Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:29][N:30]([CH3:31])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C)c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (40 mg, 0.10 mmol, prepared as described in Example 18) in DMSO (1 ml) was added dimethylamine (2M in THF, 0.052 ml, 0.10 mmol) and DIPEA (0.09 ml). The mixture was heated under microwave irradiation firstly at 140° C. for 1 h, then at 160° C. for 1 h and then at 180° C. for 1 h. Further dimethylamine (2M in THF, 0.052 ml, 0.10 mmol) was added and the mixture was heated under microwave irradiation at 160° C. for 2 h. The product was then purified by Mass Directed Automated Preparative HPLC (Method B), then further purified by chromatography using an SCX cartridge (1 g), which was eluted with MeOH (2 column volumes) and then ammonia in MeOH (2M, 1 column volume). The product-containing fractions were combined and blown down under a stream of nitrogen. Purification using an aminopropyl cartridge (1 g), which was eluted with MeOH (1 column volume), afforded the title compound (9.8 mg) as a pale orange gum.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][OH:16])=[CH:4][C:5]([N:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[OH-].[Na+].Cl.[CH3:20][NH:21]C.O1CCCC1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CO.C(#N)C>[CH3:20][NH:21][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Br:1])[C:3]([CH2:15][OH:16])=[CH:4][C:5]=1[N:12]([CH3:14])[CH3:13]
Reactant: CNC
Reactant: COC(=O)c1cc(Br)c(CO)cc1N(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CNC(=O)c1cc(Br)c(CO)cc1N(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.8 %

Procedure:
After dissolving the methyl 5-bromo-2-(dimethylamino)-4-(hydroxymethyl)benzoate (1.179 g, 4.1 mmol) in a tetrahydrofuran (10 ml)-methanol (10 ml) mixed solvent, a 1 N sodium hydroxide aqueous solution (9.8 ml, 9.8 mmol) was added and the mixture was heated to reflux for 4 hours. Next, 5 N hydrochloric acid (9.8 ml, 9.8 mmol) was added and the reaction mixture was concentrated under reduced pressure. Acetonitrile was added to the residue and the mixture was concentrated under reduced pressure, and then the same procedure was repeated twice. Acetonitrile (20 ml), a 2.0 M dimethylamine-tetrahydrofuran solution (4.1 ml, 8.2 mmol), 1-hydroxybenztriazole (1.11 g, 8.2 mmol) and dicyclohexylcarbodiimide (1.69 g, 8.2 mmol) were added to the residue in that order and the mixture was stirred at room temperature for 20 hours. The insoluble portion was filtered off, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added and the mixture was filtered through alumina. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.222 g) as a white solid. (100% yield)
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][N:22](CC5C=CC=CC=5)[CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:4])[CH3:3]>C(=O)C.[Pd]>[ClH:1].[C:2]([O:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1cccc2c1Oc1ccccc1C21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: CC=O
Agent: Cl
Product: CC(=O)Oc1cccc2c1Oc1ccccc1C21CCNCC1

Procedure:
A solution of 4-acetoxy-1'-benzylxanthene-9-spiro-4'-piperidine hydrochloride (13.5 g.) in ethanal (200 ml.) is hydrogenated using 5% w/w palladium-on-carbon catalyst, at 1 atmosphere and 25° C. The catalyst is filtered off and the solvent evaporated to dryness. The residue is crystallised from ethanol-ether to give 4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 162°-165° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>>[CH2:9]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
L-Alanine (44.6 g, 0.5 mole)) was taken up in 250 mL 2N-NaOH to which was added benzaldehyde (50 mL, 0.5 mole). The resulting suspension was stirred at room temperature for approximately 20 minutes. After this period a pale yellow solution resulted. This solution was cooled in an ice/acetone bath and sodium borohydride (5.7 g, 0.15 mole) added in 1.0 g portions while keeping the temperature below 15° C. A large flask is necessary as a good deal of foaming takes place during the course of the reaction. The above process was repeated with the same quantities of benzaldehyde and sodium borohydride. However, this time after the addition of the sodium borohydride, the resulting solution was stirred for about 11/2 hours at room temperature and then washed with either (100 mL, ×2). The ether extracts were discarded and the aqueous