Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7])[N:9]=1)#[N:27]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(OC3CCCCC3)cc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(OC3CCCCC3)ccc12

Procedure:
Prepared from 1-Cyano-6-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 28e (94% yield). MS-(+)-ion: M+1=370.32.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 39b (177 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (214 mg, 85%). LCMS (Method 4): Rt 3.65 min, m/z 765 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])=O.[NH4+]>[Pd].C(O)C.O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc(N)ccc2n1C
Temperature: 20 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
Alternative A. To a mixture of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (420 g), from step (a) or commercial sources, and 10% palladium on carbon catalyst (50% wet) (42 g) in ethanol (4200 mL) was added a solution of ammonium formate (541.5 g) in demineralized water (840 mL) at between 25-35° C. over 3 hours. The mixture was stirred for 18 hours at 20° C., and then filtered, washing the solids with ethanol (2100 mL). The combined filtrate and washings were concentrated to 840 mL under vacuum at about 20° C. The resulting slurry was granulated at 5° C., filtered, washed with chilled ethanol (420 mL), and dried to give product ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (316.5 g, 86%).
Reaction SMILES: COC([C:5]1([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:9][CH:8]=[C:7]([OH:10])[C:6]1=[O:11])=O.O1CCOCC1.Cl>O>[OH:11][C:6]1[C:7](=[O:10])[CH2:8][CH2:9][C:5]=1[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: COC(=O)C1(Cc2ccc3ccccc3c2)CC=C(O)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(Cc2ccc3ccccc3c2)=C1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
A mixture of 3-hydroxy-1-naphthalen-2-ylmethyl-2-oxo-cyclopent-3-enecarboxylic acid methyl ester (3.0 g, 10.71 mmol), dioxane (50 ml), and HCl (10N, 50 ml) was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature, poured into H2O and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether gave a brown solid (1.75 g, 69%): m.p. 120°-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.Br[C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][C:17]1([CH3:21])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([O:1][C:25]5[S:26][C:27]([CH3:30])=[N:28][N:29]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: Cc1nnc(Br)s1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(O)cc43)nc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)CC(C)(C)C4)CCO3)s1
Yield: 12.2 %

Procedure:
A mixture of Example 6 (75 mg, 0.23 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (42 mg, 0.23 mmol) and potassium carbonate (64 mg, 0.46 mmol) in DMF (7 mL) was heated to 150° C. for 10 h. The solvent was removed in vacuo and the residue was purified by prep HPLC to give the title compound (12 mg, 12%) as an off-white solid. δH (CDCl3) 1.14 (6H, s), 2.43 (2H, s), 2.67 (3H, s), 2.77 (2H, s), 4.09-4.15 (2H, m), 4.33-4.40 (2H, m), 6.96-7.06 (2H, m), 8.22-8.24 (1H, m). LCMS (ES+) 429 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:33]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:39]4[CH2:40][CH2:41][N:36]([CH:33]5[CH2:35][CH2:34]5)[CH2:37][CH2:38]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: C1CN(C2CC2)CCN1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and N-cyclopropylpiperazine bis hydrobromic salt (CAS # 159974-58-0). White solid (64%). MS (EI): 596.2 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:9][OH:10].C([O-])(=O)C.[Na+]>C(O)C>[CH:1](=[N:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cccnc1

Procedure:
Nicotinaldehyde oxime was prepared in quantitative yield by the reaction of nicotinaldehyde with hydroxylamine and sodium acetate in ethanol as for 20.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>O.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:6]([O-:9])=[O:7])[C:13]=1[OH:18]
Reactant: Oc1ccccc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1O
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of 60 mL of concentrated sulfuric acid diluted with 186 mL of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.932 mol) was added to the solution. 2-Bromo-phenol 1a (60 mL, 0.516 mol) was added dropwise at such a rate that the reaction temperature was kept below 25° C. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography (TLC) until the disappearance of the starting materials. The precipitate was dissolved in 320 mL of ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=O.[NH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[S:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:14][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 97.5 %

