Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:32])[N:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:32])[N:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]([Cl:33])=[CH:24][N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1ccnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Reaction time: 12 h

Procedure:
A stirred solution of 3-(1-tert-butyloxycarbonyl-trans-4-(2-pyridyl)-pyrrolidin-3-ylamino)-1-ethoxycarbonylmethylpyrazinone from step 8 above (2.0 g, 4.5 mmol) and N-chlorosuccinimide (0.67 g, 5.0 mmol) in CHCl3 was heated to reflux for 6 h. More N-chlorosuccinimide (0.20 g, 1.5 mmol) was added and refluxing was continued for 12 h. The reaction was diluted with CHCl3 and washed with aqueous NaHCO3. The organic phase was separated, dried over Mg SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 25-50% EtOAc:hexanes to give the title compound as an amorphous solid (1.5 g, TLC Rf=0.5, 1:1 EtOAc:hexanes; HPLC RT=7.17 min, method A).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.C(OCC)C>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.0 g (29.4 mmol) of [4-(trifluoromethyl)phenyl]acetic acid were dissolved in 67.1 ml of toluene and 46.2 ml of methanol, and 26.5 ml (52.9 mmol) of a 2 M solution of trimethylsilyldiazomethane in diethyl ether were added dropwise with cooling. After the addition had ended, cooling was removed and the mixture was stirred at RT for another 1 h, after which excess trimethylsilyldiazomethane was destroyed by addition of 2.0 ml of acetic acid. The reaction mixture was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 80:1). This gave 4.33 g of the target compound (67.6% of theory).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])=[N+]=[N-].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N:23]=[C:24]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[NH:23][C:24]1[O:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:1]=1
Reactant: [N-]=[N+]=NCC(=O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2cccnc2)o1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 3-azidoacetylpyridine (800 mg, 4.94 mmol) in dioxane 10 mL was added 2-methyl-5-nitrophenyl isocyanate (880 mg, 4.94 mmol) (commercially available), and triphenylphosphine (1.29 g, 4.94 mmol). The reaction mixture was placed in an oil bath preheated to 100° C. and stirred for 30 min. After evaporation of the solvent under reduced pressure the residue was partitioned between 4N HCl (20 mL) and dichloromethane (20 mL). The aqueous layer was neutralized with 15% NaOH and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, concentrated. The residue was silica gel column chromatographed (dichloromethane/ethanol:97/3) to give the title compound as yellow micro crystals (1.14 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[I:13]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (12.31 g) was dissolved in dichloromethane (100 mL) and methanol (12 mL), and N-iodosuccinimide (15.59 g) and trifluoromethanesulfonic acid (2 mL) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was'washed with water (100 mL) to obtain the title compound (20.52 g) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[CH3:20].O>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[C:5]([C:11]#[N:12])=[CH:6]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(Br)ccc32)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-3-cyanoindole (2.0 g) in N,N-dimethylformamide (50 mL) were added cesium carbonate (7.4 g) and 4-fluorobenzoic acid ethyl ester (3.0 g), and this mixture was stirred at 80° C. for 48 hours. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (1.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C@@H:30]3[CH2:32][C@H:31]3[C:33]([O:35]CC)=[O:34])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:38][O:39][CH2:40][C@@H:41]([NH:48][C:49]([NH2:51])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:38][O:39][CH2:40][C@@H:41]([NH:48][C:49](=[O:50])[NH:51][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C@@H:30]3[CH2:32][C@H:31]3[C:33]([OH:35])=[O:34])=[N:9][N:10]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Product: COC[C@@H](NC(=O)Nc1cc2c(cn1)c([C@@H]1C[C@H]1C(=O)O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
In a manner similar to that described in Example 30 (Step 1), trans-ethyl 2-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylate was reacted with (S)-1-(2-methoxy-1-phenylethyl)urea (BrettPhos precatalyst, KOtBu, dioxane, 80° C.) to provide trans-2-(6-(3-((S)-2-methoxy-1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylic acid. MS ESI calc'd. for C39H35N5O4[M+1]+ 638, found 638.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([OH:18])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[N:19]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(O)C>CC(C)=O>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1c(NC(C)=O)c(O)c(OC)c2occc12
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1c(NC(C)=O)c(OCCN2CCCCC2)c(OC)c2occc12

