Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4](C)(C)N1.C1([C:17](C2C=CC=CC=2)([PH2:39]=[O:40])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2F)C=CC=CC=1>C1COCC1.[Cl-].[NH4+]>[C:6]1([P:39]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=2)([CH:17]2[C:21]3[C:20](=[CH:25][C:24]([O:26][CH3:27])=[CH:23][CH:22]=3)[C:19](=[O:29])[N:18]2[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[O:40])[CH:5]=[CH:4][CH:10]=[CH:2][CH:7]=1
Reactant: COc1ccc(CN(C(=O)c2cc(OC)ccc2F)C([PH2]=O)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3cc(OC)ccc3C2P(=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a cooled solution (−78° C.) of 2,2,6,6-tetramethylpiperidine (5.7 g, 40.3 mmol) in THF (60 mL) BuLi (25 mL, 1.6 M in hexanes, 40.3 mmol) was added. To the resulting mixture a solution of N-(diphenyl-phosphinoylmethyl)-2-fluoro-5-methoxy-N-(4-methoxy-benzyl)-benzamide (9.2 g, 18.3 mmol) in THF (55 mL) was added at such a rate to maintain the temperature below −70° C. and maintained at this temperature for 30 min. The reaction mixture was then allowed to warm up to RT over 5 h, and diluted with ammonium chloride (200 mL). The product was then extracted with diethyl ether and the combined extracts washed with brine. The residue was then evaporated and purified by chromatography (SiO2, Hexane:Acetone 1:1) to afford the title product (3.6 g, 41%) as a light yellow solid. MS m/e=484.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[N-:23]=[N+]=[N-].[Na+].O.[OH-].[Na+]>Cl>[O:1]=[C:2]1[NH:23][CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH2:4][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCC(NC(=O)[C@H]2CCCN(c3ccccc3)C2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCC(NC(=O)[C@H]2CCCN(c3ccccc3)C2)CCN1
Temperature: 50 °C

Procedure:
To a solution of (3S)—N-(4-oxocyclohexyl)-1-phenylpiperidine-3-carboxamide (10 mg, 0.00003 mol, prepared as example 171) in concentrated aqueous HCl (0.5 mL), was added sodium azide (2.27 mg, 0.0000350 mol) in small portions over 3 minutes with slow agitation. The temperature was slowly increased to 50° C. The reaction temperature was maintained at 50° C. for 8.5 h and then poured into 50 g of crushed ice and water. The solution was basified with cold 50% NaOH and the resulting solution was extracted with EtOAc(×3). The EtOAc extracts were combined, dried over MgSO4, filtered and evaporated to yield the crude product, which was purified by prep-HPLC. LCMS: (M+H)+=316.2.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O>CN1C(=O)CCC1>[CH:13]1([NH:16][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: CSc1nc(Cl)n2nccc2n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1nc(NC2CC2)n2nccc2n1
Yield: 78.8 %

