Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:17]=[C:10]2[C:11]([O:13]C(=O)[NH:15][C:9]2=[CH:8][CH:7]=1)=O)(=[O:5])=[O:4].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:11](=[O:13])[C:10]2[C:9](=[CH:8][CH:7]=[C:6]([S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:17]=2)[NH2:15])[CH2:21][CH2:20]1
Reactant: CNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN1CCNCC1
Product: CNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-methylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-methylsulfamoyl)-anthranilic acid (4-methyl)-piperazide in the form of an oil (melting point of the methanesulfonate: 120°-123°).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([CH3:18])[C:11]=3[N:10]=[C:9]2[O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[CH3:29][N:30](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:18][N:12]1[CH:13]=[N:14][C:15]2[C:16](=[O:17])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]#[N:30])=[CH:3][CH:4]=3)[C:9]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[C:21]=3[F:28])=[N:10][C:11]1=2
Reactant: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Oc3ccc(F)c(F)c3F)nc21
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cn1cnc2c(=O)n(-c3ccc(C#N)cc3)c(Oc3ccc(F)c(F)c3F)nc21
Temperature: 120 °C

Procedure:
1-(4-Bromophenyl)-9-methyl-2-(2,3,4-trifluorophenoxy)-1,9-dihydro-6H-purin-6-one (68 mg, 0.1507 mmol), Zn(CN)2 (10.6 mg, 0.0904 mmol), Pd2(dba)3 (4.1 mg, 0.0045 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (5.0 mg, 0.0090 mmol) are added to DMF (1.2 mL) and H2O (0.012 mL). The mixture is purged with N2 for 3 min and then heated at 120° C. for 18 h. The mixture is passed through celite. Water (30 mL) is added and the resulting mixture is extracted with CH2Cl2 (50 mL×4). After drying the CH2Cl2 over MgSO4, the solvent is removed in vacuo. The crude product is purified by column chromatography (MeOH:CH2Cl2=2:98) to afford the title compound as a brown solid. 1H NMR (400 MHz, CDCl3) 7.86 (2H, d, J 8), 7.65 (1H, s), 7.53 (2 h, d, J 8), 6.95 (2H, m), 3.59 (3H, s). MS (M+1): 398.03; RT=1.22 min.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][CH3:25])[CH:21]=2)[NH:16]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][CH3:25])[CH:21]=2)[NH:16]1)=[O:4]
Reactant: COc1ccc2c(c1)CC(c1ccccc1N)N2
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(c1ccccc1NC(=O)C(C)(C)C)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylacetyl chloride (2.40 ml) was added dropwise to a solution of 4.68 g 2-(2-aminophenyl)-5-methoxy-2,3-dihydro-1H-indole and 3.00 ml Et3N in 150 ml CH2Cl2 at 0° C. The resulting mixture was stirred at room temperature for two hours and then quenched with water. The organic extract was washed with 7.5% NaHCO3 and sat. NaCl solution, dried (MgSO4), and concentrated to yield 5.59 g crystalline solid. Recrystallization from MeOH/water yielded 2.38 g solid, m.p. 117°-119° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)(=[O:9])=[O:8].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl.Cl.[Cl:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH:71]=[C:70]([NH2:72])[CH:69]=[N:68]2)=[CH:64][CH:63]=1.CN(C)C(=O)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH:71]=[C:70]([NH:72][C:13]3[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)(=[O:9])=[O:8])=[CH:15][CH:14]=3)[CH:69]=[N:68]2)=[CH:64][CH:63]=1
Reactant: Nc1cnn(Cc2ccc(Cl)cc2)c1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2cnn(Cc3ccc(Cl)cc3)c2)nc1
Temperature: 120 °C
Yield: 35.8 %