Procedure:
A solution of 2-bromo-1-(3-fluorophenyl)ethanone (1.95 g, 8.98 mmol), tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (2.00 g, 8.18 mmol) and potassium carbonate (2.26 g, 16.4 mmol) in dimethylformamide (60 ml) was stirred at 110° C. for 1.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (2.89 g, 97.0%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].[Na].Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
Triethylene glycol monomethyl ether (1.0 g, 6.1 mmol) and tert-butyl acrylate (390 mg, 3.05 mmol) were dissolved in dry THF and sodium metal (0.7 mg, 0.03 mmol) was added at room temperature. The mixture was stirred for 4 hours and 1 M HCl was added to quench the reaction. The mixture was extracted twice with dichloromethane, and the organic phase was dried over MgSO4 and concentrated in vacuo to provide an oil, which was purified by silica chromatography using ethyl acetate as eluent. The product was an oil, 773 mg (44%).
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].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.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:44]=1[C:55]([NH2:57])=[O:56]>C(Cl)Cl>[C:1]([C:3]1([C:6]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:44]=2[C:55]([NH2:57])=[O:56])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Reactant: N#CC1(C(=O)O)CC1
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: ClCCl
Product: N#CC1(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 1-cyanocyclopropanecarboxylic acid (0.75 g, 7 mmol) in DCM (40 mL) was added HATU (3.5 g, 10 mmol) and DIPEA (3.4 mL, 20 mmol). After stirring at room temperature for 1 h, 3-aminobiphenyl-2-carboxamide (from example 218: 1 g, 5 mmol) was added and the reaction mixture stirred for an additional 16 h. The reaction mixture was washed with water and the organic phase dried, filtered, concentrated under reduced pressure and purified by silica gel chromatography (60% ethyl acetate in hexanes) to provide 3-(1-cyanocyclopropanecarboxamido)biphenyl-2-carboxamide (0.75 g, 74% yield) as a white solid. LCMS Method T: retention time 1.53 min; [M+1]=306.2.
Reaction SMILES: CC(C)([O-])C.[K+].C([N:10]1[CH2:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:11]1=[O:23])(=O)C.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C.O>[CH:24]1([CH:30]=[C:14]2[NH:10][C:11](=[O:23])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:13]2=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)N1CC(=O)N(c2ccccc2F)C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=CC2CCCCC2)C(=O)N1c1ccccc1F
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (1.12 g, 10.0 mmol) was added in one portion to a solution of N-acetyl-3-(2-fluorophenyl)imidazolidine-2,4-dione (2.36 g, 10.0 mmol) and cyclohexanecarboxaldehyde (1.23 g, 11.0 mmol) in DMF (10 mL) at 0° C. The solution was allowed to warm to RT overnight with stirring, then diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine (saturated) dried (over MgSO4), filtered and concentrated. The crude product was recrystallized from hexane/ethyl acetate to give 5-cyclohexylmethylene-3-(2-fluorophenyl)-imidazolidine-2,4-dione, as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:28][Cl:29])[O:4][C:5]1[C:6]([N+:25]([O-])=O)=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.C1COCC1>[Pd].CO>[Cl:29][CH2:28][CH:3]([CH2:2][Cl:1])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])[C:6]=1[NH2:25]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Reaction time: 20 h

Procedure:
A mixture of 1-[3-(2-chloro-1-chloromethyl-ethoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene (3) (2.4 g, 5.3 mmoles) and 10% Pd/C in a 1:1 mixture of THF and methanol was hydrogenated on a Parr hydrogenator at 40 lb/in2 for 20 hours. The mixture was filtered through Celite. The filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (2.02 g, 4.77 mmoles), identified by HNMR analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9]([Mg]Br)[CH3:10].CCOCC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:8])[CH2:9][CH3:10]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 2-pyridine carboxaldehyde (4.0 g, 37.34 mmol) in THF (50 mL) at 0° C., add 3M ethyl magnesium bromide in ether (18.7 mL, 56.0 mmol), continue stirring for 30 min at 0° C. and then at ambient temperature for 2 h. Add water (200 mL), extract three times with EtOAc, dry over anhydrous Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a yellow oil (3.39 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[OH:27])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:35]([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[O:27][CH:35]([CH3:37])[CH3:36])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccccc2C1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2OC(C)C)Cc2ccccc2C1
Yield: 99.1 %