Procedure:
4-Chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.0 eq, 6.26 g, 31.19 mmol) was suspended in anhydrous NMP (50 ml). Cyclopropylamine (1.5 eq, 3.2 ml, 46.26 mmol) was added through syringe dropwise. Internal temperature rose to 47° C. The mixture was stirred without any external cooling for one hour. An additional amount of cypropylamine (1 ml) was added and the mixture stirred for another 1.5 hours. The mixture was slowly poured into water (500 ml) under stirring. The resulting solid was filtered, washed with water and dried in a vacuum oven to give N-cyclopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine as a tan solid (5.44 g, 79% yield). LCMS (ES): >95% pure, m/z 222 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[OH-:10].[K+].[CH3:12]O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:10][CH3:12])[N:3]=1
Reactant: CO
Reactant: [OH-]
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: [K+]
Product: COc1nc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 50.0 g (0.3 mol) of 2-amino-4,6-dichloro-1,3,5-triazine in 600 mL of methanol was added portionwise 19.5 g (0.3 mol) of 85% potassium hydroxide pellets with the temperature being kept between 15°-20°. The resulting suspension was stirred at 10°-15° for one hour and then allowed to warm to room temperature over 1.5 hours. The white solid was collected, washed three times with water, and dried in vacuo to give 37.1 g of 2-amino-4-chloro-6-methoxy-1,3,5-triazine with m.p. 221°-223.5° (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]([S:34](=[O:36])(=[O:35])[NH2:37])=[CH:32][CH:33]=3)[CH:16]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(S(N)(=O)=O)cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(S(N)(=O)=O)cc2)nn1
Yield: 69.8 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (109.0 mg, 0.31 mmol): 4-azidobenzenesulfonamide (61.5 mg, 0.31 mmol); CuSO4 (10.0 mg, 0.06 mmol); NaAsc (20.0 mg, 0.03 mmol); TBTA (10.0 mg, 0.02 mmol); in t-BuOH/EtOH/H2O (4:4:2); afforded the 42 as a white solid (119 mg, 69.8%). 1H NMR (CDCl3, 400 MHz): δ 8.93 (s, 1H); 8.45 (s, 1H); 8.39-8.05 (q, 4H); 7.33 (s, 1H); 4.83-4.77 (t, 1H); 4.57-4.48 (q, 2H); 4.28-4.23 (q, 2H); 3.64 (s, 1H); 3.50 (s, 1H); 3.40-3.21 (m, 2H); 1.28-1.23 (t, 3H). 13C NMR (MeOD-d4, 100 MHz): 170.94, 166.80, 166.72, 153.45, 151.92, 145.70, 143.49, 138.85, 127.31, 120.74, 139.76, 115.56, 61.42, 52.72, 52.67, 51, 47, 33.93, 31.91, 12.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: COc1ccc2c(c1)CCC2N
Product: COc1ccc2c(c1)CCC2NC(=O)CN1CCc2cc(OC)c(OC(C)C)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5-methoxy-indane
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH:20]=[CH2:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH:20]=[CH2:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:24])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: C=CCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: C=CCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-hex-5-enoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=360.1 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:38]=1)[C:22]1[CH:21]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)[CH:19]=CC=1O[C:15]1[C:10]2=[CH:11][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:39].[Na+].[Cl-].O[NH3+].[CH2:44]([OH:46])[CH3:45]>>[C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:38]=1)[C:10]1[CH:11]=[C:12]([OH:39])[CH:13]=[CH:14][C:15]=1[O:46][C:44]1[C:22]2=[CH:21][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[CH:19][CH:45]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Product: CC(C)(C)NC1=NC2(CS1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of N-tert-butyl-2′-(pyrimidin-5-yl)-7′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (0.475 g, 0.899 mmol), NaOH solid (0.062 mL, 3.33 mmol), and hydroxyammonium chloride (0.120 mL, 2.88 mmol) was added Ethanol (8 mL). The mixture was stirred at RT. After 48 hrs, the mixture was concentrated in vacuo and the residue partioned between DCM and water. The aqueous layer was acidified to ca. pH=7 and extracted with CH2Cl2. The combined organic fractions were adsorbed onto silica gel and purified by silica gel chromatography using 40-80% Hexanes:EtOAc to give 2-(tert-butylamino)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2′-ol as an off-white solid. MS: MH+=419.2.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH2:29][O:30][CH3:31])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]=1[CH3:39])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH2:29][O:30][CH3:31])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]=1[CH3:39])#[N:14]
Reactant: COCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (70 μl, 552 μmol) was added at 150° C. to a dimethyl sulfoxide (7 ml) solution of 4-cyano-7-fluoro-N-(2-methoxyethyl)-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-122) (169 mg, 460 μmol) and triethylamine (83 μl, 598 μmol), followed by stirring at the same temperature for 2 hours. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave the entitled compound (112 mg, 53%) as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cnc(C#N)c(Cl)c1
Temperature: 100 °C

Procedure:
A solution of ethyl 5,6-dichloronicotinate (1 eq), zinc cyanide (0.75 eq) and tetrakis(triphenyl-phosphine)palladium (0.10 eq.) in DMF (0.3 M) was degassed and then heated at 100° C. for 3 hours. Solvent was removed en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give ethyl 5-chloro-6-cyanonicotinate as a white solid.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:9]=2[CH:38]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([Cl:4])=[CH:38][C:9]=3[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[O:17]1[CH:19]([CH2:20][S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18]1.C(Cl)(Cl)Cl.CO>CN(C)C=O>[OH:17][CH:19]([CH2:20][S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: CCCCCCCCCCCCCCCCCCSCC1CO1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCSCC(O)Cn1cnc2c(N)ncnc21
Reaction time: 20 h

Procedure:
A mixture of adenine (0.829 g, 6.10 mmol), anhydrous potassium carbonate (45 mg) and rac-1,2-epoxy-3-octadecylthiopropane (2.0 g, 5.83 mmol) in anhydrous dimethyl formamide (10 mL) is stirred at 70°-75° C. for 20 hours under a nitrogen atmosphere. The reaction mixture is filtered directly without cooling and the filtrate is concentrated under reduced pressure to afford a white residue. The residue is stirred with 95:5 (v/v) chloroform-methanol. The insoluble solid is filtered, purified by chromatography, and dried in vacuo to 9-[2'-hydroxy-3'-octadecylthiopropyl]-adenine.
Reaction SMILES: C1(C[O:5][C:6](=[O:33])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]([CH:31]=3)=[N:28][S:29][N:30]=4)=[C:14]([Cl:32])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[N:30]1[S:29][N:28]=[C:27]2[CH:31]=[C:23]([C:15]3[C:16]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)=[CH:17][C:12]([CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:33])=[O:5])=[CH:13][C:14]=3[Cl:32])[CH:24]=[CH:25][C:26]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc3nsnc3c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc3nsnc3c2)c(OCC2CC2)c1
Yield: 46.4 %