phase acidified with 6N-HCl to pH 6-7. The product precipitated out of the solution. The resulting mixture was left overnight in the refrigerator and filtered the following morning. The product was washed with a little cold water and air dried. Yield 67 g (75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=1[OH:36].C(N(CC)CC)C>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:36][C:35]1[CH:34]=[C:33]([CH3:37])[CH:32]=[CH:31][C:30]=1[NH:29][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Cc1ccc(N)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CCNC(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To 50 ml of ethyl acetate, there were added 4.61 g (24.4 mmol) of N-(tert-butoxycarbonyl)-β-alanine and 5.03 g (24.4 mmol) of N,N'-dicyclohexyl carbodiimide and stirred at room temperature for 30 minutes. To the solution thus obtained, there were added 3.00 g (24.4 mmol) of 6-amino-m-cresol and 2.51 g (24.4 mmol) of triethylamine and stirred at room temperature for 17 hours. After the completion of the reaction, 100 ml of ethyl acetate was added to the solution. After filtering insoluble crystals, the filtrate was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the brown solid thus obtained was subjected to silica gel column chromatography (Si60 manufactured by Merck; 230-400 mesh; 300 g; eluent: 5% methanol-chloroform). After distilling off the solvent from the 600-1,200 ml fraction under reduced pressure, pale brown crystals were obtained. These crystals were recrystallized from chloroform and thus 1.56 g (5.3 mmol) of N-(2-hydroxy-4-methylphenyl)-3-(tert-butoxy-carbonyl)aminopropionamide was obtained as pale brown crystals. The yield was 22%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)CCc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cccc(O)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-hydroxyphenyl)propanoic acid (135 g) in EtOH (670 mL) was added concentrated H2SO4 (34.7 mL) at ambient temperature and the mixture was refluxed for 24 hours. After cooled to ambient temperature, the mixture was evaporated in vacuo. Water (400 mL) was added to the mixture and the mixture was extracted with EtOAc (600 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford ethyl 3-(3-hydroxyphenyl)propanoate (163 g) as a slightly yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]2=[O:20])[CH:10]=1)=[O:4].[Li+].[OH-]>CN(C=O)C>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]([C:7]2[CH:8]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][C:12]3=[O:20])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2c(=O)oc3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3c(=O)oc4ccccc43)c2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The 4′-methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid methyl ester from step 1 was dissolved in DMF (6 mL) and LiOH (500 mg, excess) was added. The reaction mixture was stirred at 120° C. overnight and then cooled to room temperature and partitioned between dichloromethane and saturated aqueous citric acid solution. The organic layer was concentrated under reduced pressure to give crude 4′-methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:14]=4)[N:10]=[C:9]3[C:23]([NH2:25])=[O:24])=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>N1C=CC=CC=1>[NH2:22][S:19]([C:15]1[CH:14]=[C:13]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]4[CH:26]=[CH:27][C:2]([NH:1][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=5[Cl:28])=[CH:3][C:4]4=3)[C:9]([C:23]([NH2:25])=[O:24])=[N:10]2)[CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: NC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1ccc1ccc(N)cc12
Reactant: O=C(Cl)c1ccccc1Cl
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Product: NC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1ccc1ccc(NC(=O)c3ccccc3Cl)cc12
Reaction time: 14 h

Procedure:
To a stirred solution of 8-amino-1-[3-(aminosulfonyl)phenyl]-1H-benzo[g]indazole-3-carboxamide from step 2 (76.2 mg, 0.20 mmol) in pyridine (25 mL) at RT was added 2-chlorobenzoic chloride (53 mg, 0.3 mmol). After 14 h, trisamine was added and the mixture was stirred for 2 h. The mixture was filtered through a silica gel pad with EtOAc and concentrated. The resulting title product was a solid (42 mg, 40%). Its structure was confirmed by 1H NMR and MS (521, M+1). C25H18ClN5O4S, Calc.: C: 57.75, H: 3.49; N: 13.47; Found, C: 57.06, H: 3.65, N: 13.51.
