Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([NH:5][C:6]1[C:11](=[O:12])[NH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1)(=O)C>C(O)C>[NH2:5][C:6]1[C:11](=[O:12])[NH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1
Reactant: CCOC(=O)c1cc(NC(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(=O)[nH]c1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride gas is bubbled into a solution of diethyl 5-acetamido-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (5.2 g, 0.018 mol) dissolved in absolute ethanol (400 mL) until the solution is saturated at 20° C. The reaction is stirred at room temperature overnight and is then concentrated in vacuo. The resulting residue is dissolved in water, neutralized with solid sodium bicarbonate, and extracted into methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate. filtered and concentrated in vacuo to give diethyl 5-amino-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as a yellow solid in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[N:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.C([O-])=O.[NH4+]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[N:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccncc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccncc1-c1cccc(N)c1
Reaction time: 2 h

Procedure:
Into an RBF was placed methyl 3-(3-nitrophenyl)isonicotinate (1.85 g, 7.16 mmol) and to this was added methanol (50 ml), ammonium formate (6.0 g, 35.8 mmol) and 5 wt % Pd/C (Degussa type). No initial exotherm was noticed (to the touch) and no bubbling or gas evolution was observed. After 2 h, some SM was observed to be undissolved and THF (25 ml) was added to aid in solubility. The reaction was slow at room temperature. The reaction mixture was then placed on the Buchi hydrogenator overnight. The mixture was then filtered through a pad of Celite and washed with ethyl acetate. This solution was washed with water, separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The orange oil was purified by silica gel flash chromatography using 30% ethyl acetate/Hexanes as eluent to yield 1.15 g (71% th) of an orange oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:42]1([O:51]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN1CCCC1=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:42][OH:51])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(propylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 9) (66 mg, 0.18 mmol) and N,N-diisopropylethylamine (31 μl, 0.18 mmol) in N-methyl-2-pyrrolidinone (3 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (102 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. N,N-diisopropylethylamine (93 μl, 0.54 mmol) was then added, followed by hydroxylamine hydrochloride (37.5 mg, 0.54 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and pH 7 aqueous buffer. The combined organic layers were washed sequentially with aqueous citric acid solution (5% w/v) and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10) gradually changing to dichloromethane:ethyl acetate (0:100) then to dichloromethane:methanol (95:5) to afford the title compound as an oil (31 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: BrCCOC1CCCCO1
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCCOC2CCCCO2)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.69 g, 2.34 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.41 mL, 9.34 mmol) and K2CO3 (1.61 g, 11.68 mmol) in acetone (20 mL) was refluxed overnight and cooled. The solution was filtered, dried with silica gel powder (10 g). 20% Ethyl acetate in hexanes (1 L) and 30% ethyl acetate in hexanes (1 L) were used to run flash chromatography. The title compound was obtained (265.3 mg, 27%). MS (APCI) m/z 424 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]=1[C:24](Cl)=[O:25]>>[CH2:1]([N:5]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[CH:8]=1)[C:24]([C:23]1[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[O:20][C:19]=1[CH3:18])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1oc2ccccc2c1C(=O)Cl
Reactant: CCCCNCc1ccc2cc(O)ccc2c1
Product: CCCCN(Cc1ccc2cc(O)ccc2c1)C(=O)c1c(C)oc2ccccc12
Yield: 47 %

Procedure:
Prepared in the same manner as described in step 4 of Example 48 and replacing 6-(benzylamino-methyl)-naphthalen-2-ol with 6-butylaminomethyl-naphthalen-2-ol, prepared in step 3 of Example 51, and replacing 2-butyl-benzofuran-3-carbonyl chloride with 2-methy-benzofuran-3-carbonyl chloride, prepared in step 2 of Example 20. Purification of the crude product on 300 g silica gel (230-400 mesh) using 25%-33% ethyl acetate in hexane as the eluent gave 2-methyl-benzofuran-3-carboxylic acid butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide (1.03 g, 47%) as a tan solid, mp 126-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>O1CCOCC1>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:13]2[N:12]=[C:11]([N:6]3[C:7]4[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)[CH:4]=[CH:5]3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CS(=O)c1nccc(-n2ccc3c(Br)cccc32)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(Br)cccc43)n2)CC1
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 88.6 %

Procedure:
A mixture of 4-bromo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indole (4.98 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (5.07 g) in 1,4-dioxane (100 mL) was stirred at 110° C. under N2 for 5.5 h. The solvent was removed in vacuo to provide an oil, which solidified at RT. The product was flash chromatographed on silica, eluting with hexanes/EtOAc (7:3 to 6:4) to provide 4-[4-(4-bromoindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (5.82 g, 89%) as a white powder.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccccc2C=O)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(COc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of sodium chlorite (1.37 g; 15.10 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.19 g; 9.89 mmol; 3.6 eq.) in water (8 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.7 mL) and 3-(2-formyl-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (800 mg; 2.75 mmol; 1 eq.) in 1,4-dioxane (8 mL) and the resulting mixture was stirred at room temperature for 1 hour. The 1,4-dioxane was evaporated in vacuo, water was added and the pH made acidic with 1M HCl. The precipitate was filtered off to afford the title compound (827 mg, 98%) as a white solid. HPLC (max plot) 100%; Rt 3.58 min. UPLC/MS: (MS−) 306.4 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[CH:14]=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:14][C:13]2[CH:16]=[C:9]([C:3]3([C:1]#[N:2])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C2(C#N)CCOCC2)cc1C=O
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C2(C#N)CCOCC2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 89 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C(O)(=O)C.O.[H][H]>O1CCOCC1.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(N2CCC(N=[N+]=[N-])CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1

