Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:25]([C:27]1[N:28]=[CH:29][N:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=1)=[O:26].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:25]([C:27]3[N:28]=[CH:29][N:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)=[O:26])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cn1cnc(C=O)c1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)c1
Yield: 76.8 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.77 g), ethyl (4-formyl-1H-imidazol-1-yl)acetate (0.45 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (60 mg), triethylamine (0.12 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (0.90 g, yield 77%) was obtained as a yellow oil from a fraction eluted with ethyl acetate. MS: 531 (Me).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1.[CH:13](O)=[O:14]>>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH:11][CH:13]=[O:14])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1
Reactant: O=CO
Reactant: Nc1c(Cl)ncnc1NCCO
Product: O=CNc1c(Cl)ncnc1NCCO

Procedure:
The starting 4-β-hydroxyethylamino-5-formamido-6-chloropyrimidine was prepared by heating in 80% formic acid, 4-β-hydroxyethylamino-5-amino-6-chloropyrimidine, M.P. (Koffer) 139° C, itself prepared according to the method of SCHAEFFER and BHARGAVA, Biochemistry (1965) 71.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=2.[NH:18]1C=CN=[CH:19]1>C1(C)C(C)=CC=CC=1>[N:12]1([CH2:11][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[CH:13]=[CH:19][N:18]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1CN(C)C
Solvent: Cc1ccccc1C
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1Cn1ccnc1
Yield: 89.4 %

Procedure:
Treatment of 2, N,N-trimethyl-5-nitro-1H-indole-3-methanamine (J.Org.Chem.,28,2921(1963)) (5.60 g) with imidazole (1.90 g) in xylene (100 ml) according to the method of Preparation 1 gave the title compound (5.50 g),m.p. 240°-242° C. Found: C,61.02; H,4.41; N,21.68. C13 H12N4O2 requires: C,60.92; H,4.72; N,21.87%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CCOCC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH:11]([OH:13])[CH2:12][NH:8][CH2:9]3)[CH2:15][CH2:16]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)N1CCN(C2CNCC2O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2. 4M HCl/dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was diluted with ether, filtered. The white solid was washed with ether and dried to give desired product (99% yield). 1H-NMR (300 MHz, DMSO, HCl salt): δ 3.0-4.0 (m, 12 H), 4.85 (m, 2 H), 7.25 (d, 2 H), 7.54 (d, 2 H) Retention Time (LC method: formic acid polar): 1.01 min. MS (M+H+): 310
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([O:20][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 19.4 g amount of p-nitrobenzenesulfonyl chloride is added to 16.5 g of phenol in 80 ml of pyridine. The mixture is heated on a steam bath for one hour then is filtered and cooled to room temperature. The resulting yellow solution is poured into 300 ml of 10% aqueous sodium carbonate solution and stirred vigorously until the product is crystallized out. The solid is filtered, washed with water and dried, then is recrystallized from 300 ml of hot ethanol to give 20.0 g of 4-nitro-benzenesulfonic acid phenyl ester.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][O:11][N:12]([CH3:16])[C:13](Cl)=[O:14]>>[CH3:10][O:11][N:12]([CH3:16])[C:13](=[O:14])[O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CON(C)C(=O)Cl
Product: CON(C)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino N-methoxy-N-methylcarbamate is prepared from tert-butyl N-hydroxycarbamate and N-Methoxy-N-methylcarbamoyl chloride according to Scheme 1. (2.48 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.83 (1H, s), 3.76 (3H, s), 3.23 (3H, s), 1.48 (9H, s).
Reaction SMILES: C(O[C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=1)CCC.[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]=[CH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>CCOCC>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]3[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=[C:6]([OH:10])[C:24]=3[C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: CCCCOc1cnc(C(=O)OCC)o1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
In a heavy walled round bottom flask with screw top were combined ethyl 5-butoxy-1,3-oxazole-2-carboxylate (2.53 g, 11.88 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (1.22 g, 5.94 mmol; see Example 1, Step 3) and trifluoroacetic acid (0.46 mL, 5.94 mmol). The vessel was sealed and placed in an oil bath heated to 130° C. The reaction mixture was stirred for 3 days. The dark brown reaction mixture was cooled and a crystalline precipitate formed. The mixture was diluted with ether and the solids collected by filtration and washed with ether to give the product as tan shiny plates. Further product can be obtained by evaporating the mother liquor, adding more trifluoroacetic acid and re-heating the mixture.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].C(=O)([O-])O.[Na+]>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
3-Amino-1-propanol (4.5 g, 60.0 mmol) was added slowly to a mixture of 4-chloro-3-nitropyridine (8.0 g, 50.5 mmol) and sodium hydrogen carbonate (4.2 g, 50.0 mmol) in ethanol (200 ml). The mixture was stirred for 3 h at ambient temperature and the solvent removed under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the residue, which was extracted with ethyl acetate (3×200 ml). The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated. Crystallisation from ethyl acetate gave 4-(3-hydroxypropylamino)-3-nitropyridine (4.3 g, 43%) as an orange crystalline solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:28][O:29]C(=O)C)[O:15]C(OC(=O)C)[C@H:9]([O:16]C(=O)C)[C@@H:8]([O:20]C(=O)C)[C@H:7]1[O:24][C:25](=[O:27])C)(=O)C>C[O-].[Na+]>[OH:29][CH2:28][C:6]([CH2:5][OH:4])([OH:15])[C@@H:7]1[O:24][CH:25]([OH:27])[C@H:9]([OH:16])[C@H:8]1[OH:20]
Reactant: CC(=O)OCC1(COC(C)=O)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: OCC(O)(CO)[C@@H]1OC(O)[C@H](O)[C@H]1O
Yield: 27.3 %