Procedure:
Into a Vial was added the 6-Chloro-pyridine-3-sulfonic thiazol-2-ylamide (82 mg, 0.00030 mol), 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (21 mg, 0.000036 mol), Tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.000012 mol), [B] 1-(4-chlorobenzyl)-1H-pyrazol-4-amine dihydrochloride (1.0E2 mg, 0.00036 mol) and N,N-Dimethylacetamide (4.0 mL, 0.043 mol). The mixture was sparged with argon for ˜5 min. Sodium tert-butoxide (140 mg, 0.0015 mol) was added and the reaction mixture was heated at 120° C. for 30 min in microwave. The reaction mixture was filtered through celite. The filtrate was diluted with Ethyl acetate and washed with 0.1 N HCl solution. The aqueous phase was neutralized with 1.0 N NaOH solution, extracted with Ethyl acetate. The combined organic phase was washed with water (3×) and brine, dried over Na2SO4, filtered and was concentrated to give the crude product that was purified on Gilson (Prep LC, reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS and combined accordingly. LC/MS showed the product was only ˜90% pure. The combined product solution was concentrated to remove the acetonitrile, neutralized with 1.0 N NaOH solution and then extracted with Ethyl acetate (3×). The combined organic layers were dried over sodium sulfate, filtered and was concentrated to give the product as free base, which was purified again on ISCO (0% to 100% Ethyl acetate in DCM). 48 mg of the product was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:14]2)[C:3]=1[C:4]#[N:5].[NH4+].[Cl-]>[Fe].CCO>[NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([F:22])([F:20])[F:21])[CH2:14]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc([N+](=O)[O-])c1N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc(N)c1N
Temperature: 90 °C

Procedure:
A mixture of 2-amino-3-nitro-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (200 mg, 0.64 mmol), Fe (178 mg, 3.18 mmol), aqueous NH4Cl (5 mL) and EtOH (5 mL) was heated under Ar at 90° C. for 2 h. The mixture was thereafter basicified to pH ˜9-10 and filtered through celite and the celite pad was washed with EtOH and EtOAc. The organic layer was concentrated and the residue was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O to give the sub-title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC#N>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1
Solvent: CC#N
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 82 °C
Reaction time: 50 h
Yield: 65.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 4-fluorobenzonitrile (24.9 g) in CH3CN (500 mL) was added morpholine (53.8 g), and the mixture was stirred at 82° C. for 50 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=10/1→4/1) to give 4-morpholin-4-yl-benzonitrile (25.3 g, 65%).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:22]([O:24]CC)=[O:23])=[C:18]([CH2:20][CH3:21])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O1CCOCC1.ClCCl>[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH2:20][CH3:21])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1c(CC)nc2c(OCC3CCCCC3)cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 ml of 2N aqueous sodium hydroxide solution was added to a solution of 26 mg (0.082 mmol) of ethyl 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylate in 1.15 ml of dioxane, and the mixture was stirred at room temperature overnight. The mixture was then acidified with 1.5 ml of 6N aqueous hydrochloric acid, diluted with 5 ml of dichloromethane and filtered over an Extrelut® cartridge. The cartridge was washed with 30 ml of dichloromethane, the filtrate was concentrated and the residue formed was dried under high vacuum. This gave 24 mg (97% of theory) of 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid as a crude product which was used as such for the next reaction.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:19])[CH:13]3[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4].CN(C)C=O.[C:25]([O-:30])(=[O:29])[C:26]([CH3:28])=[CH2:27].[Na+].[I-].[Na+]>O>[C:25]([O:30][CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:19])[CH:13]3[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4])(=[O:29])[C:26]([CH3:28])=[CH2:27]
Reactant: C=C(C)C(=O)[O-]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A mixture of 28.9 g of the 2-chloroacetic ester obtained in Example 1-1-1 and 40 g of dimethylformamide was added dropwise to a mixture of 12.4 g of sodium methacrylate, 3.0 g of sodium iodide and 50 g of dimethylformamide at a temperature below 30° C. The mixture was stirred at the temperature for 8 hours. 100 ml of water was added below 30° C. This was followed by ordinary post-treatment and recrystallization from toluene and n-hexane, obtaining 29.1 g of the target compound (yield 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]CC)=[O:16])[C:9]2=[O:20])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:20])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 90C (0.40 g, 1.07 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.21 g, 8.57 mmol) in water (5 mL) was added and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and then concentrated to give the title compound. MS (DCI) m/z 346 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:13]=1)[CH:9]=O.[NH2:27][C:28]1[C:33]([NH2:34])=[CH:32][C:31]([Br:35])=[CH:30][N:29]=1>>[Br:35][C:31]1[CH:32]=[C:33]2[NH:34][C:9]([C:8]3[CH:11]=[C:12]([O:14][CH2:15][C:16]4[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:13]=[C:6]([O:5][CH2:4][C:3]4[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=4[F:1])[CH:7]=3)=[N:27][C:28]2=[N:29][CH:30]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: Cc1cccnc1COc1cc(C=O)cc(OCc2ccccc2F)c1
Product: Cc1cccnc1COc1cc(OCc2ccccc2F)cc(-c2nc3ncc(Br)cc3[nH]2)c1