Procedure:
A mixture of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-hydroxy benzofuran, 22.2 g (0.15 mole) of 2-piperidino chlorethane and 41.6 g (0.3 mole) of potassium carbonate in 250 ml of acetone was brought to reflux for 2 hours. Then it was filtered, the solvent evaporated, the residue obtained was taken up again in acetone and 20 ml of 7 N hydrochloric ethanol were added. It was filtered and recrystallized in 400 ml of propanol.
Reaction SMILES: CS[C:3]1[N:8]=[C:7](/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH:6]=[CH:5][N:4]=1.O[O:18][S:19]([O-:21])=O.[K+].[CH2:23]1COCC1>O>[CH3:23][S:19]([C:3]1[N:8]=[C:7](/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH:6]=[CH:5][N:4]=1)(=[O:21])=[O:18]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) (3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was treated with a solution of oxone (25.8 g, 41.5 mmol, 3.0 equiv.) in water (175 mL). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was filtered and washed with water (20 mL) and diethyl ether (20 mL) to afford (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6) as a solid (2.48 g, 3.94 g theoretical, 63%). LC-MS m/z 286 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:27])=[CH:22][CH:21]=1.C(OC(C)=O)C.O>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5]3)(=[O:35])=[O:36])=[CH:30][CH:29]=2)=[CH:38][CH:39]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12

Procedure:
Stir a mixture of 3-isopropyl indole in dry DMF (20 ml) under N2 add potassium t-butoxide 1.0 M (1.2 ml, 1.2 mmol) dropwise. Stir the resulting solution for 30 minutes at ambient temperature. Add 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.360 g, 1.1 mmol) portionwise and stir the resulting mixture overnight. Pour the reaction mixture into a mixture of EtOAc—H2O. Separate the EtOAc layer, extract with H2O wash with brine and dry (MgSO4). Filter and evaporate to give the crude product. Chromatograph on the ISCO eluting with hexane-EtOAc to give a white solid (0.150 g). Mass spectrum (m/e) (M+H) 451.1492; found 451.1488.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1>O1CCCC1>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][C:8](=[O:12])[C:9]#[C:10][CH3:11])[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: CCCC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and butyryl chloride (0.380 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. The residue was washed with boiling methanol and dried in vacuo to give 0.773 g of brown powder; mp 276-277° C.(dec).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:33][C:29]1[CH:28]=[C:27]([NH:26][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoic acid (1.0 g, 2.85 mmol) in DMF (20 mL) was added 3-aminophenol (0.31 g, 2.85 mmol), HBTU (1.1 g, 2.85 mmol), DIEA (2 mL, 11.4 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (100 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then the resulting solution was used directly for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:24]=[C:13]3[C:14]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.O>[CH3:32][S:33]([N:21]1[CH2:20][CH:19]=[C:18]([C:14]2[C:13]3[N:12]([N:11]=[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:24]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:22]1)(=[O:35])=[O:34]
Reactant: COc1ccc(Nc2nc3c(C4=CCNCC4)cccn3n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Nc2nc3c(C4=CCN(S(C)(=O)=O)CC4)cccn3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-methoxy-phenyl)-[8-(1,2,3,6-tetrahydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine (47.0 mg, 0.146 mmol) and triethylamine (31.0 uL, 0.222 mmol) in dichloromethane (2 mL) was added dropwise methanesulfonyl chloride (14.0 L, 0.181 mmol). The mixture was stirred at room temperature for 1 hour then diluted with dichloromethane (20 mL) and water (20 mL). The organic was washed with water and saturated aqueous sodium bicarbonate (10 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purfied via chromatography using amine modified silica gel column (4.7 g) using 5%→100% ethyl acetate:hexane solvent gradient. The title compound, [8-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine, was isolated as a yellow solid (0.037 g, 63%). MP=194-198° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.33 (dd, J=6.6, 0.9 Hz, 1H), 7.52-7.47 (m, 2H), 7.32 (dd, J=7.5, 0.8 Hz, 1H), 7.29-7.25 (m, 1H), 6.94-6.89 (m, 2H), 6.86 (dd, J=7.5, 6.8 Hz, 1H), 6.73 (s, 1H), 4.10-4.06 (m, 2H), 3.81 (s, 3H), 3.57 (t, J=5.7 Hz, 2H), 2.87 (s, 3H), 2.84-2.78 (m, 2H). MS=400 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][N:5]=1)[CH3:2].C(OC([N:20]1[CH2:25][CH2:24][O:23][C@H:22]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=2[Cl:33])[CH2:21]1)=O)(C)(C)C>>[ClH:33].[Cl:33][C:27]1[CH:28]=[C:29]([NH:32][C:10](=[O:12])[C:8]2[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=2)[CH:30]=[CH:31][C:26]=1[C@H:22]1[O:23][CH2:24][CH2:25][NH:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2Cl)C1
Reactant: CCOc1cc(C(=O)O)ccn1
Product: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Product: Cl