Reaction SMILES: FC1C=CC(C#N)=CC=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)S2(=O)=O)=[CH:14][CH:13]=1)#[N:11].[H-].[Na+].CN1CCC[C:41]1=[O:45]>[Cu]>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:25][CH2:24]3)[C:41]2=[O:45])=[CH:14][CH:13]=1)#[N:11]
Reactant: CN1CCCC1=O
Reactant: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3)S2(=O)=O)cc1
Agent: [Cu]
Agent: N#Cc1ccc(F)cc1
Agent: [H-]
Product: COC(=O)CCC1CCC(N2CCN(c3ccc(C#N)cc3)C2=O)CC1

Procedure:
2-(4-cyano-phenyl)-5-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide 4-Fluoro-benzonitrile and sodium hydride in N-methylpyrrolidone were used without copper salts.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(ccc(=O)n5C)c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(ccc(=O)n5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (5.2 mg, 0.008 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H31ClN3O4S: 624.2; found: 624.2. 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.58-7.47 (m, 4H), 6.81 (d, J=9.6 Hz, 1H), 5.35 (s, 1H), 3.79 (s, 3H), 2.63 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].[C:25](O)(=[O:28])[CH2:26][OH:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:26](=[O:27])[CH2:25][OH:28])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: O=C(O)CO
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#CC=C1CCN(c2ccc(N3C[C@H](CNC(=O)CO)OC3=O)cc2F)CC1
Reaction time: 3 h
Yield: 70 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (2.87 mmol), glycolic acid (5.74 mmol), dicyclohexylcarbodiimide (7.17 mmol), 4-dimethylaminopyridine (100 mg) in dichloromethane (50 ml) was stirred for 3 hours. The reaction mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography over a silica gel to give title compound in 70% yield.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[N:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:33][C@@H:30]1[O:29][C:28]([C:25]2[NH:24][C:23]([C:21]3[CH:22]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[N:11]=[N:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][CH:15]=4)[CH:20]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:27][CH:26]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nn4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Reaction time: 4 h
Yield: 88.2 %

Procedure:
3-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-6-(methylsulfonyl)pyridazine (116 mg, 0.24 mmol) synthesized in Example (118d) was dissolved in methylene chloride (5 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.26 mL, 0.26 mmol) was added at −78° C. under nitrogen atmosphere. Subsequently, the temperature was brought back to room temperature, followed by stirring for 4 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (100 mg, yield 89%) as a white solid.
