)cc1
Yield: 58 %

Procedure:
4-Nonylphenylboronic acid (30 mg, 0.12 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (26 mg, 0.1 mmol) were reacted according GP11 to give 25 mg of the title compound (160FE63). MS (ESI) 431 (MH+). Purity for MH+ (UV/MS) 85/85.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30].[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH:18]=2)([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:11][CH:12]=2)[N:6]=1
Reactant: CCCCN
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCNCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 74.9 %

Procedure:
A small vial (10 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (90 mg, 250 μmol) and methanol (2 ml). To this was added butylamine (20 mg, 273 μmol). After stirring overnight at room temperature sodium borohydride (24 mg) was added, then after another 4 hours 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 78 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.83 (m, 3H) 1.21 (quin, J=7.9 Hz, 2H) 1.31 (quin, J=6.3 Hz, 2H) 2.38 (t, J=7.0 Hz, 2H) 2.93 (s, 3H) 3.56 (s, 2H) 6.61 (br. s., 4H) 6.67 (br. s., 1H) 7.04 (d, J=8.8 Hz, 2H) 7.12 (t, J=74.18 Hz, 1H) 7.13-7.27 (m, 3H) 7.37 (s, 1H) 7.42 (d, J=8.8 Hz, 2H); MS (APPI) m/z 417 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1.[Zn]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([OH:17])([CH3:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)c1ccc(-c2ccc(F)cn2)cc1F
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cn2)cc1F
Temperature: 0 °C

Procedure:
A mixture of 1-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]ethanone (3.6 g, 15.3 mmol) and ethyl bromoacetate (12.8 g, 76.5 mmol) in tetrahydrofuran (35 mL) was added dropwise to a refluxing suspension of zinc (Reike, activated) (5 g) in tetrahydrofuran (100 mL). After stirring at reflux for a further 15 min, the reaction was cooled, poured into ice water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 10-50% ethyl acetate/hexane over 48 fractions afforded ethyl 3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanoate.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2OC)(=[O:23])=[O:22])=[CH:17][CH:16]=1.ClC1C=C(S(N=C2C3C(=CC=CC=3)[C:47](=[O:54])C(Cl)=C2)(=O)=O)SC=1Cl>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:54][CH3:47])=[CH:29][CH:30]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Product: COc1ccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2)cc1

Procedure:
5.2.41 N,N-dimethyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide (13f) was prepared according to the procedure for 13d except using 4,5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and 3-mercapto-N,N-dimethylpropanamide( ) which afforded the title compound 16.1 mg (48%) as a white solid, m.p.: ° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:10]1=[O:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:10]1=[O:22])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CN2CC[C@H](O)C2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
Triethylamine (0.509 ml, 3.65 mmol) was added to a cooled solution of (S)-3-hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one (0.5 g, 2.436 mmol, intermediate I) in anhydrous DCM (12.18 ml) at 0° C. under a nitrogen atmosphere. Methanesulfonyl chloride (0.198 ml, 2.56 mmol) was then added dropwise and the reaction was allowed to stir at 0° C. for 15 min before quenching with a satd. sodium bicarbonate solution (10 mL). The mixture was allowed to warm to rt and the aqueous layer was separated and extracted with DCM (2×). The combined organic layers were dried over MgSO4 and evaporated in vacuo to give a white solid (0.73 g) which was then purified by silica gel chromatography (40 g of silica) eluting with a gradient of 0% to 50% ethyl acetate in hexanes to provide 0.63 g (91%) of the desired product as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[O:26]=[S:25]1(=[O:27])[CH2:24][CH2:23][CH2:22][N:2]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-aminomethylbenzoate hydrochloride (1.61 g) and triethylamine (2.45 mL) were dissolved in dichloromethane (40 mL), 3-chloropropane-1-sulfonyl chloride (1.17 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (8 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.46 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:ethyl acetate) to give the title compound (1.95 g).
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C:20]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]3)=[O:16])=[N:10]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])(=[O:53])[CH3:52]>CN(C=O)C.C(OCC)(=O)C>[C:55]([O:54][C:51](=[O:53])[CH2:52][N:5]1[CH2:4][CH2:3][C:2]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@H:17]3[C@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@:20]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]3)=[O:16])=[N:10]2)([OH:1])[CH2:7][CH2:6]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC3(O)CCNCC3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(CC(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(4-hydroxy-piperidin-4-ylmethyl)-1H-pyrazol-3-yl]-amide (80 mg, 0.12 mmol) was dissolved in DMF (3 mL) with cesium carbonate (100 mg, 0.31 mmol) then t-butyl acetate (0.1 mL, 0.677 mmol) was added stirred 16 hours at 25° C. The reaction mixture was diluted with ethyl acetate and separated with water (3×), the organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by reverse phase column chromatography (20-95% acetonitrile/water) to yield compound rac-[4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-acetic acid tert-butyl ester (68 mg, 74.7%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.P(Cl)(Cl)([Cl:18])=O>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccco2)nc(N)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c(Cl)nc(N)nc1-c1ccco1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
Following the method of Hull (J. Chem. Soc. 1957, 4845), a stirred suspension of 3.26 g (16.1 mmol) 2-amino-4-furan-2-yl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 3.7 ml (40.3 mmol) phosphorus oxychloride was heated at reflux for 90 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane, and poured cautiously onto 100 ml rapidly stirred ice-water such that the temperature remained around 10° C. The phases were separated and the aqueous phase further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 0.16 g (4%) 2-amino-4-chloro-6-furan-2-yl-pyrimidine-5-carbonitrile as an orange crystalline solid. EI-MS m/e (%): 222 (M{37Cl}+, 34), 220 (M{35Cl}+, 100), 143 (30).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7](=[O:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][N:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6][C:7]1=[O:12]
Reactant: NN
Reactant: COC(=O)c1ccn(C)c(=O)c1
Solvent: O
Solvent: CCO
Product: Cn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
The title compound of example 24 (4.0 g, 23.9 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (5.8 mL, 119 mmol) was added and the reaction was stirred at 78° C. for 3 hours. The reaction mixture was then cooled to room temperature and the product was filtered off to give 3.13 g (78% yield) of the title compound as a light yellow solid.