Procedure:
The final product (217) was obtained using the procedure described for Example 191 except that 3-(2-fluorobenzyloxy)-5-((3-methylpyridin-2-yl)methoxy)benzaldehyde (217c) and 2,3-diamino-5-bromopyridine were used. 1H NMR (400 MHz, 90% DMSO-d6; 10% CDCl3) δ ppm 8.46 (br s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.78 (m, 1H), 7.52 (s, 1H), 7.48 (m, 1H), 7.45 (m, 2H), 7.40 (m, 2H), 7.16 (t, 1H, J=8.2 Hz), 7.08 (t, 1H, J=8.2 Hz), 6.79 (s, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 2.31 (s, 3H). Calc'd for C26H20BrFN4O2; m/z (M+2H+)=521; found 521.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)[CH2:29][CH2:30]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-pyridin-2-yl-piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=449.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16]CN(C(C)C)C(C)C.CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][N:11]([CH3:16])[CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1NCC2CC21c1ccc(Cl)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CI
Product: CC1N(C)CC2CC21c1ccc(Cl)c(Cl)c1

Procedure:
To a dried, 5 mL round-bottomed flask was added (±)-1-(3,4-dichlorophenyl)-(R/S)-2-methyl-3-aza-bicyclo[3.1.0]hexane, Hunig's Base, and DMF under Ar (g) with stirring. Methyl iodide was added drop wise with stirring over 5 min and the resulting solution stirred under ambient temperature overnight. The solution was concentrated under reduced pressure and purified after drying. The residue was purified by HPLC which failed to remove the impurities. This was further purified on a prep TLC plate eluting with 20/1 CHCl3/MeOH (v/v). The desired band was collected, extracted with CHCl3/MeOH, and concentrated after filtration to afford the desired free base. Yield: 0.005 g 15%; LCMS (+)ESI: m/z=256 [MH]+ (100); 258 [MH+2]+; (65); 1H NMR (300 MHz, CDCl3) : 7.33 (d, H, J=12 Hz, ArH), 7.32 (d, 1H, J=2 Hz, ArH), 7.08 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.31 (q, 1H, J=6 Hz, CHNH2), 2.83 (s, 2H, CH2N), 2.32 (s, 3H, NCH3), 1.79 (m, 1H, CH2CH), 1.40 (t(br), 1H, ArCCH2), 0.73 (d, 3H, J=7 Hz, CHCH3), 0.60 (dd, 2H, J=8 Hz, 4 Hz, ArCCH2); 13C NMR (75 MHz, CDCl3) : 131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9, 18.4, 11.6.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH2:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][N:22]=[C:23]=[O:24].O>O1CCCC1>[CH3:21][NH:22][C:23]([NH:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[CH2:4][CH2:5]1)=[O:24]
Reactant: CN=C=O
Reactant: NC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)NC1CCC(=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a stirred mixture of 10 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine hydrochloride in 200 ml of dry tetrahydrofuran (THF) under a nitrogen atmosphere, 76 ml of triethylamine is added dropwise. The mixture is stirred for an additional 5 minutes, and 3 ml of methylisocyanate is added dropwise. The reaction mixture is stirred for 1 hour at room temperature and the solid collected. The filter cake is washed with THF and then with 3 × 50 ml of water. The THF filtrate is concentrated in vacuo to afford some product. The water-insoluble solid is air dried to afford 8.8 g of the title compound melting point 219°-221° C. Recrystallization from about 150 ml of methanol yeilds 7.4 g of the above product, melting point 220°-223° C.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C:29]1([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C:29]1([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)C1(N)CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NC2(C(=O)N(C)C)CCCCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.72 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 75-3 (2.55 mmol, crude form) as starting materials, 0.24 g of the title compound (pale yellow solid) was obtained by a similar method to Step 4-2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][N:5]=[C:4](C#N)[CH:3]=1.IC1C(N)=CC([NH:23][C:24]([CH3:31])([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:25])=NC=1>>[CH3:25][C:24]([NH:23][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([C:8]#[C:9][Si:10]([CH3:11])([CH3:12])[CH3:13])=[CH:6][N:5]=1)([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:31]
Reactant: C[Si](C)(C)C#Cc1cnc(C#N)cc1N
Reactant: CC(C)(C)CC(C)(C)Nc1cc(N)c(I)cn1
Product: CC(C)(C)CC(C)(C)Nc1cc(N)c(C#C[Si](C)(C)C)cn1