Procedure:
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 0.19 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.038 g, 55%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.02 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96 (m, 1H), 1.78-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97 (d, J=6.4 Hz, 6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.2, 154.6, 154.0, 140.5, 136.7, 134.0, 132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24]S[C:22]4[N:26]=[CH:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:29][C:21]3=4)=[C:7]([CH3:19])[C:8]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.OO.[OH:39][S:40]([O-:42])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][S:40](=[O:42])(=[O:39])[C:22]4[N:26]=[CH:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:29][C:21]3=4)=[C:7]([CH3:19])[C:8]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])O
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CCSc4ncc(N5CCOCC5)cc43)c2C)c1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CCS(=O)(=O)c4ncc(N5CCOCC5)cc43)c2C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-(7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine (45 mg, 0.09 mmol) in EtOAc (2.5 mL) was added disodium tungstate (30.4 mg, 0.092 mol) and water (0.5 mL). The reaction was cooled at 0° C. and then H2O2 (56.6 μL, 1.85 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (10 mg) was added followed by H2O2 (0.5 mL, 30%) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (15 mL). The separated organic layer was washed with brine (15 mL), dried over MgSO4, filtered and evaporated in vacuo to give 1-(7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59 (1H, d, J=4.7 Hz), 7.86-7.91 (2H, m), 7.70-7.77 (2H, m), 7.38 (1H, ddd, J=9.2, 8.0, 2.5 Hz), 7.25 (1H, dd, J=5.0, 0.9 Hz), 5.58 (1H, d, J=2.5 Hz), 4.18-4.27 (2H, m), 3.59-3.75 (6H, m), 2.84-3.02 (4H, m), 2.51 (3H, s), 2.44 (3H, s). Mass Spectrum (ESI) m/e=520.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.Cl[C:13](OC1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[CH:40][CH:41]=[N:42]2)=[CH:37][CH:36]=1>C(Cl)Cl.CO>[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:45]3[CH2:50][CH2:49][N:48]([C:13]([NH:9][CH:6]4[CH2:5][CH2:4][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH2:7]4)=[O:14])[CH2:47][CH2:46]3)=[CH:40][CH:41]=[N:42]2)=[CH:37][CH:36]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: NC1CCC(C(F)(F)F)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC(C(F)(F)F)CC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 4-trifluoromethyl cyclohexyl amine, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(piperazin-1-yl)quinoline are reacted to afford the product after flash chromatography with CH2Cl2-MeOH. LC-MS: 441 (M++1). 1H NMR (CDCl3) δ 8.78 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.46 (d, 1H), 6.85 (d, 1H), 4.60 (d, 1H), 4.03 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 2.10 (m, 1H), 1.85 (m, 4H), 1.50–1.70 (m, 4H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.[OH-].[Na+].O>C(O)C>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccs1
Reactant: CC(=O)/C=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccccc1)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
A mixture of 65.1 g (0.45 mol) of E-4-phenyl-3-buten-2-one, 50 g (0.45 mol) of 2-thiophenecarboxaldehyde, 4 mL of aqueous 10% sodium hydroxide, 50 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The solid which separated was collected by filtration and air dried to give 85.6 g (80% yield) of E,E-1-(2-thienyl)-5-phenyl-1,4-pentadien-3-one as a yellow solid. 1H NMR, IR, and FDMS analyses were consistent with the expected structure.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[OH:26].[NH2:27]C1C=CC(C(O)=O)=CC=1O>>[OH:7][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[N:27]=[N:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[OH:26]
Reactant: Cc1ccc(-n2[nH]c(C)cc2=O)cc1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: COC(=O)c1ccc(N)c(O)c1
Product: COC(=O)c1ccc(N=Nc2c(C)nn(-c3ccc(C)cc3)c2O)c(O)c1

Procedure:
Following the procedure of Example 1, except substituting 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one for 3-methyl-1-(4-methylphenyl)-3-pyrazolin-5-one and methyl 4-amino-3-hydroxybenzoate for 4-amino-3-hydroxybenzoic acid, the title compound was prepared as a red solid (0.059 g, 10%). MS(ES) m/z 367 [M+H].
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.[H-].[Na+].[H][H].[CH3:10][C:11]([CH3:25])([CH3:24])[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][C:16]=1[Cl:23])=[O:13]>CN(C)C=O>[CH3:10][C:11]([CH3:25])([CH3:24])[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:17][C:16]=1[Cl:23])=[O:13]
Reactant: [H][H]
Reactant: c1cn[nH]n1
Reactant: CC(C)(C)C(=O)Oc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1ccc(Cn2nccn2)cc1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A mixture of 2.26 g of 2H-1,2,3-triazole, 1.31 g of sodium hydride (60% oil dispersion) and 100 ml of anhydrous N,N-dimethylformamide was stirred at 60° to 70° C. under a nitrogen atmosphere for 2 hours. After the evolution of hydrogen gas ceased, the mixture was cooled to 10° C. To this mixture was added dropwise an anhydrous N,N-di-methylformamide (150 ml) solution of 10 g of 4-bromomethyl-2-chlorophenyl 2,2-di-methylpropanoate at room temperature under stirring over 1 hour, and the mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-dimethylpropanoate.