Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]([F:66])([F:65])[O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=1>CN(C=O)C>[F:49][C:50]([F:65])([F:66])[O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:59]=1
Reactant: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2OC(F)(F)F)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 65.3 %

Procedure:
DIEA (0.011 mL, 0.065 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.059 mmol) and HATU (0.025 g, 0.065 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-trifluoromethoxy-biphenyl-3-ylamine (0.015 g, 0.059 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 63% yield: LCMS (ESI) m/z 442 (MH+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C@@H:21]3[CH2:23][O:22]3)=[C:14](C(=O)C)[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:29].[OH-].[K+]>C(Cl)(Cl)Cl.CO>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:20][C@@H:21]([CH2:23][OH:22])[O:29][C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OC[C@@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@H](CO)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-benzenesulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone (2.04 g; 0.059 mol) and meta-chloroperoxybenzoic acid (4.13 g; 0.018 mol, max. 77%) in chloroform (20 mL) was heated under reflux for 18 hours. After cooling to ambient temperature the mixture was diluted with chloroform, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. This crude residue (0.85 g; 0.0024 mol) dissolved in methanol (5 mL) was added to a solution of 10% aqueous potassium hydroxide (4 mL) at 0° C. The mixture was stirred for 30 minutes at room temperature. Solvent was removed in vacuo, and the residue was dissolve in ethyl acetate, washed with 10% aqueous hydrochloric acid followed by saturated brine, dried (Na2SO4) and concentrated in vacuo to give (7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-yl)-methanol as an oil (1.44 g; 77%): MS (M+H)+ 307.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:16][CH2:15][O:12][C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[NH2:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1ccc(N)cc1OCCN1CCCCC1

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 1-(2-chloroethyl)piperidine hydrochloride using a similar procedure to Descriptions 1 and 2 (40%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[S:10]([CH:13]1[CH2:17][CH2:16][O:15]C1=O)(=[O:12])=[O:11].[Si]([O:26][CH2:27][C@H:28]([CH3:46])[O:29][C:30]1[CH:31]=[C:32]([CH:42]=[C:43]([OH:45])[CH:44]=1)[C:33]([NH:35][C:36]1[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=1)=[O:34])(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:9][C:5]1[C:6]([O:45][C:43]2[CH:42]=[C:32]([CH:31]=[C:30]([O:29][C@@H:28]([CH3:46])[CH2:27][OH:26])[CH:44]=2)[C:33]([NH:35][C:36]2[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=2)=[O:34])=[CH:7][C:2]2[O:15][CH2:16][CH2:17][CH2:13][S:10](=[O:11])(=[O:12])[C:3]=2[CH:4]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 150 °C
Yield: 34.3 %

Procedure:
A solution of 3-[(2,4,5-trifluorophenyl)sulfonyl]dihydrofuran-2(3H)-one (126 mg, 0.45 mmol) and 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (203 mg, 0.50 mmol) in acetonitrile (3.5 mL) was treated with caesium carbonate (650 mg, 2.0 mmol) and heated in a microwave reactor at 150° C. for 1.5 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was then chromatographed on silica, eluting with a gradient of 0 to 10% methanol in ethyl acetate, to afford the title compound (78 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[CH2:23]([CH:22]([NH:21][C:16]1[C:15]([N+:27]([O-:29])=[O:28])=[C:14]([O:1][C:2]2[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=2[CH3:8])[N:19]=[C:18]([CH3:20])[N:17]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(C)c(O)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Oc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 3-hydroxy-2,4,6-trimethylpyridine (41 mg, 0.3 mmol) in 1 ml of dry THF was treated with 60% sodium hydride in oil (13 mg, 0.3 mmol) at rt. The reaction mixture was cooled to −78° C. and a solution of (6 chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (78 mg, 0.3 mmol) in 1 ml of dry THF was added. The reaction was stirred at −78° C. for 1 hour, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 91 mg (84%) of white solid of the title compound, mp 134-135° C. 1H NMR (CDCl3) δ 8.30 (d, 1H), 6.89 (s, 2H), 4.30 (m, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.97 (t, 6H) ppm.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Br)=[O:4].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: O=C(Br)C(Br)CCBr
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCC(Br)C2=O)cc1