Procedure:
The compound was prepared following the procedure same as that of 4-amino-5-[(trimethylsilyl)ethynyl]pyridine-2-carbonitrile starting from 5-iodo-N2-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(N2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (0.8 g) was dissolved in CH2Cl2 (50 mL), N-methyl-4-piperidone (1 g) was added to the mixture, followed by 2.5 g NaBH(OAc)3 and glacial AcOH (1 mL). The mixture was stirred at RT overnight. Saturated NaHCO3 solution (50 ml) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 EtOAc:MeOH to afford the title compound as an orange oil. MS:290 (M+1). Calc'd. for C16H23N3O2—289.37.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15]I>C1COCC1.CCOCC>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:15])[CH:5]=1
Reactant: CC(C)(CO)c1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCC(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a suspension of NaH (0.22 g, 9.00 mmol, 95%) in THF (30 mL) was added dropwise at ambient temperature the solution of 2-(3-bromo-phenyl)-2-methyl-propan-1-ol (1.7 g, 7.46 mmol) in THF (10 mL). After 10 min MeI (0.8 mL, 15 mmol) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ether and washed twice with water. Organic layer was separated and concentrated to obtain the desired product (1.64 g, 91%) as a clear oil. NMR (DMSO-d6): 7.52 (m, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 3.38 (s, 2H), 3.20 (s, 3H), 1.12 (s, 6H). MS (DCI): 260 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)Cl.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>CN(C=O)C.C(Cl)Cl>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (10.0 g; 54.0 mmol), SOCl2 (20.0 mL; 270 mmol) and DMF (2-3 drops) was refluxed for 4 h, concentrated and the residue was dissolved in DCM (25 mL) and slowly added to a mixture of 4-bromoaniline (9.3 g; 54.1 mmol) and TEA (11.4 mL; 81.0 mmol) in DCM (50 mL) at 0° C. The mixture was stirred for 1 h at rt, concentrated, EtOAc was added and the organic phase was washed with aqueous NaHCO3, aqueous HCl (1 M), dried over Na2SO4, filtered and concentrated to give the sub-title compound. Yield: 18.0 g (98%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:22])=[C:12]([C:17]([O:19]CC)=[O:18])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:23][CH3:24])=[C:5]([CH3:25])[O:4][N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:22])=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:23][CH3:24])=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(O)c(C(=O)O)cnc2cc1-c1c(C)noc1C
Yield: 94 %

Procedure:
Ethyl 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylate (for a preparation see Intermediate 4) (28.4 g, 83 mmol) was suspended in a mixture of ethanol (200 ml) and NaOH (2M, 124 ml, 249 mmol) and the mixture was heated at reflux overnight, then evaporated to around 100 ml volume and the resulting solution washed with MTBE (100 ml). The aqueous layer was acidified to pH4 with 1M HCl, then the resulting solid collected by filtration and washed with water and dried overnight at 40° C. in the vacuum oven to give 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid (24.5 g, 78 mmol, 94% yield) as pale yellow solid. LCMS Rt 0.76 min, MH+ 315
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:18]=2[CH3:31])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:32]>CO.C(O)C.[C].[Pd]>[ClH:32].[CH2:27]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:17]([C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[C:18]1[CH3:31])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCn1c(C)c(C(=O)NC2CCN(Cc3ccccc3)CC2)c2cc(O)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCCCn1c(C)c(C(=O)NC2CCNCC2)c2cc(O)ccc21
Reaction time: 6 h

Procedure:
To a solution of 9 g of N-(1-benzyl-4-piperidyl)-1-butyl-5-hydroxy-2-methylindole-3-carboxamide in 100 ml of methanol were added 5 g of an 18% hydrochloric acid in ethanol and 4 g of 10% palladium carbon, and the mixture was subjected to catalytic hydrogenation at atmospheric pressure for 6 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was crystallized with ethyl acetate and the resulting crystals were recrystallized from ethanol to give 4 g of 1-butyl-5-hydroxy-2-methyl-N-(4-piperidyl)indole-3-carboxamide hydrochloride, melting at 164°-168° C.