Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:35][I:36]>>[I-:36].[C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=1[CH3:35])[C:5](=[O:27])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1
Product: [I-]
Temperature: 115 °C

Procedure:
A mixture of 0.808 g of product from Example 5 and 5.39 ml of methyl iodide is heated, in a sealed dark tube, at 115° C. for 23 hours. The cooled reaction mixture is concentrated in vacuo and the residue purified by column chromatography (silica gel: 20% methyl alcohol/chloroform) to give 0.63 g of the desired product as cream crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 120 °C
Yield: 80.4 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg) and tripotassium phosphate (651 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (177 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D77) (500 mg) as a brown oil. MS (ES): C23H24ClNO2S requires 413. found 414.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])C1C=CC=CC=1.CS([O:40][C@@H:41](C1C=C2C(C=NN2CC2C=CC(OC)=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.CN1C2C(=CC=CC=2)CC1=O>>[CH3:41][O:40][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:25]2[C:26]3[C:22](=[CH:21][CH:20]=[C:19]([C@H:17]4[C@@:10]5([C:11]6[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:8]([CH3:1])[C:9]5=[O:35])[CH2:18]4)[CH:27]=3)[CH:23]=[N:24]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(Cn2ncc3ccc([C@@H](COS(C)(=O)=O)OS(C)(=O)=O)cc32)cc1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Agent: CN1C(=O)Cc2ccccc21
Product: COc1ccc(Cn2ncc3ccc([C@@H]4C[C@@]45C(=O)N(C)c4ccccc45)cc32)cc1
Yield: 80 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-(4-methoxybenzyl)-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (2.03 g, 4.47 mmol) and 1-methylindolin-2-one (658 mg, 4.47 mmol). Purification using Biotage Isolera (silica gel, 20-50% EtOAc in hexane) yielded the title compound as a yellowish crystalline solid (1.47 g, 80%); 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.13-7.06 (m, 3H), 6.97 (d, J=7.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.3 Hz, 2H), 6.50 (t, J=7.6 Hz, 1H), 5.78 (d, J=7.6 Hz, 1H), 5.58-5.47 (m, 2H), 3.72 (s, 3H), 3.36-3.30 (m, 4H), 2.22-2.19 (m, 1H), 2.16-2.12 (m, 1H); MS ESI 410.2 [M+H]+, calcd for [C26H23N3O2+H]+ 410.19.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[CH:18]=O.[CH3:20][NH2:21].[CH2:22]=[N:23][CH:24](S(C1C=CC(C)=CC=1)(=O)=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:20][N:21]1[C:18]([C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[CH:22]1
Reactant: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CN
Reactant: C=NC(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccccc2)c1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
A mixture of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbaldehyde (129 mg, 0.479 mmol) and MeNH2 (40% aqueous solution, 0.050 mL, 0.575 mmol) in DMF (3.5 mL) was stirred at room temperature for 90 min. To the mixture were added N-methylidene-1-[(4-methylphenyl)sulfonyl]-1-phenylmethanamine (131 mg, 0.479 mmol) and K2CO3 (66.2 mg, 0.479 mmol) at room temperature. The mixture was stirred at room temperature for 27 h. The mixture was diluted with water, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=40/60 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with AcOEt/hexane to yield the title compound (145 mg, 76% yield) as a pale yellow solid: mp 214-216° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.60 (3H, s), 6.74 (1H, d, J=8.0 Hz), 7.15-7.32 (3H, m), 7.45-7.53 (2H, m), 7.71-7.89 (4H, m), 7.91-7.98 (1H, m), 9.04 (1H, d, J=8.0 Hz). Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.50; H, 3.89; N, 14.04.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][CH:15]([NH2:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:24]([CH:15]([CH3:14])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: CC(N)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(CCc1ccccc1)N1Cc2cccc(I)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 1-methyl 3-phenyl-propylamine (0.065 g, 0.4 mmol), and K2CO3 (0.083 g, 0.6 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(1-methyl-3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.098 g, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.32 (d, 3H), 1.94 (m, 2H), 2.54-2.78 (m, 2H), 4.21 (dd, 2H), 4.64 (q, 1H), 7.12-7.24 (m, 6H), 7.41 (d, 1H), 7.88 (d, 1H). GC-MS: m/z 391 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([BH3-])#[N:20].[Na+].O>CO.CC(O)=O>[NH2:20][CH2:17][C:15]1[CH:14]=[CH:13][C:3]([O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:2]([Br:1])[CH:16]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc(CN)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.1 %

