Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(C)CC1=C2c3ccc(O)cc3CCC2CCNC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 7.5 g of the slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one (Example 1) in 125 ml of methylene chloride is added slowly to 125 ml of a stirred 10 percent solution of boron tribromide in methylene chloride, precooled in a dry ice-acetone bath. The mixture is allowed to warm to room temperature slowly and is stirred overnight. It is cooled in an ice bath, 100 ml of water and 100 ml of 3 N aqueous sodium hydroxide are added and stirring is continued for one half hour. The basic aqueous solution is separated, washed with diethyl ether, neutralized to pH=8-9 with hydrochloric acid and allowed to stand overnight. The product, collected by filtration and subsequent extraction with chloroform, is suspended in 5 percent aqueous sodium bicarbonate and the suspension is stirred for 4 hours. The insoluble product is collected, dried and recrystallized from ethanol, to yield 1-(2-isopropylaminopropyl)-9-hydroxy-3,4,5,5a,6,7-hexahydro- 2H-naphth[1,2-d]azepin-2-one as a single diastereoisomer, melting at 202°-204°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=[N:26][NH:25][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)C(c1ccc(F)cc1)C(C=O)c1ccc(SC)cc1
Solvent: CCO
Solvent: O
Product: CSc1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 5.3 %

Procedure:
The aldehyde-ester, hydrate, and hydroxy lactone from Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution was stirred at reflux in a Soxhelet apparatus containing molcular sieves. After 18 hours, the reaction mixture was cooled and the volatile materials removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous HCl. The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (4:1 hexanes/ethyl acetate) to obtain the title compound (yield: 50 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.75 (d, J=12 Hz, 1H), 3.87 (d, J=12 Hz, 1H), 6.93–7.08 (m, 6H), 7.16 (d, J=9 Hz, 2H), 8.71 (s(br), 1H). MS (DCI/NH3) m/z 315 (M+H)+ and m/z 332 (M+NH4)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([O:29]C)=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].[ClH:31]>CO>[Cl:31][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NOCCBr)c2n1
Reactant: Cl
Solvent: CO
Product: O=C(NOCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 90 °C

Procedure:
A mixture of (R)-N-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (70 mg, 0.146 mmol) and HCl (4 N dioxane, 3.65 mL, 14.6 mmol) was sealed in a pressure tube and heated at 90° C. for 3 hours. The reaction mixture was then cooled, diluted with MeOH, concentrated, and dried on high vacuum to obtain the desired product which was used in the next step directly without further purification, assuming quantitative conversion.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:37])/[C:22](=[N:29]\[O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])/[C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)[C:18](=[O:38])[N:17]2[S:39]([OH:42])(=[O:41])=[O:40])[N:11]=1.Cl[S:44]([NH:47]C(=O)OC(C)(C)C)(=[O:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:28][C:25]1[S:26][CH:27]=[C:23](/[C:22](=[N:29]/[O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])/[C:21](=[O:37])[NH:20][C@H:19]2[C@@H:16]([CH2:15][N:12]3[N:11]=[C:10]([CH2:9][NH:8][S:44](=[O:46])(=[O:45])[NH2:47])[CH:14]=[N:13]3)[N:17]([S:39]([OH:42])(=[O:41])=[O:40])[C:18]2=[O:38])[N:24]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNS(N)(=O)=O)n1)c1csc(N)n1)C(=O)O

Procedure:
Prepared in an analogous manner to example 53, using 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid TFA salt, crude compound (200 mg, 0.318 mmol), tert-butyl chlorosulfonylcarbamate (68 mg, 0.318 mmol), DIPEA (113 mL, 0.636 mmol) and DMF (1 mL). LCMS: m/z=609.1 (M−1). 1H NMR (400 MHz, D2O): δ 7.65 (s, 1H), 6.98 (s, 1H), 5.40 (d, J=6.0 Hz, 1H), 4.85-4.83 (m, 1H), 4.76-4.74 (m, 2H), 4.13 (s, 2H), 1.26 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:33]4[S:29][C:30](=[O:35])[NH:31][C:32]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(-c4ccnc(F)c4)nc23)S1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.7 %

