Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:25]1[N:26]=[C:27]([NH:42][CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=3)[NH:30][C:29]=2[N:41]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:24]([C:25]1[N:26]=[C:27]([NH:42][CH2:43][CH2:44][CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=3)[NH:30][C:29]=2[N:41]=1)(=[O:23])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(C(O)c3ccccc3)nc(NCCCN3CCCCC3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(C(=O)c3ccccc3)nc(NCCCN3CCCCC3)c12
Reaction time: 1 h
Yield: 79 %

Procedure:
Dess-Martin periodinane reagent (22.67 mg, 0.053 mmol) was added to a mixture of methyl 2-(hydroxy(phenyl)methyl)-4-((3-(piperidin-1-yl)propyl)amino)-9H-pyrimido[4,5-b]indole-7-carboxylate (compound of Example 22) and TFA (15.7 mg, 0.027 mmol) in DCM (1000 μL, 15.54 mmol) to give a light orange solution. After 1 h, the solvent was evaporated and the residue was purified by flash chromatography to afford Example 23: methyl 2-benzoyl-4-((3-(piperidin-1-yl)propyl)amino)-9H-pyrimido[4,5-b]indole-7-carboxylate (10 mg, 79% yield) as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.36 (m, 2H) 1.36-1.48 (m, 4H) 1.74-1.88 (m, 2H) 2.14-2.44 (m, 6H) 3.52-3.68 (m, 2H) 3.91 (s, 3H) 7.54 (t, J=7.8 Hz, 2H) 7.69 (t, J=7.4 Hz, 1H) 7.76 (t, J=5.1 Hz, 1H) 7.90 (dd, J=8.2, 1.4 Hz, 1H) 7.94 (d, J=7.0 Hz, 2H) 8.10 (d, J=1.4 Hz, 1H) 8.52 (d, J=8.2 Hz, 1H) 12.43 (s, 1H); HRMS m/z 472.2342 (M+H)+; HPLC 97.1% @ 220 nm and 98.9% @ 254 nm, RT=1.86 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=3[CH:11]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 6-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.89 g, 1.86 mmol) in MeOH (5.0 mL) and THF (5.0 mL) and is treated with NaOH (2.0 M, 10.0 mL). The resulting mixture is stirred at RT for 2 h. The mixture is concentrated, acidified with HCl (1 N) until pH-3, and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified using silica gel column chromatography (50% EtOAc/Hex) to afford the title compound (840 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 27 °C
Reaction time: 22 h
Yield: 91.8 %

Procedure:
(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (3.57 g) was added to a mixed solution (35.7 ml) of ethanol and water (97:3), and they were stirred at 27° C. for 22 hours and then at 33° C. for 4 hours. 11.3% aqueous citric acid solution (40.3 g) was added to the obtained mixture, and they were cooled to −10° C. The crystals thus formed were taken by the filtration, washed with water (35.7 ml) and dried under reduced pressure to obtain intended (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.88 g) in a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:12])[OH:11])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH:10]([OH:11])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C(C)O)sc2c(Cl)c1Cl
Yield: 86.4 %

Procedure:
To a solution of 17 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 11.8 g of ethyl bromoacetate in 50 ml 2-butanone and the mixture is heated at 95°. To the mixture is added 12 g of potassium carbonate and 5.3 ml of dimethylformamide and the reaction mixture is refluxed at 100° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The aqueous phase is extracted two times with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from acetone and hexane gives 19.5 g of ethyl[(6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetate, mp 101°-103°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:22]=[CH:21][C:9]2[O:10][CH2:11][CH2:12][N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[CH:7]=1)(=O)C.[OH-].[Na+]>O1CCOCC1.O>[OH:4][CH2:5][C:6]1[N:22]=[CH:21][C:9]2[O:10][CH2:11][CH2:12][N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:8]=2[CH:7]=1
Reactant: CC(=O)OCc1cc2c(cn1)OCCN2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cnc(CO)cc21
Yield: 108.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-[(acetyloxy)methyl]-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (0.84 g, 2.7 mmol) in 1,4-dioxane (20 ml) and water (5 ml) was treated with 2M sodium hydroxide solution (2.72 ml, 5.4 mmol). After 0.5 hour the mixture was concentrated to a volume of 5 ml and then partitioned between ethyl acetate and water. The organic extract was dried and evaporated to afford a colourless oil (0.78 g, 105%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)o1

