Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[C:12]([C:14]2[O:16][N:32]=[C:31]([C:29]3[CH:30]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=3[O:35][CH3:36])[N:33]=2)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 16 (113 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10) afforded the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]1(O)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][CH:19]([CH3:21])[CH2:18][O:17][C:16](=[O:22])[NH:15][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:13][CH2:12][S:11][CH2:10][CH:9]=2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Reaction time: 3 h

Procedure:
2-Methylpropyl [3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (IV, EXAMPLE 2, 50 g, 152.7 mmol) is slurried in 150 ml methylene chloride. Trifluoroacetic acid (21.1 ml, 274.9 mmol, 1.8 equiv.) is added and the resulting mixture is stirred at 25° for 3 hr. The reaction is quenched with 75 ml of 47% aqueous potassium carbonate and stirred at 25° for 2 hr to dissolve any salts. Water (75 ml) is added and the phases are separated. The organic layer is collected, washed with 75 ml saline followed by 75 ml water. The organic phase is then concentrated and dried under reduced pressure over night to give 2-methylpropyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate. TLC Rf=0.85 (methanol/methylene chloride, 5/95); mp=99-100°; NMR (CDCl3) d 7.28, 7.12, 6.99, 6.74, 5.99, 3.95, 3.33-3., 2.84, 2.63, 2.02-1.91 and 0.96; CMR (CDCl3) d 159.5, 153.4, 138.4, 134.5, 129.6, 126.8, 124.0, 113.8, 106.2, 71.5, 29.3, 27.9, 25.8, 25.1 and 18.9; MS (CI, NH3) m/z (relative intensity) 327 (80), 310 (100), 309(87), 281 (23), 264 (38), 235 (30), 224(33), 189 (20), 165(25) and 161 (23).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A mixture of 4-bromo-2-methyl-6-nitro-1H-benzo[d]imidazole (67 g, 258 mmol), 1-(bromomethyl)-3-chloro-2-methylbenzene (68 g, 309 mmol), prepared as described in example 1, step b, and cesium carbonate (126 g, 387 mmol) in DMF (800 mL) was stirred at 80° C. for 2 h. After cooled to room temperature, the mixture was poured into 1.5 L of water. The resulting precipitate was filtered, washed with water (300 mL), ether (100 mL) and dried in vacuo to give the crude product (100 g, 98%) as a brown solid; LC/MS: MS (ES+) m/e 394 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.48 (s, 3H), 2.54 (s, 3H), 5.73 (s, 2H), 6.06 (d, J=7.8 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([N+:29]([O-])=O)=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:32])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:29][C:23]1[CH:22]=[C:21]2[C:26]([C:27](=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[C:19](=[O:32])[NH:20]2)=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(=O)n(CCCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Yield: 96 %

Procedure:
A mixture of 30 parts of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]-butyl]-7-nitro-2,4(1H,3H)-quinazolinedione, 500 parts of acetic acid and 2 parts of a solution of thiophene in methanol 4% was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was stirred in 80 parts of 2-propanol, 300 parts of water and 100 parts of ammonium hydroxide. The aqueous phase was decanted and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 27 parts (96%) of 7-amino-3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 213.0° C. (8).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]1([C:20]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=3[OH:33])[N:23]=[C:22]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:35]=3[OH:41])[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:42].[K+]>>[C:14]1([C:20]2[N:21]=[C:22]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:36][C:35]=3[OH:41])[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:42])=[CH:28][C:27]=3[OH:33])[N:25]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: OCCCCCCCCCCCBr
Agent: [K+]
Product: OCCCCCCCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCCCCCCCO)cc3O)n2)c(O)c1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
Under nitrogen, 32.4 g (128 mmol) of 11-bromo-1-undecanol are added at 80° C. to a solution of 20.0 g (54 mmol) of 2-phenyl-4,6-bis(2,4-dihydroxyphenyl)-1,3,5-triazine, 6.6 g (109 mmol) of potassium hydroxide and 150 ml of diglyne. The mixture is heated at 100° C. for 14 hours and filtered while hot, and the filtrate is cooled to 0° C. The solid which crystallizes therefrom is filtered off, pressed and dried for 24 hours under reduced pressure (60 mmHg, 60° C.), giving 27.6 g (72% yield) of 2-phenyl-4,6-bis[2-hydroxy-4-(11-hydroxyundecyloxy)phenyl]-1,3,5-triazine as a pale yellow solid of melting point 126°-135° C. The 1H-NMR spectrum (CDCl3, 300 MHz) is in agreement with the desired product.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:13][C@H:12]2[C@H:8]([N:9]=[C:10]([NH:14][CH2:15][CH3:16])[S:11]2)[C@@H:7]([OH:17])[C@@H:6]1[OH:18])=[N+:2]=[N-:3].C(O)C.CC(O)(C)C.[C:27]1([C:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.[Cu].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:15]([NH:14][C:10]1[S:11][CH:12]2[O:13][CH:5]([CH2:4][N:1]3[CH:36]=[C:35]([C:33]([OH:37])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:34])[N:3]=[N:2]3)[CH:6]([OH:18])[CH:7]([OH:17])[CH:8]2[N:9]=1)[CH3:16]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@@H]2S1
Reactant: C#CC(C)(O)c1ccccc1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCO
Product: CCNC1=NC2C(OC(Cn3cc(C(C)(O)c4ccccc4)nn3)C(O)C2O)S1
Reaction time: 24 h
Yield: 21 %