Procedure:
To a solution of ethyl 4-(4-azidopiperidin-1-yl)benzoate (7.62 g, 27.8 mmol) in dioxane (190 mL) was added acetic acid (27 mL) and water (54 mL). Then, 10% Pd/C (0.750 g) was added and the mixture was hydrogenated under 1 atmosphere of hydrogen for 5 hours. The mixture was filtered through Celite, concentrated, and 0.5 M HCl (500 mL) was added. The solution was washed with ethyl acetate (2×300 mL) and the aqueous phase basified with ammonium hydroxide, to pH 12. The aqueous phase was saturated with sodium chloride, extracted with CH2Cl2 (2×300 mL), dried over anhydrous MgSO4, filtered, and concentrated, to afford ethyl 4-(4-aminopiperidin-1-yl)benzoate.
Reaction SMILES: [CH3:1][C:2]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])([CH3:6])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.C(Cl)Cl.[Br:25]N1C(=O)CCC1=O>>[Br:25][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:6]
Reactant: CC[Si](CC)(CC)OC(C)(C)C(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)C(=O)CBr
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a stirred solution of 13 (2.40 g; 10.4 mmol) and triethylamine (2.92 ml; 2.12 g; 21.0 mmol) in methylene dichloride (50 ml) triethylsilyl trifluoromethanesulfonate (2.37 ml; 2.75 g; 10.4 mmol) was added dropwise at 0° C. After 15 min. N-bromosuccinimide (2.05 g; 11.5 mmol) was added and a cooling bath was removed. After 30 min. saturated aqueous solution of NH4Cl (10 ml) and water (50 ml) was added and the mixture was extracted with methylene dichloride (3×100 ml). Organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane—5% ethyl acetate/hexane) to give 1.55 g (5.25 mmol; 50% yield) of 14. 1H NMR (400 MHz, CDCl3) δ 0.64 (6H, q, J=7.9 Hz), 0.97 (9H, t, J=7.9 Hz), 1.41 (6H, s), 4.44 (2H, s); 13C NMR (101 MHz, CDCl3) δ 6.5, 7.0, 27.8, 33.6, 80.4, 206.2; MS (EI) m/z 294 and 296 ([M−Et]+, 24 and 23), 187 (45), 173 (100); exact mass calculated for C9H18O2BrSi ([M−Et]+) 265.0254. found 265.0247.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][C:14]([CH3:18])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:36][C:37]([F:48])([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:38][C:37]([F:48])([F:47])[F:36])[C:14]([CH3:18])=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-4A-1a, 1.86 g, 5.0 mmol) in anhydrous THF (30 ml) at room temperature was added lithium hexamethyidisilazide (7.5 ml, 7.5 mmol). A reddish solution was formed. Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (2,2 ml, 15 mmol) was subsequently added in one portion. The reaction mixture was stirred at 60° C. for 1.5 h, quenched with water, and concentrated under vacuum. MeOH was added to the residue to give a slurry which was then cooled to 0° C. A yellowish solid was formed and collected by filtration to give the desired product 4A-1 (1.63 g, 72%): MS (m/z) 453.1 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 1H), 7.46-7.40 (m, 2H), 7.39-7.32 (m, 2H), 7.31-7.28 (m, 2H), 5.00-4.80 (br m, 2H), 2.87 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=1.CS(O[CH2:26][C@@H:27]([NH:29]C(OC(C)(C)C)=O)[CH3:28])(=O)=O>CN(C)C=O.O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:26][C@@H:27]([NH2:29])[CH3:28])=[C:10]([CH:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(c1cc(F)ccc1O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1cc(F)ccc1OC[C@H](C)N)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (28.6 g, 87.8 mmol) was added to a solution of crude 4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenol (C44) (6.00 g, 28.8 mmol) in N,N-dimethylformamide (60 mL). After addition of (2S)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (P12) (7.5 g, 29.6 mmol), the reaction mixture was heated in a 60° C. oil bath for 30 minutes, then treated with additional P12 (7.5 g, 29.6 mmol) and heated for 18 hours. At this point, the reaction mixture was allowed to cool to room temperature, diluted with water (500 mL), and extracted with diethyl ether (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material (11.23 g) was dissolved in dichloromethane (200 mL); trifluoroacetic acid (40 mL) was added, and the reaction mixture was stirred for 1 hour. After removal of solvents in vacuo, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluents: 75% ethyl acetate in heptane, then ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a roughly 1:1 mixture of two diastereomers, as assessed by 1H NMR. Yield: 5.44 g, 20.5 mmol, 71%. LCMS m/z 266.1 (M+1). 1H NMR (400 MHz, CDCl3) δ [1.31 (d, J=6.6 Hz) and 1.32 (d, J=6.6 Hz), total 3H], 1.41 (d, J=7.2 Hz, 3H), 3.50-3.59 (m, 1H), 3.82-4.22 (m, 3H), 6.79-6.84 (m, 1H), 6.92-6.98 (m, 1H), 7.05-7.11 (m, 1H). Also obtained was material enriched in the higher Rf diastereomer (1.10 g, 4.15 mmol, 14%) and material enriched in the lower Rf diastereomer (324 mg, 1.22 mmol, 4%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([OH:14])(=O)=[O:12])[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([Cl:16])(=[O:14])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1cccc2cccnc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccc2cccnc12
Temperature: 140 °C