Procedure:
In analogy to Example 83, step a) using 2-ethoxy-4-pyridinecarboxylic acid (CAS 91940-86-2) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (+)-(R)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. Light yellow foam. MS (ISP): 362.0 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].O>C1COCC1>[OH:12][CH:9]1[CH2:10][C:11]2[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc2c1CC(O)CC2
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (30.0 mg, 0.18 mmol) and pyridine (21.8 mg, 0.28 mmol) in 1.0 mL THF was added phenyl chloroformate (30.2 mg, 0.19 mmol), and the mixture was stirred for 1 hour at room temperature. To the product mixture was added water and extracted with ethylacetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was triturated with ethylacetate and hexane to afford phenyl (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (25.2 mg, 48% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([OH:28])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([O:28][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH:18]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step i) and the product from example 35 step ii).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[C:11]([NH2:15])=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[CH2:1]([N:4]1[C:10]2[C:11]([NH:15][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCNC(=O)c2cccc(N)c21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCN1CCNC(=O)c2cccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)c21
Temperature: 120 °C
Yield: 4.7 %

Procedure:
1-Allyl-9-amino-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (68 mg, 0.31 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (102 mg, 0.34 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (85 μL) was added, and the resulting mixture was heated to 120° C. in the microwave for 50 min. The resulting solution was diluted with CH2Cl2, washed with NaHCO3, dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 2-[2-(1-Allyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (7 mg, 3%). mp 186° C. (dec); LCMS: m/z=478.28 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 1H), 8.02 (s, 1H), 7.73 (m, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 6.88 (m, 1H), 5.86 (m, 1H), 5.24 (m, 2H), 4.20 (m, 2H), 3.41 (m, 6H), 2.96 (d, J=4.5 Hz, 3H).
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Using General Procedure I; a solution of methyl [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (83%) of the title compound as a pale-orange solid.
Reaction SMILES: C(OC([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48](CN)[CH:47]=1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:8][CH2:39][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:38])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: NCc1cccnc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)NCc3cccnc3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (187 mg) described in Example 769 and C-pyridin-3-yl-methylamine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (111 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:38](=[O:39])[CH2:37][C:32]2[NH:31][C:30]3[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=3[S:34](=[O:35])(=[O:36])[N:33]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (100.6 mg, 0.345 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (U.S. Pat. No. 7,939,524 B2) (120.8 mg, 0.362 mmol), 4-dimethylaminopyridine (10.6 mg, 0.086 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (70.9 mg, 0.362 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and dried under high vacuum to afford the crude (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester as a faintly yellow oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C27H31FN4O7S2 (M+H+) 607.17. found 607.2.