Procedure:
t-Butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (0.5 g, 1.59 mmol, 1 eq) was dissolved in MeOH (23 mL) along with HOAc (14 mL) and NH4OAc (6.23 g, 81 mmol; 51 eq). After stirring at room temperature room temperature for 4 h, sodium cyanoborohydride (146 mg; 2.27 mmol, 1.4 eq) was added and the mixture was stirred for an additional 18 h at room temperature. Water (4 mL) was added and the mixture was concentrated in vacuo. The resultant residue was purified by preparative HPLC to afford 91 mg (18.2%) of t-butyl 2-(4-(aminomethyl)-2-bromophenoxy)acetate (6).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C@H:6]1[CH2:10][NH:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH2:14](O)[CH3:15]>>[ClH:3].[CH2:14]([O:12][C:11]([C@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CCO
Product: CCOC(=O)[C@H]1C[C@@H](O)CN1
Product: Cl

Procedure:
3.27 g(27.5 mmol) of thionyl chloride was added dropwise to a suspension of cis-4-hydroxy-D-proline (3.00 g, 2.9 mmol) in ethanol (15 ml) and the mixture was refluxed for 2 hours. The mixture was concentrated, acetone was added to the residue and the solution was cooled on ice. The resultant precipitate was filtered and 4.23 g of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-hydroxypyrrolidine hydrochloride was obtained as colorless needles (94.5%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.[C:34]([C:37]1[O:38][C:39]2[C:45]([CH:46]([O:48][C:49](=[O:51])[CH3:50])[CH3:47])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[C:49]([O:48][CH:46]([C:45]1[C:39]2[O:38][C:37]([C:34](=[O:36])[CH2:35][Br:1])=[CH:41][C:40]=2[CH:42]=[CH:43][CH:44]=1)[CH3:47])(=[O:51])[CH3:50]
Reactant: [Br-]
Reactant: CC(=O)OC(C)c1cccc2cc(C(C)=O)oc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)OC(C)c1cccc2cc(C(=O)CBr)oc12
Reaction time: 6 h
Yield: 69.1 %

Procedure:
25.1 g of trimethylphenylammonium tribromide were added at 20°-25°C to a stirred solution of 16.4 g of 2-acetyl-7-(1'-acetoxyethyl)benzofuran in 250 ml of dry tetrahydrofuran. The resulting solution was stirred for 6 hours in order to complete the precipitation of trimethylphenylammonium monobromide. The mixture was poured into 1000 ml of water to which sodium chloride was added to saturation. The product was extracted with diethyl ether, the combined diethyl ether extracts were washed with water and with brine and dried over anhydrous sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated to dryness. The residual solid was crystallized from diethyl ether to give 8.7 g of 7-(1'-acetoxyethyl)-2-bromoacetylbenzofuran in the form of pale yellow crystals of melting point 86°-88°C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32].O>C1COCC1>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by dissolving 4-Trifluoromethyl-phenylamine (475 mg, 2.95 mmol) in THF (20 ml) at room temperature. To this solution was added Hunig's base (762 mg, 5.86 mmol) and then a solution of the product from Example 172a (600 mg, 2.95 mmol) in THF (10 mL) was added drop wise over 5 minutes. After complete addition the reaction mixture was allowed to stir at room temperature for 1 hr and was poured into water and the title compound collected by filtration (900 mg, 93%).
Reaction SMILES: [NH2:1]/[C:2](=[N:8]\[O:9][C:10]([C@H:12]([CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)/[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C1(C)C(C)=CC=CC=1>[C:17]([O:16][C:14](=[O:15])[CH2:13][C@H:12]([C:10]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=1)[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)/C(N)=N/OC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of tert-Butyl (3R)-3-[({[(Z)-1-amino-2-ethoxy-2-oxoethylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (Preparation 169) (21.0 g, 50.82 mmol) in xylene (400 ml) was heated at 130° C. for 17 hours, then allowed to cool to room temperature. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (5:95) gradually changing to ethyl acetate:pentane (20:80) to afford the title compound as a colourless oil (20.0 g).