Procedure:
Equal quantities by weight of 8-quinolinesulfonic acid and phosphorous pentachloride were ground together in a mortar. This mixture was then refluxed at approximately 140° C. for 3 hours after which work-up of the reaction mixture gave 8-quinolinesulfonyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])(=[O:24])=[O:23])=[O:20])=[CH:17][C:16]=1[O:34][CH3:35])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:49][C@H:50]([CH2:53][C:54]([F:57])([F:56])[F:55])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:35][O:34][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:2])[NH:52][CH2:51][C@H:50]([CH3:49])[CH2:53][C:54]([F:57])([F:56])[F:55])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])(=[O:24])=[O:23])=[O:20]
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](CN)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a mixture of 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (103.5 g), 4-dimethylaminopyridine (112.4 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (51.8 g) in tetrahydrofuran (distilled from sodium benzophenone ketyl) (2.0 L), which had been stirred for 2 hours, was added (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (42.6 g); and the reaction mixture was stirred overnight (about 18 hours, incomplete reaction) then heated to reflux for two hours (complete reaction). The cooled reaction mixture was diluted with ethyl acetate (2 L) washed with 1N hydrochloric acid (twice) and brine, dried (MgSO4) and evaporated. The residue (138.6 g) was combined with impure product from similar procedures (28.0 g) and purified by flash chromatography, eluting with methylene chloride:ethyl acetate (sequentially, 1:0, 9:1 and 3:1) to afford a solid which was triturated twice with ether to give the crude title compound (135.2 g) which was recrystallized from ethanol (1.2 L) and acetone (0.3 L) (concentrated by boiling to about 0.9 L and refrigerated) and dried under vacuum to provide the title compound (117.1 g, 65% recovery) as a white crystalline solid; mp 141.5°-143.5° C.; NMR (300 MHz, DMSO-d 6): 1.01 (d, 3H, CH3), 2.0-2.2 (m, 2H, CF3CH2), 2.3-2.5 (m, 1H, CHCH3), 2.61 (s, 3H, ARCH3), 3.23 (br t, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.92 (s, 3H, OCH3), 4.07 (s, ArCH2Ar'), 7.13 (s, 1H), 7.17 (d, 2H), 7.38-7.69 (m, 6H), 7.72 (d, 1H), 8.05 (d, 1H), 8.11 (s, 1H), 8.46 (br t, 1H, NHCO).
Reaction SMILES: O.[Na].[CH3:3][CH:4]([C:7](=O)[CH3:8])[CH:5]=O.[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:7]([CH3:8])=[C:4]([CH3:5])[CH:3]=1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(C)C=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C#N)c(=O)[nH]c1C
Temperature: 127 °C
Reaction time: 21 h
Yield: 66.4 %

Procedure:
Water was added to 2-methyl-3-oxobutanal sodium salt (1-013-01) (34.73 g), and to the reaction mixture was added 2-cyanoacetamide (23.91 g) and 1.76 mol/L piperidinium acetate (119.4 mL), and the reaction mixture was stirred under reflux in an oil bath at 127° C. After 21 h, to the reaction mixture was added gradually dropwise acetic acid (42.7 mL) at 65° C. as internal temperature for 15 min. After the stirring was continued until internal temperature became to 24° C., the resulting crystal was filtered, and washed with water to give 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (27.76 g, 65.9%, m.p. 258-263° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[C:10]([CH3:17])[CH:9]=2)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([CH3:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(C)cc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
A solution of 0.13 g (0.56 mmol) 5-methoxy-6-methyl-1H-indole-2-carboxylic acid ethyl ester in 3 mL dichloromethane was cooled to −78° C. 1.11 mL (1.1 mmol, 1 M solution in dichloromethane) boron tribromide were added and the cooling bath was removed. After stirring 2 h at room temperature, the solution was poured into 10% aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of n-heptane: ethyl acetate (100:0 to 70:30 v/v) as eluant, to afford 53 mg (43%) of the title compound as a light-yellow solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 2 equivalents of 4-(1-pyrrolidinyl-methyl)-aniline, melting point 45-50° C. in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.