Procedure:
In a 10 mL rb flask was added (3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (40 mg, 0.15 mmol, 1.00 eq.), copper turnings (66 mg; 1.05 mmol; 7.00 eq.) and copper(II)sulfate pentahydrate (7.5 mg; 0.03 mmol; 0.20 eq.). The flask was evacuated and filled with nitrogen. This procedure was repeated twice before ethanol (0.5 ml)/water (0.7 ml)/2-methylpropan-2-ol (1.3 ml) and 2-phenylbut-3-yn-2-ol (22 mg; 0.45 mmol; 3.00 eq.) was added into the mixture and stirred for 24 h to get the reaction completed. Product formation was confirmed by LCMS. The solution was diluted with 2 mL H2O, dried and separated with mass based prep HPLC to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[O:9]1[CH2:13][CH2:12][N:11]=[C:10]1[C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[N:4][C:5]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([C:10]4[O:9][CH2:13][CH2:12][N:11]=4)=[CH:29][CH:28]=3)[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nn1
Reactant: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A mixture of 4.1 parts of 3,6-dibromopyridazine, 4.34 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine, 6.4 parts of sodium carbonate and 188 parts of N,N-dimethylformamide was stirred overnight at 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1.1 parts (16.4%) of 3-bromo-6-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine; mp. 169.1° C. (comp. 75).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.28 g (0.005 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]quinazoline-2-carboxylic acid ethyl ester prepared as described in Example 2A is suspended in 100 ml of dichloromethane and treated with 7.9 ml (0.011 mole) of 20% di-isobutylaluminum hydride (Dibal). The resultant yellow solution is stirred at room temperature for 45 minutes, 2.0 ml (0.003 M) of Dibal solution is added and stirring continued for 17 hours.
Reaction SMILES: [Mg].O1CCCC1.Cl[CH2:8][C:9]([CH3:11])=[CH2:10].[CH3:12][CH:13]([CH3:18])[C:14](=[CH2:17])[CH:15]=[O:16]>C1(C)C=CC=CC=1>[CH3:11][C:9]([CH2:8][CH:15]([OH:16])[C:14](=[CH2:17])[CH:13]([CH3:18])[CH3:12])=[CH2:10]
Reactant: C=C(C=O)C(C)C
Reactant: C=C(C)CCl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)CC(O)C(=C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of magnesium turnings (146 grams) and tetrahydrofuran (2,000 grams) is heated to reflux with vigorous agitation. To this mixture is added a mixture of 3-chloro-2-methylpropene (500 grams), toluene (75 grams), and 3-methyl-2-methylenebutanal (500 grams prepared according to Example I), at such a rate as to maintain reflux. The addition requires approximately four hours. The mass is stirred at reflux for 30 minutes and is then cooled to room temperature and quenched into excess ice cold 10% aqueous acetic acid mixture. The organic layer is washed successively with an equal volume of water, saturated sodium carbonate solution and saturated salt solution. Rapid distillation at 3-12 mm/Hg pressure using a short column followed by careful redistillation (after bulking) through a 12"×1" Goodloe packed column yields 580 grams of 2,6-dimethyl-5-methylene-1-hepten-4-ol, boiling point range 73°-78° C. at 9 mm/Hg pressure.
Reaction SMILES: [H-].[Na+].NC1C(C2(OC)C=CC=[C:12]([C:16]([C:18]3C[C:20]([O:31]C)([C:24]4[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)=[O:17])C2)=CC=CN=1.[CH2:35](I)[CH2:36][CH2:37][CH3:38].O.O1CCC[CH2:42]1>>[CH2:35]([NH:30][C:25]1[C:24]([C:20](=[O:31])[C:21]2[CH:22]=[CH:23][CH:18]=[C:16]([O:17][CH3:42])[CH:12]=2)=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCI
Reactant: C1CCOC1
Reactant: COC1(c2cccnc2N)C=CC=C(C(=O)C2=CC=CC(OC)(c3cccnc3N)C2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCNc1ncccc1C(=O)c1cccc(OC)c1
Temperature: 55 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a suspension of sodium hydride (60%, 578 mg, 14.5 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of 3-(2-aminopyridyl)-(3-methoxyphenyl)ketone (3.00 g, 13.1 mmol) in tetrahydrofuran (24 ml) under ice-cooling, and further thereto was added dropwise a solution of butyl iodide (3.63 g, 19.7 mmol) in tetrahydrofuran at room temperature, and the mixture was stirred at 50-60° C. for 6 hours. The mixture was cooled to room temperature, and thereto was added water. The mixture was extracted with toluene, and washed successively with a 5% aqueous sodium hydrogen carbonate solution, water and a 5% aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=¼) to give the title compound (2.96 g, 10.4 mmol, 79%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].[CH3:26][Sn](C)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH3:26])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1
Reactant: C[Sn](C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1N1CCOCC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Yield: 43 %