Procedure:
A solution of 5-C-(acetoxymethyl)-1,2,3,4,6-penta-O-acetyl-L-arabino-hexopyranose (7) (4.0 g, 8.7 mmol) in 0.05M methanolic sodium methoxide (50.0 ml) is stirred at room temperature for 2 hours. The reaction mixture is deionized with Amberlite IR-120 (H+) and evaporated to oily residue. Purification on a silica column with chloroform:methanol (4:1) followed by chloroform:methanol (3:2) gives 0.5 g (27%) of (8).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6]([C:8]([O:10]C)=O)=[CH:5][CH2:4][N:3]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].Br[CH2:19][Cl:20].C([Li])CCC.P([O-])([O-])([O-])=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[Cl:20][CH2:19][C:8]([C:6]1[CH2:7][C@@H:2]([CH3:1])[N:3]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:4][CH:5]=1)=[O:10]
Reactant: ClCBr
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)C[C@H]1C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC=C(C(=O)CCl)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 1-allyl 4-methyl (2R)-2-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (0.30 g, 1.25 mmol) and bromochloromethane (125 μl) in THF (15 ml) was added −90 to −80° C. a solution of n-butyllithium in hexane (1.59M, 1.15 ml) over a 15 minutes period. After stirring for additional 15 minutes, the reaction mixture was poured into a mixture of-ice (10 g) and phosphate buffer (pH 7.0, 10 ml). After ethyl acetate was added thereto and the mixture was separated by a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (25 g) chromatography to give allyl (2R)-4-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (255 mg, 80%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][N:25]=[CH:24]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Nc1ccc2ncncc2c1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3ncncc3c2)cc1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (151 mg, 0.723 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinazoline (100 mg, 0.689 mmol) was added. The resulting mixture was stirred for 4 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (47 mg, 21%), single spot at Rf 0.57 (ethyl acetate). mp 202.1-202.6° C., HPLC purity 96% (tR 2.14 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 9.30 (1H, s), 9.24 (1H, s), 7.99-7.92 (2H, m), 7.77 (2H, d, J=8.4 Hz), 7.68-7.63 (2H, m), 7.23 (1H, d, J=7.7 Hz), 2.57 (2H, t, J=7.6 Hz), 1.57 (2H, sextet, J=7.6 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 326.24 (M−). FAB-MS (MH+, C17H17N3O2S): calcd 328.1119, found 328.1118.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:19][C:20]1[CH:25]=[C:24]([CH:26]=O)[CH:23]=[C:22]([CH3:28])[N:21]=1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[CH:7]=3)[N:1]=2)[CH:23]=[C:22]([CH3:28])[N:21]=1
Reactant: NC(=O)c1cc(CCN2CCOCC2)ccc1N
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CCN4CCOCC4)cc3c(=O)[nH]2)cc(C)n1
Temperature: 120 °C