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN(C)C=O.[C:9]([N:11]=[C:12](SC)[NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)#[N:10]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:19]=2)=[N:11][C:9]([NH2:10])=[N:3]1
Reactant: CNN
Reactant: CSC(=NC#N)NCCCOc1cccc(CN2CCCC2)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCC2)c1

Procedure:
Methyl hydrazine (6.9 g) and dry dimethylformamide (10.95 g) were heated at reflux in toluene for 1 hr. N'-Cyano-N-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]carbamimidothioic acid, methyl ester (10 g) was then added and the mixture heated at reflux for 5 hr. Evaporation of the solvent gave the title compound as a yellow oil which was converted to the fumarate salt in ethanol. The title compound was regenerated as the free base with aqueous sodium carbonate, and extracted into ethyl acetate. Evaporation of the solvent and trituration of the residue with light petroleum (b.p. 60°-80°) gave the title compound as a white solid (3.4 g) m.p. 95°-95.5°. TLC silica; methanol:0.88 ammonia (80:1) single spot Rf 0.5.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[CH3:23].C(N(CC)C(C)C)(C)C.O.[Cl-].[Na+].O>CS(C)=O>[CH3:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:3][N:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: c1cc2c(cn1)CNCC2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCc2ccncc2C1
Temperature: 115 °C
Yield: 61.6 %

Procedure:
A mixture of commercially available 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (456 mg, 2.2 mmol), 2-fluoro-5-nitrotoluene (512 mg, 3.3 mmol), and N,N-diisopropylethylamine (2.0 mL, 11.4 mmol) in 8.0 mL DMSO was heated at 115° C. for 20 hours. The reaction was added to a H2O/brine mixture, then extracted with EtOAc. The EtOAc portion was washed with a H2O/brine mixture, aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to an oil. An impure sample from a previous reaction (1.0 mmol scale) was combined, and then chromatographed eluting with CHCl3/EtOAc to give the title compound as a yellow solid (365 mg, 42% combined yield). 1H NMR (CDCl3) δ: 8.40-8.43 (m, 2H), 8.05-8.11 (m, 2H), 7.14 (d, J=5.0 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 4.27 (s, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.04 (t, J=5.6 Hz, 2H), 2.42 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][C:30]([OH:32])=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(Cl)CCl>O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:5][O:4][N:3]([CH3:2])[C:30](=[O:32])[CH2:29][CH2:28][CH:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Molecular sieve pellets (4 Å), N,O-dimethylhydroxylamine hydrochloride (227 mg, 3.32 mmol), and DIEA (0.41 mL, 0.30 g, 2.4 mmol) were added to a solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid (500 mg, 1.94 mmol, from Step A) in 1,4-dioxane (10 mL). 4-(Dimethylamino)pyridine (57 mg, 0.47 mmol) and EDC (483 mg, 2.52 mmol) were added and the mixture was stirred for 16 h at rt. The mixture was partitioned between EtOAc (50 mL) and 1 N aq. HCl (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The organic layers were washed with sat'd NaCl (30 mL), dried (Na2SO4), decanted, and evaporated to give 583 mg of N-methoxy-N-methyl-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionamide.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:5])=[O:4].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1.C1N2CCN(CC2)C1>C(#N)C>[CH3:1][N:2]([CH3:19])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:20][C:21]1[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=1)=[O:18])(=[O:14])=[O:15])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)Cc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CS(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of 2.6 g of the product of Example 5, 0.9 g of 2-amino-4,6-dimethoxypyrimidine and a few crystals of DABCO in 15 ml of dry acetonitrile was heated at 50°-55° for 1 hour under a nitrogen atmosphere, then stirred overnight at room temperature. The precipitate was filtered off, washed with acetonitrile and dried to give 2.1 g of 2-[(dimethylamino)sulfonylmethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 172°-176°.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:19][C:20]1[S:21][C:22]([C:26]2[CH:27]=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([Cl:32])=[N:30][CH:31]=2)=[C:23]([CH3:25])[N:24]=1>CC(N(C)C)=O>[Cl:32][C:29]1[N:30]=[CH:31][C:26]([C:22]2[S:21][C:20]([NH:19][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:24][C:23]=2[CH3:25])=[CH:27][C:28]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Reactant: O=C(O)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)c2ccccc2)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