Procedure:
To a suspension of 2-(3,5-dichloro-2-hydroxy-benzenesulfonylamino)-indan-2-carboxylic acid ethyl ester (30) (226 mg, 0.53 mmol), anhydrous Cs2CO3 (300 mg, 0.92 mmol), and KI (15 mg, 0.09 mmol) in DMF (15 mL) is added 2-bromopropane (432, 4.60 mmol). The resulting reaction suspension is filled with argon and run in a microwave reaction: 110° C., 2.5 h. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10%-60% EtOAc in heptane) to give a pure product (31) as a white semi-solid (248 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][C:6]([C:13]([OH:15])=[O:14])=[N:7]2.[C:17]1([S:23]([N:26]=C=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:26][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH:5]=[C:6]([C:13]([O:15][CH2:11][CH2:2][CH2:3][CH3:4])=[O:14])[NH:7]2
Reactant: O=C(O)C1=Nc2cc(Cl)cc(Cl)c2C(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: CCCCOC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 16 h

Procedure:
Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, butyl ester (1.00 g, 3.2 mmol) and benzenesulfonyl isocyanate (0.85 mL, 6.3 mmol) in acetonitrile (15 mL). Heat to reflux under an inert atmosphere. After 16 hours, quench with methanol (5 mL). Evaporate in vacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from ethyl acetate/hexane to give the title compound as a solid: TLC Rf =0.38 (silica gel, 2% acetone/dichloromethane); mp; 94°-95° C. Elem. Anal. calculated for C20H18Cl2N2O4S: C, 52.98; H, 4.00; N, 6.18. Found: C, 53.27; H, 3.95; N, 6.12.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 2.18 g) and 1-bromo-2-methoxyethane (1.18 ml) were dissolved in DMF (30 ml) and sodium hydride (301 mg) was added while stirring. After stirring at RT for 2 h, the solvent was drawn off. The residue was taken up in EA, and the mixture was washed with water, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-30% in 60 min). 2.0 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:15][NH2:16].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCC(O)c1cccc(F)c1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CC(C)NCC(O)c2cccc(F)c2)cc1

Procedure:
1-(4-Methoxyphenyl)propan-2-one (2.25 g) and 2-hydroxy-2-(3-fluorophenyl)ethanamine (2.13 g) were condensed ahd subsequently reduced with sodium borohydride (2.75 g) by an analogous procedure to that described in Example 1. The crude product was recrystallised from diethyl ether-hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-fluorophenyl)ethanamine, mp 85°-9° C., as a 37:63 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[CH:19][C:18]=3[NH:29][C:30]([C:32]3[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH:20]=[CH:19][C:18]=3[NH:29][C:30]([C:32]3[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (4 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 85.3 mg (62%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.70(s, 1H), 11.44(s, 1H), 8.41(m, 2H), 7.91(s, 1H), 7.78(m, 1H), 7.68(m, 1H), 7.62(m, 1H), 7.58(m, 3H), 7.40(m, 1H), 7.23(m, 1H), 6.92(s, 1H), 3.86(s, 2H), 3.36(m, 4H), 2.62(m, 2H), 2.29(m, 6H), 1.60(m, 6H). MS (ES, m/z): 612 [M+H]+.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[Cl:17][CH:18]([F:33])[C:19]([F:32])([F:31])[O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:17][CH:18]([F:33])[C:19]([F:31])([F:32])[O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:23][CH:22]=1
Reactant: NCCOc1ccc(OC(F)(F)C(F)Cl)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(OC(F)(F)C(F)Cl)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.71 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-[4-(2-chloro-1,1,2-trifluoroethoxy)phenoxy]ethylamine (1.08 g) and triethylamine (0.40 g) and the mixture was further stirred at room temperature for one hour.