Procedure:
To a solution of 2-amino-5-(2-morpholin-4-yl-ethyl)-benzamide (0.18 g, 0.70 mmol) in N,N-dimethyl acetamide (7 mL) under nitrogen atmosphere were added 2,6-dimethyl-pyridine-4-carbaldehyde (0.10 g, 0.70 mmol), sodium hydrogensulfite (58.5 wt %, 0.15 g, 1.40 mmol) and p-toluenesulfonic acid (0.34 g, 1.80 mmol). The resulting mixture was heated at 120° C. for 16 hours, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was diluted with methylene chloride (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution, then water, and dried over anhydrous sodium sulfate. The crude orange solid (0.21 g) was purified by column chromatography (silica gel 230-400 mesh; 95:5 methylene chloride and MeOH as eluent) to give the title compound as a yellow solid. Yield: 0.11 g (42%). MP 248.5-249.3° C. 1H NMR (400 MHz, CDCl3): δ 11.6 (s, 1H), 8.18 (s, 1H), 7.87-7.76 (m, 3H), 7.76-7.65 (m, 1H), 3.76 (t, J=4.49 Hz, 4H), 2.99 (t, J=8.01 Hz, 4H), 2.71 (s, 6H), 2.75-2.65 (m, 2H), 2.56 (br s, 4H). MS (ES+) m/z: 363.16 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:6]1[CH:5]=[C:4]([C:12]2[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=[C:2]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ncccc1-c1cc(Br)cc(C(C)(C)C)c1
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Product: COc1ncccc1-c1cc(Oc2ccccc2)cc(C(C)(C)C)c1
Temperature: 115 °C
Yield: 31.2 %

Procedure:
step 1—A mixture of 3-(3-bromo-5-tert-butyl-phenyl)-2-methoxy-pyridine (123 mg, 0.384 mmol), phenol (46 mg, 0.489 mmol), Pd(OAc)2 (4.1 mg, 0.018 mmol), 2-di-tert-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (9.9 mg, 0.023 mmol) and K3PO4 (167 mg, 0.787 mmol)) in a Schlenk flask was purged with argon before toluene (5 mL) was added. The reaction under an argon atmosphere was heated overnight at 115° C. The reaction was cooled to RT, filtered through CELITE, and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 2% EtOAc) to afford 40 mg (41%) of 3-(3-tert-butyl-5-phenoxy-phenyl)-2-methoxy-pyridine (124).
Reaction SMILES: C([NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][NH:16]C=O)=[N:11][CH:12]=1)=O.[OH-].[Na+]>Cl>[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][NH2:16])=[N:11][CH:12]=1
Reactant: O=CNCCCc1ccc(CCCNC=O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCc1ccc(CCCN)nc1
Temperature: 2.5 °C

Procedure:
A solution of N-(3-{5-[3-(formylamino)propyl]pyridin-2-yl}propyl)formamide (13-1) (13.25 g) in 6N HCl (100 mL) was refluxed for 1.5 h. The solution was cooled to 0-5° C. and the pH was adjusted to pH 12.5 with 50% sodium hydroxide (35 mL). The solution was extracted three times with s-BuOH, the extracts were combined, and the solvent was switched to toluene. The solution contained 10.0 g of the title compound 12-1 as determined by HIPLC assay.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][N:4]([C:1](=[O:3])[CH3:2])[C:5]1[S:6][CH:7]=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1scc(C)c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of 2-acetylamino-3-benzoyl-4-methylthiophene in 20 ml of dimethylformamide is added 0.207 g of 63% sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 1.64 g of methyl iodide in 4.9 ml of dimethylformaide is added thereto. The mixture is stirred at room temperature for 3 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to give crystals, which are recrystallized from ether to give N-methyl-2-acetylamino-3-benzoyl-4-methylthiophene as crystals having a melting point of 121.5° - 122.5°C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:30]([CH3:31])=[N:29][CH:28]=[N:27]3)=[C:22]([F:32])[CH:21]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:32][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]3[N:17]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[C:30]([CH3:31])=[N:29][CH:28]=[N:27]1
Reactant: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ncnn1-c1ccc(Nc2nc3n(n2)CCCCC3c2ccc(F)cc2)cc1F
Yield: 31.7 %