Procedure:
4-Fluoro-phenylboronic acid (611 mg, 4.4 mmol) was coupled to 5-bromo-2-furoic acid (1 g, 4.8 mmol) using Method F to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]([S:16]Cl)=[O:15].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14](=[O:15])[S:16][N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(N)=O
Reactant: O=C(Cl)SCl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1-c1nsc(=O)o1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To a solution of 4-chloro-2-methoxybenzamide (0.82 g, 4.42 mmol) in toluene (20 ml) was added chlorocarbonylsulfenyl chloride (0.73 ml, 8.84 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×50 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (1.03 g, 96% crude yield) that was carried forward as such without further purification. MS: 244.16 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])=O.[Na+].O>CN(C)C=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:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[C:4]([C:13]([O:15][CH3:16])=[O:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(Cl)c1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(Cl)cc2nc1C(=O)OC
Yield: 134.8 %

Procedure:
A stirred mixture of dimethyl 4,7-dichloroquinoline-2,3-dicarboxylate (5.00 g, 15.9 mM), sodium formate (1.63 g, 23.9 mM) and tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.80 mM) in anhydrous dimethylformamide (75 mL) under a nitrogen atmosphere was heated at 90°-95° C. for 7 hr. No reaction occurred so the reaction mixture was degassed and an additional quantity of tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.80 mM) was added and the reaction mixture again heated at 90°-95° C. for 6 hr. The cooled reaction mixture was poured into water and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave an gummy solid (6.0 g). Trituration of this residue with ethyl acetate and subsequent filtration separated a crystalline solid which was shown to be dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate. The filtrate was concentrated and the residue was flash chromatographed over silica gel (eluant: hexane/ethyl acetate, 3/2) to provide the title diester (1.13 g, 25.4%) as a light yellow crystalline solid; MS(CI): 280 (M+H).
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10][C:9]=2[C:8]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:7][CH:6]=1.O.O.O.C([O-])(=O)C.[Na+].[N+:35]([C:38]1[CH:39]=[C:40]([CH3:47])[CH:41]=[CH:42][C:43]=1[C:44](Cl)=[O:45])([O-:37])=[O:36].C([O-])(=O)C.[Na+].Cl>O.CCOCC>[Na+:1].[Na+:1].[Na+:1].[N+:35]([C:38]1[CH:39]=[C:40]([CH3:47])[CH:41]=[CH:42][C:43]=1[C:44]([NH:4][C:5]1[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10][C:9]=2[C:8]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:7][CH:6]=1)=[O:45])([O-:37])=[O:36]
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: Cc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c([N+](=O)[O-])c1
Yield: 778.9 %

Procedure:
To a stirred solution of 22.5 g of 8-amino-1,3,5-naphthalenetrisulfonic acid trisodium salt in 160 ml of water is added 11.0 g of the preceding product with a small amount of ether. Stirring is continued, and after one hour 1.0 g of sodium acetate trihydrate and 1.0 g of 3-nitro-p-toluoyl chloride are added. The mixture is stirred an additional 3 hours and the above addition of sodium acetate and 3-nitro-p-toluoyl chloride is repeated. The mixture is stirred an additional hour, acidified to Congo Red indicator paper with hydrochloric acid and filtered. The filtrate is neutralized with sodium hydroxide, concentrated, dissolved in 50 ml of water and added to one liter of ethanol with stirring for 16 hours. The solid is filtered and forms a gel on washing with ethanol. The gel is dissolved in water and evaporated. The residue is dissolved in 35 ml of hot water and 320 ml of absolute ethanol is added with stirring. The mixture solidifies and water is added to allow filtration. The solid is washed with ether and dried in vacuo. The filtrate is treated by stirring with one liter of ethanol, the separated solid is collected, washed with ether, and dried to yield a combined total of 23.9 g of 8-(3-nitro-p-toluamido)-1,3,5-naphthalenetrisulfonic acid trisodium salt.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@@H]1C)CO2
Yield: 98 %