Procedure:
To a stirred solution 0.38 mmol 5-chloro-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A44(a)) in 3 ml dioxane were added 0.02 mmol bis(tri-tert-butylphosphine)palladium(0), 0.84 mmol cesium fluoride and 0.77 mmol tetramethylstannane and the mixture was heated at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (43% yield). MS (m/e): 219.4 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:8]1[CH:9]=[C:10]([C:18]([O:20]C)=[O:19])[C:11]([C:14](OC)=O)=[N:12][CH:13]=1.[NH2:22][C:23]([CH3:30])([CH:27]([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.O>[O:3]1[CH2:4][CH2:5][CH2:6][CH2:7][O:1][CH:2]1[C:8]1[CH:13]=[N:12][C:11]([C:14]2[NH:26][C:24](=[O:25])[C:23]([CH:27]([CH3:29])[CH3:28])([CH3:30])[N:22]=2)=[C:10]([CH:9]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: COC(=O)c1cc(C2OCCCCO2)cnc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C1(C)N=C(c2ncc(C3OCCCCO3)cc2C(=O)O)NC1=O
Temperature: 25 °C
Yield: 57.2 %

Procedure:
5-(1,3-Dioxepan-2-yl)-2,3-pyridinedicarboxylic acid, dimethyl ester (0.9 g, 0.00305 mol) in toluene is added to 2-amino-2,3-dimethylbutyramide (0.4 g, 0.00305 mol) and potassium tert-butoxide (0.69 g, 0.0061 mol) in toluene. The mixture is heated for 3 hours from 60° to 70° C. The reaction mixture is cooled to room temperature, water is added and the mixture is concentrated in vacuo to give an oil. The oil is diluted with water and washed with ether. The aqueous solution is acidified to pH 3.1 with 2 normal hydrochloric acid solution and extracted with methylene chloride. The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (0.63 g, 57%) mp 60°-69° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(N)c1
Product: COc1ccc(S(=O)(=O)Nc2cccc(OC)c2)cc1
Yield: 99.7 %

Procedure:
Using m-anisidine (0.99 ml, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.50 g (99.7%) of the title compound in the form of light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br.[Br:21][C:22]1[CH:23]=[C:24]([CH2:29]Br)[C:25]([NH2:28])=[N:26][CH:27]=1.O>CN(C=O)C>[NH2:28][C:25]1[C:24]([CH2:29][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:23][C:22]([Br:21])=[CH:27][N:26]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1cc(Br)cnc1N)c1ccccc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 33.9 %