A mixture of benzoic acid (27 mg), diisopropylethylamine (0.053 mL), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (84 mg) and DMA (0.5 mL) was stirred at room temperature under an atmosphere of nitrogen for 5 minutes. N-[5-(2-Amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]methanesulfonamide (32 mg) was added and the mixture was stirred and heated to 80° C. for 30 minutes. The solvent was evaporated and the residue was triturated under water. The resultant gum was purified by HPLC using a Phenomenex ‘Luna’ preparative reversed-phase column (10 microns silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% trifluoroactic acid) and acetonitrile as eluent. There was thus obtained the title compound as a solid (17 mg); NMR Spectrum: (DMSOd6) 2.44 (s, 3H), 3.19 (s, 3H), 7.57 (t, 2H), 7.64-7.69 (m, 1H), 7.95 (s, 1H), 8.12 (d, 2H), 8.42 (s, 1H), 9.91 (s, 1H), 12.87 (s, 1H): Mass Spectrum: M−H− 421.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]#N.[OH-:14].[Na+].C([OH:19])CC>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:19])=[O:14]
Reactant: N#Cc1c(N)ccc2ncccc12
Reactant: [OH-]
Reactant: CCCO
Agent: [Na+]
Product: Nc1ccc2ncccc2c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 6-amino-5-quinolinecarbonitrile (0.99 g, 5.9 mmol, prepared as described in Chem. Pharm. Bull., 1985, 33, 13260-1366) in 1-propanol (50 mL) was treated with 10 mL concentrated NaOH and heated to 100° C. for 18 hours. The mixture was concentrated, diluted with water, and washed twice with diethyl ether. The aqueous phase was acidified to pH 5 with 1M HCl and extracted with ethyl acetate in a continuous extractor. The organic extracts were dried (MgSO4), filtered, and concentrated to provide the desired product (0.55 g). MS (DCI) m/e 206 (M+NH4)+.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].C1(=O)CCCCC1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[C:1]1(=[C:10]([C:8]#[N:9])[C:11]([NH2:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(N)=O
Reactant: Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O=C1CCCCC1
Product: N#CC(C(N)=O)=C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
600 ml of toluene, 200 g of cyanoacetamide, 193 g of cyclohexanone, 15 g of ammonium acetate and 24 g of acetic acid are placed in a 2 litre flask equipped with a mechanical stirrer, thermometer and Dean-Stark trap connected to a condenser, under nitrogen flow. The mixture is heated under reflux, simultaneously separating the water by distilling the water-toluene azeotrope. The separated water is collected in the Dean-Stark trap and removed at suitable time intervals. After 2 hours, on completion of the azeotropic distillation, it is cooled to 70° C., washed with 400 ml of a saturated sodium bicarbonate solution and cooled to 15° C. The precipitated solid is filtered off, washed with 70 ml of toluene, then 70 ml of water and dried in an oven at 40° C. under vacuum. 213 g of 2-cyclohexylidene-2-cyanoacetamide are obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1)[CH3:2].[OH-].[NH4+:14].O>O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: CCn1cc(S(=O)(=O)Cl)c(C)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(S(N)(=O)=O)c(C)n1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-sulfonylchloride (0.154 g, 0.73 mmol, Matrix Scientific) in tetrahydrofuran (10 mL) was added dropwise an aqueous solution of 30% ammonium hydroxide (0.20 mL, 1.7 mmol). The reaction mixture was stirred for 1 hour, water (2 mL) was added, and the solvent was concentrated under reduced pressure to precipitate a solid. The solid was isolated by filtration, rinsed with water, and dried to afford 41 mg of the title compound. 1H NMR (CDCl3) δ 7.80 (s, 1H), 4.75 (br s, 1H), 4.11 (q, 2H), 2.44 (s, 3H), 1.49 (t, 3H).