Procedure:
A solution of 3-(4(S),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, SFC (Table 1, Method 8), Rt=4.151 min, 0.240 g, 0.60 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at 25° C. for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(S),7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #54-2, Enantiomer 2, SFC (Table 1, Method 9), Rt=4.945 min, 0.246 g, 98%) as a yellow solid. LC/MS (Table 1, Method 5) Rt=2.048 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([C:18]2[N:22]3[N:23]=[C:24](Cl)[CH:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH2:29]4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH:10]=1)C1C=CC=CC=1.[C@H:32]1([NH2:39])[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1>CO>[NH2:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([NH:39][C:24]2[CH:25]=[C:26]([NH:27][CH:28]3[CH2:29][CH2:30]3)[C:21]3[N:22]([C:18]([C:16]([NH:15][C:11]4[CH:10]=[C:9]([OH:8])[N:14]=[CH:13][N:12]=4)=[O:17])=[CH:19][N:20]=3)[N:23]=2)[CH2:33][CH2:34]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1cc(OCc2ccccc2)ncn1)c1cnc2c(NC3CC3)cc(Cl)nn12
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(O)ncn4)n3n2)CC1
Temperature: 160 °C

Procedure:
A mixture of N-(6-(benzyloxy)pyrimidin-4-yl)-6-chloro-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (70 mg, 0.161 mmol, 15C) and (trans)-cyclohexane-1,4-diamine (367 mg, 3.21 mmol) was heated at 160° C. for 2 hrs. The reaction mixture was diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropylamino)-N-(6-hydroxypyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (13 mg, 19.12% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.280 minutes. [M+H]=424.15. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35-12.78 (1H, m), 11.67 (1H, s), 8.29 (1H, s), 7.96 (1H, s), 7.69-7.94 (2H, m), 7.63 (1H, d, J=1.76 Hz), 7.05 (2H, s), 5.96 (1H, s), 3.62-3.85 (1H, m), 2.93-3.17 (1H, m), 2.05-2.24 (2H,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](OC2N(C3C=CC=CC=3)N=NN=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:28][CH3:29])[C:7]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:5])[CH3:2].[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:28][CH3:29])[C:7]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2c(OC)cccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCc1c(C(=O)OCC)ccc2c(OC)cccc12

Procedure:
A solution of 1-butyl-5-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester in a mixture of tetrahydrofuran (25 mL) and ethanol (75 mL) was hydrogenated over 10% palladium on carbon (1.3 g) at 50° C. and three atmospheres. After the uptake of hydrogen had stopped, the catalyst was removed by filtration and the filtrate was concentrated to dryness. The resulting material was dissolved in diethyl ether (150 mL) and the solution extracted with 1N sodium hydroxide (2×50 mL). After the base extracts were backwashed with diethyl ether, the combined organic layers were dried (MgSO4) and evaporated to yield 3.6 g of 1-butyl-5-methoxy-2-naphthalenecarboxylic acid ethyl ester as an oil. A portion was distilled on a Kugelrohr apparatus (140° C.; 0.1 mm) to furnish the analytical sample. Anal. Calcd for C18H22O3 : C, 75.50; H, 7.74 Found: C, 75.02; H, 7.97
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)[CH:5]=[CH:6][C:7]=1[OH:8].C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(-c3ccc(O)c(Cl)c3)ccc2c1
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(3-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (346 mg, 2.59 mmol) in THF (37 mL) according to method A to yield 380 mg (68%) of yellowish solid: mp 174-175° C.; 1H NMR (DMDO-d6): δ 7.09 (1H, d, 8.47 Hz), 7.31 (1H, d, J=8.89 Hz), 7.60 (1H, dd, J=8.20 Hz, J=2.26 Hz), 7.78 (1H, d, J=2.22 Hz), 7.84 (1H, d, J=8.99 Hz), 7.88 (1H, dd, J=9.00 Hz, J=1.80 Hz), 8.05 (1H, d, J=8.86 Hz), 8.14 (1H, d, J=1.60 Hz), 10.37 (1H, s), 10.49 (1H, s);MS (ESI) m/z303/305/307 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[NH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][CH:30]2[S:34][C:33](=[O:35])[NH:32][C:31]2=[O:36])=[CH:27][CH:26]=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][O:21][CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][CH:30]4[S:34][C:33](=[O:35])[NH:32][C:31]4=[O:36])=[CH:37][CH:38]=3)[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccncc2)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(S(=O)(=O)c2ccncc2)cc1
Yield: 57.3 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 150 mg of 4'-(4-pyridylsulfonyl)acetophenone and 183 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 173 mg of the title compound, melting at 213°-215° C., were obtained.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[Na+]>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2c1CCC=C2
Agent: [Na+]
Agent: [OH-]
Product: C1=Cc2cccc(OCC3CO3)c2CC1