Procedure:
A solution of 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (230 mg, 0.502 mmol), sodium iodide (376 mg, 2.51 mmol), and diisoproplylethylamine (0.088 mL, 0.50 mmol) in acetone (10 mL) was heated in a sealed vessel at 100° C. for 2 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (10-80% EtOAc/chloroform, linear gradient) to afford 67 mg (30% yield) of the titled compound as a pink solid. LC-MS (M+H)+ 422.3. 1H NMR (500 MHz, chloroform-d) δ ppm 7.93 (s, 1H) 7.65 (dd, J=12.51, 2.44 Hz, 1H) 721-7.24 (m, 1H) 7.09-7.16 (m, 2H) 6.99-7.08 (m, 3H) 6.90 (s, 1H) 4.21-4.31 (m, 3H) 2.37 (s, 3H) 2.15-2.26 (m, 1H) 2.03-2.12 (m, 1H) 1.81-2.01 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:23][CH:24]=1)[C:10]([O:17][CH:34]([F:36])[F:35])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using (3-[4-(2,2-dimethylpropionyl)benzyl]-8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy)acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([C:6]1[C:7](=[O:31])[N:8]([C:12]([NH:14][CH2:15][CH:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:30])=[C:23]([S:26](=[O:29])(=[O:28])[NH2:27])[CH:24]=3)[O:19][CH2:18][CH2:17]2)=[O:13])[CH2:9][C:10]=1[CH3:11])[CH3:5].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH2:4]([C:6]1[C:7](=[O:31])[N:8]([C:12]([NH:14][CH2:15][CH:16]2[C:25]3[C:20](=[CH:21][C:22]([O:30][CH2:1][CH3:2])=[C:23]([S:26](=[O:28])(=[O:29])[NH2:27])[CH:24]=3)[O:19][CH2:18][CH2:17]2)=[O:13])[CH2:9][C:10]=1[CH3:11])[CH3:5]
Reactant: CCI
Reactant: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(O)c(S(N)(=O)=O)cc32)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Temperature: 0 °C

Procedure:
2.16 ml (0.027 mol) of ethyl iodide are added to a suspension of 9 g (0.022 mol) of 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-methyl)-6-sulfamoyl-7-hydroxychroman and 6.1 g (0.044 mol) of potassium carbonate in 60 ml of acetone. After stirring under reflux for three hours, the mixture is introduced into ice/water and cautiously acidified with concentrated hydrochloric acid. The precipitate is filtered off with suction, washed several times with cold water, dried and recrystallized from ethanol/DMF. 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-methyl)-6-sulfamoyl-7-ethoxychroman of melting point 192° C. is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)=O.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>CO.O>[CH2:22]([O:29]/[N:30]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: O=Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(/C=N/OCc2ccccc2)cc1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 8 mL sealed vial was mixed N-(4-formylphenyl)isoindoline-2-carboxamide (50 mg, 0.188 mmol) in methanol (1 ml). A solution of O-benzylhydroxylamine hydrochloride (45.0 mg, 0.282 mmol) and sodium acetate (46.0 mg, 0.338 mmol) in water (1.000 ml) was then added and the reaction was stirred overnight at room temperature. The reaction was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with brine, dried with sodium sulfate, decanted, and concentrated. Purification by chromatography provided the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.21 (s, 1H), 7.65 (m, 2H), 7.50 (m, 2H), 7.44-7.28 (m, 9H), 5.14 (s, 2H), 4.78 (bs, 4H); MS (ESI(+)) m/e 372 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH2:18]([N:13]1[C:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: Cc1ccccc1B(O)O
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccccc1C)CCNCC2
Yield: 108.5 %

Procedure:
The title compound (138 mg) was prepared according to Example 263 using 206 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 95 mg of 2-methylphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3, 255.17. found, m/z 256.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.42 (m, 2H), 7.38-7.35 (m, 1H), 7.25-7.24 (m, 1H), 4.69 (br s, 2H), 4.03-3.17 (m, 5H), 2.76-2.68 (m, 2H), 2.15 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).