Procedure:
2,4-Dibromobutyryl bromide (BBBB, 12.13 g, 0.039 mole) was added via an addition funnel to a cold (5° C.), well stirred slurry of 4-aminobenzonitrile (4-ABN, 4.0 g, 0.034 mole), Na3PO4 (3.05 g, 0.019 mole) and acetonitrile (42 mL) while maintaining a temperature below 30° C. during the addition. The addition funnel was rinsed with acetonitrile (2 mL). Upon completion of the coupling (determined by LC), K2CO3 (9.36 g, 0.069 mole) was added via an addition funnel while maintaining the reaction temperature below 30° C. Upon completion of the reaction (determined by LC), the slurry was filtered. The flask and the cake were washed with acetonitrile (40 mL). The filtrate and the wash were combined to afford a solution of 4-(3-bromo-2-oxopyrrolidin-1-yl)benzonitrile in acetonitrile. Qualitative LC analysis showed the product with 96.1 area % purity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[O:7][C:6]=1[CH3:13])=[O:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[O:7][C:6]=1[CH3:13])=[O:4]
Reactant: COC(=O)c1cc(C(C)O)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)=O)oc1C
Reaction time: 72 h
Yield: 83.5 %

Procedure:
Manganese dioxide (669 g) is added portionwise to a solution of 5-(1-hydroxy-ethyl)-2-methyl-furan-3-carboxylic acid methyl ester (94.5 g) in dichloromethane (1000 ml). After 72 hours at room temperature, the reaction mixture is filtered through a plug of silica gel and the filtration cake is washed several times with ethyl acetate. The filtrate is concentrated in verve to yield 5-acetyl-2-methyl-furan-3-carboxylic acid methyl ester (78 g) as a yellow solid. The crude product obtained is used without further purification. MS (HPLC/MS): 183 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH:17]=[C:18](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h

Procedure:
A solution of 1-3 (1.70 g, 4.13 mmol) in THF (80 ml) was cooled to -78° and treated with n-BuLi (4.25 mmol) with stirring for 15 min. The reaction was then quenched with 10% KHSO4 (25 ml) and the solvent was removed. The residue was taken up in Et2O (150 ml) and this was washed with 10% KHSO4 solution, brine, and dried (Na2SO4).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[NH:12][C:11]([CH3:23])=[C:10]2[C:24]#[N:25])=[CH:5][CH:4]=1)#[N:2].ClCCl.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[N:12]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=3)[C:11]([CH3:23])=[C:10]2[C:24]#[N:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(-c3cccs3)nc2N1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(-c3cccs3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-5-methyl-2-thiophen-2-yl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (70 mg, 230 μmol) was stirred in abs. dichloromethane (60 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (131 mg, 690 μmol, 3 eq.), anhydrous copper(II) acetate (125 mg, 690 μmol, 3 eq.), abs. pyridine (1668 μl) and triethylamine (70 mg, 690 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (44 mg, 230 μmol, 1 eq.), anhydrous copper(II) acetate (42 mg, 230 μmol, 1 eq.) and abs. pyridine (500 μl) were then added, and the mixture was stirred at RT for a further 3 d. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and pyridine and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (40.1 mg, 36% of theory).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]([CH3:8])=[N:6][N:5]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:31])/[C:16](=[N:23]\[O:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)/[C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[C:12](=[O:32])[N:11]2[S:33]([OH:36])(=[O:35])=[O:34])[N:4]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][N:48]([C:56](=[N:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])N1C=CC=N1)[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:43])([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17](/[C:16](=[N:23]/[O:24][C:25]2([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]2)/[C:15]([NH:14][C@@H:13]2[C:12](=[O:32])[N:11]([S:33]([OH:36])(=[O:34])=[O:35])[C@@H:10]2[CH2:9][N:5]2[N:4]=[C:3]([CH2:2][NH:1]/[C:56](=[N:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])/[N:48]([C:49]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:55])[CH2:47][CH2:46][CH2:45][NH:44][C:42](=[O:43])[O:41][C:37]([CH3:40])([CH3:39])[CH3:38])[C:7]([CH3:8])=[N:6]2)=[O:31])[N:18]=1
Reactant: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN
Reactant: CC(C)(C)OC(=O)N=C(N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN/C(=N/C(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a soln of 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (33.9 mg, 0.062 mmol) and tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (54.2 mg, 0.116 mmol) in DMF (624 μl) at 0° C. was added DIPEA (32.7 μl, 0.187 mmol). After stirring at rt for 16 h, the solution was concentrated in vacuo and used as such without further purification. LCMS: Rt=0.75 min, m/z=943.7 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9]([Cl:16])=[C:10]([Cl:15])[C:11]([O:13]C)=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1>>[C:1]([C:4]1[S:8][C:7]2[C:9]([Cl:16])=[C:10]([Cl:15])[C:11]([OH:13])=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 56.6 %