Procedure:
7,8-Dihydro-α-naphthol prepared from 5-hydroxy-α-tetralone is allowed to react with epichlorohydrin in an aqueous solution of sodium hydroxide to give 1-(2,3-epoxypropoxy)-7,8-dihydronaphthalene [cf. J. Med. Chem. 21, 913 (1978)].
Reaction SMILES: [CH3:1][C:2]12[CH2:13][NH:12][C:10]3[C:11]1=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5][C:4](=[O:14])[CH2:3]2.[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[Br:15][C:7]1[C:6]2[NH:5][C:4](=[O:14])[CH2:3][C:2]3([CH3:1])[CH2:13][NH:12][C:10]([C:11]=23)=[CH:9][CH:8]=1
Reactant: CC12CNc3cccc(c31)NC(=O)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (±)-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one from Step A (525 mg, 2.79 mmol) in CH2Cl2 (15 mL) at 0° C. was added N-bromosuccinimide (496 mg, 2.79 mmol) and the mixture was allowed to warm slowly to ambient temperature. After 5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3CN —100:0 to 75:25, to give the title compound. MS: m/z=267 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.[CH3:21]S(O)(=O)=O.NC1C=CC=CC=1>>[NH2:20][C:8]([NH:4][C:5]1[CH:7]=[CH:21][CH:1]=[CH:2][CH:6]=1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: CS(=O)(=O)O
Solvent: Nc1ccccc1
Product: Cc1ccc(S(=O)(=O)N=C(N)Nc2ccccc2)cc1

Procedure:
The compound of Example 5 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of aniline solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 289.35; found mol. wt. (M+H) 290.2; 579.0 (Dimer)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C(OP(C#N)(OCC)=O)C.CCN(C(C)C)C(C)C.[CH:37]1([CH2:40][C@H:41]([NH2:48])[C:42]2[N:46]=[C:45]([CH3:47])[O:44][N:43]=2)[CH2:39][CH2:38]1>COCCOC>[CH:37]1([CH2:40][C@H:41]([NH:48][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:42]2[N:46]=[C:45]([CH3:47])[O:44][N:43]=2)[CH2:39][CH2:38]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)no1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DME (3 mL). Diethoxy-phosphorylformonitrile (226.0 mg, 0.80 mmol), DIEA (0.63 mL, 4.2 mmol) and (S)-2-cyclopropyl-1-(5-methyl-[1, 2, 4]oxadiazol-3-yl)-ethylamine (Example 20e, 82.2 mg, 0.64 mmol) were added and the reaction mixture was heated at 100° C. for 10 min under microwave condition. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19×250 mm/acetonitrile/10 mM ammonium acetate in water) to give the desired product (20 mg, 11.72%) as white solid; LC-MS (UV peak area, ESI) 96.20%, 384.2 (M+H).