Procedure:
To 7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 30 mg, 0.1 mmol) in EtOH (1 mL) was added piperidine (13 μL, 0.1 mmol), and thiazolidine-2,4-dione (12 mg, 0.1 mmol). The reaction was stirred at 80° C. for 2 hours. The solid formed was isolated by filtration, washed with water then ethanol. The recovered solid was further purified by washing with 20% methanol/dichloromethan to provide 9 mg of 5-((7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (23%). LCMS (M+1=397)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K6) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (332 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:20][CH:19]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)(C)O
Product: C=CCc1ccccc1C(=O)C(OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Benzoin methyl ether (50 g) and t-butanol (500 g) were added to a 1 liter, 3neck, round bottom flask equipped with magnetic stirrer, and placed in an oil bath at 80° C. To this mixture, 33.7 g of potassium t-butoxide was added and the solution stirred for 15 minutes. Allyl Bromide (42.3 g) was added dropwise over a 1 hour period and stirring was continued at 85° C. for 2 more hours then cooled to room temperature. After evaporation of t-butanol and filtration of potassium bromide, the product was distilled at 125° C.±2° C. and 0.05 mgHg to yield 49.2 g of allylbenzoin methyl ether which crystallized upon cooling.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)[C:6]2[CH2:7][CH2:8]O[C:5]=2[C:4]=1[Cl:51].C([O-])([O-])=O.[K+].[K+].[CH3:58][O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1.[OH2:69]>CC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:51][C:4]1[C:5]2[O:69][CH2:8][CH2:7][C:6]=2[C:10]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:11][C:3]=1[CH2:2][C:63]1[CH:64]=[CH:65][C:60]([O:59][CH3:58])=[CH:61][CH:62]=1
Reactant: O
Reactant: Clc1c(CBr)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1OCC2
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a mixture of compound 67 (700 mg, 0.9 mmol), K2CO3 (497 mg, 3.6 mmol) and 4-methoxyphenyl boronic acid (341 mg, 2.25 mmol) in acetone (9.0 mL) and H2O (3.0 mL) was added bis(triphenylphosphine)palladiumchloride (63 mg, 0.09 mmol) at 0° C. under atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then, stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 68 (340 mg, 46%) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[O:17][CH2:16]1)[C:5](=[O:15])[N:6]2[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[F:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35].ClCCl>C1(C)C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[O:17][CH2:16]1)[C:5](=[O:15])[N:6]2[CH2:11][C:12]([NH:35][C:34]1[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=1[F:32])=[O:14]
Reactant: Nc1ccccc1F
Reactant: O=C(O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of (4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.24 g, 0.59 mmol) and oxalyl chloride (0.15 mL, 1.76 mmol) in toluene (7.00 mL) was added one drop of DMF and the resulted mixture was stirred at ambient temperature overnight. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (5.00 mL) and 2-fluoroaniline (0.18 mL, 1.89 mmol) was added at ambient temperature. The mixture was stirred at ambient temperature for one hour. More dichloromethane (100 mL) was added. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.23 g, 76%): 1H NMR (300 MHz, CDCl3) δ 8.20 (t, 1H), 7.80 (br, 1H), 7.27-7.17 (m, 2H), 7.16-7.03 (m, 3H), 6.97-6.88 (m, 1H), 6.78-6.60 (m, 2H), 5.08 (d, 1H), 4.93 (d, 1H), 4.68 (d, 1H), 4.49 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 177.1, 163.9, 157.8, 143.6, 131.0, 128.8, 128.1, 124.7, 121.8, 120.0, 115.0, 111.6, 108.1, 99.8, 77.5, 59.2, 44.7; MS (ES+) m/z 503.4 (M+1), 505.4 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C(#N)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:42]([NH:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)=[O:43])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2ccccc12)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in acetonitrile (10 ml) were added triethylamine (0.089 ml, 0.64 mmol) and 1-naphthyl isocyanate (0.062 ml, 0.43 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (135 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][C:23]([OH:25])=[O:24])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][C:23]([O:25][C@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:49][CH2:50]2)[CH:37]=1)[CH2:33][C:32]1[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=1[Cl:26])=[O:24])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1cccc2c1ccn2CC(=O)O)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Yield: 80.3 %