Procedure:
To a solution of phenyl glycine ethyl ester (4.94 g, 27.6 mmol) and K2CO3 (11.42 g, 82.7 mmol) in anhydrous DMF (300 mL) under argon was added 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (9.52 g, 27.6 mmol). The mixture was stirred for 12 h at 40° C. Water (500 mL) was added and the mixture was extracted with ethyl acetate (3×500 mL). Combined organic layers were washed with water (2×400 mL) and brine (400 mL), dried over MgSO4, filtered and concentrated to a brown oil. Purification by column chromatography (silica gel, gradient elution of 30% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) gave ethyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(phenyl)amino)acetate (3.41 g, 34%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.89-7.88 (m, 1H), 7.36-7.35 (m, 1H), 7.17-7.11 (m, 2H), 6.68-6.64 (m, 1H), 6.47-6.44 (m, 2H), 6.09 (s, 2H), 4.30-4.29 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 1.19 (t, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([O:28]C)=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:4])=[O:3].CO.[OH-].[Na+].Cl>CO.[H][H]>[NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:3])=[O:4]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(N)(=O)=O)cc3n2C1
Reactant: [H][H]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(N)(=O)=O)cc21
Temperature: 60 °C
Yield: 93.5 %

Procedure:
Methyl 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (725 mg, 1.39 mmol) was dissolved into MeOH//THF (1:1, 16 mL) and treated with 1M aqueous NaOH (3 mL). The reaction mixture was stirred and heated at 60° C. for 0.5 h and cooled to rt. The reaction solution was diluted with MeOH/H2 O (2:1, 15 mL), neutralized with 1M aqueous HCl (3 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (650 g, 1.3 mmol, 92%) as a bright yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.16-2.22 (m, 10H), 2.82-2.96 (m, 1H), 3.94 (s, 3H), 4.07-4.29 (m, 1H), 5.57-5.80 (m, 1H), 7.14-7.23 (m, 2H), 7.55-7.63 (m, 2H), 7.88-7.94 (m 2H), 8.18 (s, 1H). LCMS: m/e 510 (M+H)+, ret time 2.85 min, column B, 4 minute gradient.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]3[OH:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][O:21]C(=O)C.IC>>[CH:1]1([C:4]2[N:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]3[O:17][CH2:19][CH2:20][OH:21])[CH2:2][CH2:3]1
Reactant: CC(=O)OCCBr
Reactant: O=C(O)c1cc(O)c2ccnc(C3CC3)c2n1
Solvent: CI
Product: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2n1

Procedure:
The intended compound was produced according to the procedures described in reference examples 35 and 36 but using 8-cyclopropyl-4-hydroxy-[1,7]naphthyridine-2-carboxylic acid and acetic acid 2-bromoethyl ester in place of 1-Cyclopropyl-5-hydroxy-isoquinoline-7-carboxylic acid methyl ester and iodomethane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Reaction time: 17 h
Yield: 60.4 %

Procedure:
To a solution of (2-benzyloxyphenyl)acetic acid (36 g) in dimethylformamide (360 ml) were added potassium carbonate (61.2 g) and methyl iodide (31.6 g) successively. After being stirred for 17 hours, the mixture was filtered and the filtrate was poured into aqueous 1N hydrochloric acid solution (1.8 l). The separated oil was extracted with diethyl ether and the organic layer was washed with brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to afford methyl (2-benzyloxyphenyl)acetate (23 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[CH:33]1([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>CC(N(C)C)=O>[CH:33]1([NH:39][CH2:40][CH2:41][CH2:42][NH:43][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:3]3[C:2](=[O:1])[C:6]4[N:7]=[N:8][C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:5]=4[NH:4]3)=[CH:16][CH:17]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCCCNC1CCCCC1
Reactant: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCCCNC1CCCCC1)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-(3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoyl chloride (97 mg, 0.30 mmol) was dissolved in anhydrous DMA (2 ml). Diisopropylethylamine (39 mg, 53 μl, 0.60 mmol) was added followed by N-cyclohexyl-1,3-propanediamine (52 mg, 0.60 mmol). The mixture was stirred for 30 min. Water (5 ml) was added to give a dark red suspension. The mixture was extracted with n-butanol (2×20 ml). The combined organic phases were washed with water and concentrated under vacuum until precipitation was observed. Hexane (20 ml) and ethyl acetate (10 ml) were added, the solids were collected by filtration and dried under vacuum. The product was isolated as a dark red powder (82 mg, 0.18 mmol, 62%). LCMS: m/z 445 [M+H]+.