Reaction SMILES: C([NH:4][C:5]1[CH:19]=[C:18]([Cl:20])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:7]([Cl:21])[CH:6]=1)(=O)C.[OH-].[K+]>CO.O>[NH2:4][C:5]1[CH:6]=[C:7]([Cl:21])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(=O)Nc1cc(Cl)c(OCCCCCC(=O)O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(Cl)c(OCCCCCC(=O)O)c(Cl)c1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
7.5 g (22.4 mmol) of 6-(4-acetylamino-2,6-dichlorophenoxy)hexanoic acid in 140 ml of 1 m potassium hydroxide solution in methanol/water (3:1) were boiled under reflux overnight. The methanol was removed in a rotary evaporator, and the residue was diluted with about 30 ml of water and acidified to pH 5 with glacial acetic acid. The mixture was stirred in an ice bath for 30 minutes and then filtered with suction. The crude product was subjected to column chromatography using n-heptane/ethyl acetate=1/1 and produced 4.3 g (14.7 mmol, 66%) of the required product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[CH3:18][Mg+].[Br-]>C1COCC1>[OH:1][C:2]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of benzyl 3-oxopiperidine-1-carboxylate (2.33 g, 10 mmol) in dry THF (50 mL) at −78° C. was added MeMgBr (3.6 mL, 3M solution in THF, 11 mmol) slowly. The reaction was allowed to stir at −78° C. for 10 min then slowly warmed to r.t. The reaction was quenched with NH4Cl and dissolved in EtOAc (300 mL) and washed with saturated NH4Cl and brine, dried and filtered, and concentrated to give the crude. The crude material was further purified by silica gel chromatography to yield benzyl 3-hydroxy-3-methylpiperidine-1-carboxylate. (53% yield). LCMS (m/z): 250.1 (MH+); LC Rt=2.98 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:17]([O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCC[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of commercial (S)-3-hydroxypyrrolidin-2-one (5 g, 49.5 mmol) in DCM (198 ml) was treated with DMAP (0.199 g, 1.632 mmol), imidazole (6.73 g, 99 mmol), and TBDMS-Cl (8.94 g, 59.3 mmol). The reaction mixture was stirred at rt for 16 h, and then was washed with a satd. NaHCO3 solution. The organic layer was concentrated and the crude reaction product was purified by silica gel chromatogpraphy eluting with 50% ethyl acetate in petroleum ether. The desired product was isolated as a white solid (8.1 g, 76%). LC/MS (M+H)+=216.2. 1H NMR (400 MHz, chloroform-d) δ 6.40 (br. s., 1H), 4.26 (t, J=7.8 Hz, 1H), 3.42-3.34 (m, 1H), 3.29-3.21 (m, 1H), 2.36 (dtd, J=12.7, 7.3, 3.3 Hz, 1H), 2.07-1.96 (m, 1H), 0.91 (s, 9H), 0.15 (d, J=7.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[C:7]([C:8]([C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccnc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccnc1F
Temperature: 75 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Manganese dioxide (5 g, 57.51 mmol) was added to a solution of (2-fluoropyridin-3-yl)(1-trityl-1H-imidazol-4-yl)methanol (1.3 g, 2.99 mmol) in dichloromethane (25 ml). The reaction mixture was heated to 75° C. and stirred for 18 hours. The crude mixture was cooled down to room temperature and filtered through a path of celite. The mother liquors were concentrated in vacuo to afford the title compound (1.1 g, 85% yield).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:22])[NH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:8]2[NH:7][C:6](=[O:22])[C:5]([CH:2]([NH:1][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[CH2:3][CH3:4])=[N:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(-c2ccc(C)c3ccccc23)[nH]c1=O
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(C)c3ccccc23)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 600 mg (2.04 mmol) 6-(1-aminopropyl)-3-(4-methyl-1-naphthyl)-1,2,4-triazin-5(4H)-one, 270 mg (2.04 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH3:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22].C(N(CC)CC)C>C(O)C>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][C:7](=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[C:25]#[N:26])[CH2:12]1
Reactant: CS(=O)(=O)CC#N
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CC(N2CCCC2)=CC(=C(C#N)S(C)(=O)=O)C1

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (4.7 g., 0.015 mol.), methylsulfonylacetonitrile (1.8 g., 0.015 mol.) and triethylamine (4.6 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 5 minutes. After chilling, the crude dye is collected on a filter, washed with methanol and dried. After one recrystallization from pyridine/methanol, the yield of purified dye is 1.2 g. (27%), m.p. 260°-261°C. with decomposition. The above dye compound has excellent absorption characteristics in the ultraviolet region of the spectrum as shown in Table 1 below.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][CH:21]([OH:23])[CH3:22]>>[CH:21]([O:23][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1)([CH3:22])[CH3:20]
Reactant: CC(C)O
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3c(C)cccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give (1-Isopropoxy-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 297(MH+).