Procedure:
To a solution of 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (250 mg, 0.679 mmol) in DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (285 mg, 0.679 mmol), EDC (390 mg, 2.036 mmol) and DMAP (41.5 mg, 0.339 mmol) were added, and the mixture was reacted at room temperature overnight. The mixture was partitioned between DCM and 1N HCl and the aqueous phase was extracted with DCM (3×20 ml); the solvent was removed to give (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (420 mg, 0.545 mmol, 80% yield). MS/ESI+ 770.9 [MH]+. This intermediate was used in the following steps without purification.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Cl[S:21]([C:24]1[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41])(=[O:23])=[O:22]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:21]([C:24]2[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[CH:26][C:25]=2[O:40][CH3:41])(=[O:23])=[O:22])[C:3]1=[O:12]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 78.7 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.860 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. Chromatography on silica using a DCM/AcOEt mixture (99/1; v/v) as the eluent gives 1.38 g of the expected product, which is used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][CH3:13].C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>CN(C)C=O.[Cu]=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccncc2cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: COc1cc2ccncc2cc1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
7-Bromo-6-methoxyisoquinoline (200 mg), tetrakistriphenylphosphine palladium(0) (97 mg), and copper(II) oxide (134 mg) were suspended in N,N-dimethylformamide (5 ml), tri-n-butyl-(2-pyridyl)-tin (618 mg) was added to the suspension, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, the reaction solution was then fitlered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-methoxy-7-pyridin-2-yl-isoquinoline (122 mg, yield 62%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([CH:42]=[O:43])=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CC(C)=O>[Cl:19][C:20]1[C:25]([CH:42]([C:36]2[CH:35]=[C:34]3[C:39]([CH:40]=[CH:41][C:32]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:33]3)=[CH:38][CH:37]=2)[OH:43])=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1cnccn1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.820 mL, 0.686 g, 4.86 mmol) in dry THF (15 mL), cooled by CO2(s)/acetone, is added nBuLi (2.5M in hexanes; 1.95 mL, 4.88 mmol). The cooling bath is replaced with an ice/water bath for 15 min, and then the solution is re-cooled to −78° C. After 5 min, a solution of 2-chloropyrazine (0.370 mL, 0.475 g, 4.14 mmol) in THF (0.5 mL) is added. 25 min later, a solution of 2-phenylquinoline-7-carbaldehyde (890 mg, 3.82 mmol) in dry THF (7 mL) is added slowly over 5 min from a syringe which is then rinsed with THF (1 mL), and the mixture is stirred at −78° C. for 2 h and then warmed up to 0° C. for 0.5 h. The reaction is quenched by adding citric acid (0.25M aqueous solution). The mixture is extracted with EtOAc (4×30 mL), and the combined EtOAc extracts are washed with water, sodium bicarb solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (4×50 mL, then 1-16)→>2% EtOAc in CH2Cl2 (17-30)→5% (31-59)→7% (60-85)→10% (86-110)] to obtain the title compound as an off-white foam. 1H NMR (CDCl3, 400 MHz) δ 4.80 (d, J=7.6 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 7.43-7.56 (m, 3H), 7.58 (dd, J=1.8, 8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.06 (brs, 1H), 8.10-8.15 (m, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H). MS (ES+): m/z 348.0/350.0 (100/37) [MH+]. HPLC: tR=3.3 min (MicromassZQ, polar—5 min).
Reaction SMILES: [C:1]([NH2:6])(=[S:5])[CH2:2][CH2:3][CH3:4].[CH:7]([CH:9](Cl)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH2:2]([C:1]1[S:5][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=1)[CH2:3][CH3:4]
Reactant: CCCC(N)=S
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CCCc1ncc(C(=O)OCC)s1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
A mixture of 38 g of thiobutyramide, 54.2 g of ethyl 2-formyl-2-chloro-acetate, 185 ml of dioxane and 22 g of magnesium carbonate was heated for 4 hours at 60°C and the precipitate formed was removed by filtration. The dioxane was distilled from the filtrate and the residue was taken up in 665 ml of a 1-1 ethyl ether-water mixture. The ether phase was recovered by decantation and was washed with aqueous 10% hydrochloric acid solution and then with water until the wash waters were neutral, dried over magnesium sulfate and distilled to dryness. The residue was distilled to obtain 57 g of ethyl 2-n-propylthiazol-5-carboxylate boiling at 95°-106°C under 0.5 mm Hg.
Reaction SMILES: C(OC1C(OCC)=CC=C2C=1C=CN2)C1C=CC=CC=1.C([O:28][C:29]1[C:37]([O:38][CH3:39])=[C:36]2[C:32]([CH:33]=[CH:34][NH:35]2)=[CH:31][CH:30]=1)C1C=CC=CC=1>>[OH:28][C:29]1[C:37]([O:38][CH3:39])=[C:36]2[C:32]([CH:33]=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: COc1c(OCc2ccccc2)ccc2cc[nH]c12
Agent: CCOc1ccc2[nH]ccc2c1OCc1ccccc1
Product: COc1c(O)ccc2cc[nH]c12
Yield: 86 %

Procedure:
This compound is obtained according to the operating method described in Example 1d, in which the 4-benzyloxy-5-ethoxyindole is replaced by 6-benzyloxy-7-methoxyindole. A white powder is obtained (yield: 86%, m.p.=83°-84° C.).