Procedure:
A mixture of 9.5 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene and 95 g of pyridine hydrochloride is heated at 185°-200° for four and one-half hours and allowed to cool. While still fluid in nature, the reaction mixture is poured onto ice and the resulting aqueous mixture is extracted three times with ethyl acetate. The organic fractions are combined, washed one time with water, two times with 2 N hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated. The residue is recrystallized from acetone-hexane to give 5.1 g of 2-acetyl-6,7-dichloro-5-hydroxybenzo[b]thiophene, mp 199°-201°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]2[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (5-(2-methoxy-ethoxy)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M222) (340 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (196 mg, 72%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]([C@@H:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH3:22][O:23][C:24]([C@@H:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[N:34]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:25]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.132 g, 0.396 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). cis-2-(4-Fluoro-benzylamino)-cyclooctanecarboxylic acid methyl ester (0.117 g, 0.396 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g, 0.416 mmol). Then N-methylmorpholine (0.84 g, 0.832 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclooctanecarboxylic acid methyl ester (0.241 g, 0.396 mmol), as an orange oil. LC-MS (ESI) calcd for C27H33FN4O7S2 608.18, found 609.4 [M+H+].
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:20][N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1ccc(Cl)c(Cl)c1
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: NS(=O)(=O)c1ccc2c(c1)CCN2Cc1ccc(Cl)c(Cl)c1
Yield: 60.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-(3,4-dichlorobenzoyl)indoline-5-sulfonamide (Intermediate 58, 70 mg, 0.19 mmol) was converted to the title compound (41 mg, 61%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 7.63-7.58 (m, 2H), 7.48-7.43 (m, 2H), 7.31 (dd, J=8.3, 2.1 Hz, 1H), 6.91 (s, 2H), 6.60 (d, J=8.1 Hz, 1H), 4.41 (s, 2H), 3.46 (t, J=8.7 Hz, 2H), 3.03-2.98 (m, 2H); MS(ESI+) m/z 356.9 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (0.282 g, 0.864 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (0.29 g, 1.728 mmol) and anhydrous K2CO3 (0.24 g, 1.73 mmol) in DMF (10 mL) was heated at 100° C. overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.31-8.32 (m, 1H), 7.63-7.53 (m, 4H), 7.26-7.14 (m, 2H), 6.53-6.50 (m, 1H), 4.20-4.11 (m, 1H), 3.92 (s, 3H), 3.60-3.25 (m, 2H), 3.01-2.94 (m, 1H), 2.38 (s, 1H), 2.22 (s, 2H), 1.45-1.22 (m, 4H), 1.04 (d, J=7.0 Hz, 3H), 0.73-0.44 (m, 1H); ESI-MS (m/z): 472 [M+1]+. [α]25D=−8.9° (c=0.1, MeOH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])=[O:14])=[C:8]([OH:22])[CH:7]=[CH:6]2)#[N:2].[ClH:23].[NH3:24]>CO>[ClH:23].[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:16][C:17](=[O:21])[N:18]([CH3:19])[CH3:20])=[O:14])=[C:8]([OH:22])[CH:7]=[CH:6]2)(=[NH:24])[NH2:2]
Reactant: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C#N)ccc12
Reactant: N
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C(=N)N)ccc12

Procedure:
600 Milliliters of anhydrous methanol was added to 29.8 g of 6-cyano-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol, and dry hydrogen chloride gas was passed through the solution under cooling with ice and stirring to saturate the solution with hydrogen chloride gas, followed by further stirring for 24 hours under cooling with water. The reaction mixture was added dropwise to 3.0 liters of anhydrous methanol, followed by stirring for 1 hour under cooling with ice and the precipitate was collected by filtration. This was added to a solution prepared by passing dry ammonia gas through 240 ml of anhydrous methanol under cooling with ice and stirring to saturate the methanol with the gas, followed by stirring for 96 hours under cooling with water. The precipitate was collected by filtration and washed with 150 ml of methanol, 100 ml of water and 100 ml of acetone. To this collected precipitate was added 100 ml of a methanol solution saturated with dry hydrogen chloride gas, followed by stirring for 2 hours under cooling with ice. The precipitate was collected by filtration and washed with a small amount of diisopropyl ether to obtain a crude product. This was dissolved in 1.2 liter of 50% hydrous methanol and 10 g of active carbon was added thereto, followed by stirring for 1 hour at room temperature. Insoluble matter was filtered off and the filtrate was concentrated to 200 ml under reduced pressure. Then, the precipitate was collected by filtration and washed with small amounts of cold methanol and acetone to obtain 18.7 g of the desired product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CN(C1C=CC=CN=1)C>ClCCl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
(S)-5-hydroxymethylpyrrolidin-2-one (1.15 g) was dissolved in dichloromethane (40 mL), triethylamine (1.67 mL), p-toluenesulfonyl chloride (2.00 g) and dimethylaminopyridine (0.12 g) were added under ice-cooling, and the mixture was stirred at room temperature 18 hr. The reaction mixture was concentrated under reduced pressure, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and the solvent was evaporated to give the title compound (1.88 g).