Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:20][C:21]1[C:30]2[C:25](=[C:26]([O:32][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:28][C:29]=2[F:31])[N:24]=[CH:23][C:22]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([N:24]1[C:25]2[C:30](=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH3:35])[C:21](=[O:20])[C:22]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:23]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCCOc1ccc(F)c2c(O[Si](C)(C)C(C)(C)C)c(-c3ccc(OC)cc3)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(C(=O)COCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Benzyloxyacetyl chloride (1.9 ml, 3 equivalent weight) was added to a dichloromethane solution (50 ml) of 4-(tert-butyldimethylsilyloxy)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-quinolin (1.5 g, 3.4 mmol) while ice-cooling and the mixture was stirred overnight at room temperature. An aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction using ethyl acetate. The thus-obtained organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=2:1). The purified product was concentrated under reduced pressure, giving a colorless oily substance of 1-(2-benzyloxyacetyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (250 mg, yield: 15%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:19])([F:18])[C:5]([F:17])([C:13]([F:16])([F:15])[F:14])[CH2:6][CH:7](I)[C:8]([F:11])([F:10])[F:9]>[Cl-].C[N+](CCCC)(CCCC)CCCC.O>[F:9][C:8]([F:10])([F:11])/[CH:7]=[CH:6]/[C:5]([F:17])([C:4]([F:3])([F:18])[F:19])[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(I)CC(F)(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)/C=C/C(F)(C(F)(F)F)C(F)(F)F
Temperature: 97 °C
Yield: 57.4 %

Procedure:
Referring to scheme (17A) above, to a three-neck 500 mL flask equipped with a agitator, an inlet for a starting material addition, and a packed column topped with a reflux distillation head, thermocouple, and collection flask can be charged 60.40 g of KOH (0.917 mole), 5.86 g of Methyltributylammonium chloride (Aliquat 175, ˜5% by wt) in 150 mL of deionized water to form a solution. The resulting solution can be heated 97° C. and 110 g (0.281 mole) 1,1,1,2,5,5,5-heptafluoro-2-(trifluoromethyl)-4-iodopentane can be added drop-wise and sub-surface via syringe pump over the course of 2 hr period. During this addition the resulting product can be collected in the overhead collection flask and the reaction can be continued to be heated until the overhead temperature reached 94° C. The collected material can be dried over magnesium sulfate to give 74.18 g of crude reaction product which by GC analysis consisted on primary product and starting material. The crude reaction material was distilled to afford 42.6 g of (E)-1,1,1,4,5,5,5-heptafluoro-4-(trifluoromethyl)pent-2-ene (57.5% isolated yield). (1H-NMR (CDCl3): □ 6.45 (d, J=12 Hz, 1H), 6.45 (dhep, 1H). 13C-NMR (CDCl3): 90.5 (dhep, J=27, 202 Hz, CFCH), 120 (qd, 27, 287 Hz, CF3CF), 121.6 (q, J=220 Hz, CHCF3), 124.4 (m, CHCF), 128.2 (qd, J=21, 36 Hz, CHCF3). 19F-NMR (CDCl3w/CCl3F): □ −66.4 (d, JH−F=3 HzCF3CH), −76.9 (d, JF−F=8 Hz, CF3CF), −186.9 (m, CF3CF).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].[N+]([C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)([O-])=O>CS(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CN(C)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Dimethylaminoethanethiol hydrochloride was suspended in dry DMSO and sodium hydride was added. The reaction mixture was left stirring for 40 minutes before 5-nitro-2-furancarboxaldehyde was added. The reaction mixture was allowed to stir for 30 minutes at room temperature, to give the title compound. This is the starting aldehyde used in the synthesis of compound 5253.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)=[O:18]>C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)=[O:18]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)n2)c(N)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)n1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 3-amino-6-chloro-1-(ethoxycarbonyl)-2-(6-methylpyridine-2-carbonyl)indole (Example 111, step 1). m.p.: 210-211° C. (ethyl acetate)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([NH:20][CH2:21][CH2:22][OH:23])=[N:10][C:9]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:31]CO[CH2:28][CH:27]1CN>>[O:23]1[CH2:28][CH2:27][O:26][CH2:31][CH:22]1[CH2:21][NH:20][C:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:24]#[N:25])[N:10]=1
Reactant: COc1ccc2c(NCCO)nc(C#N)c(-c3cccc(F)c3)c2c1
Reactant: NCC1COCCO1
Product: COc1ccc2c(NCC3COCCO3)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile, using 1,4-dioxan-2-ylmethylamine in place of 2-aminoethanol, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:40])[CH:31]=[CH:32][CH2:33][CH2:34]OS(C)(=O)=O)[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:47][NH:48][CH3:49]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:40])[CH:31]=[CH:32][CH2:33][CH2:34][N:48]([CH3:49])[CH3:47])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CS(=O)(=O)OCCC=CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCC=CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 50 °C
Yield: 20 %

Procedure:
In a 25 ml rb flask were placed methanesulfonic acid 5-{4-[3-chloro-4-(pyridine-2-ylmethoxy)-phenylamino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl}-5-oxo-pent-3-enyl ester (0.15 g, 0.25 mmol) in DMF (5.0 ml) and to the solution was added cesium carbonate (0.16 g, 0.5 mmol) followed by dimethylamine (0.5 ml of 2M solution in THF) and heated at 50° C. overnight. The yellow solution was purified by HPLC twice to provide 27.5 mg of light brown solid (20.0%). 1H-NMR (DMSO-d6) δ 8.592-8.574 (m, 1H), 8.378 (s, 1H), 8.181 (s, 1H), 7.890-7.847 (m, 1H), 7.781-7.752 (m, 1H), 7.572-7.552 (d, 1H), 7.514-7.492 (m, 1H), 7.372-7.341 (m, 1H), 7.237-7.207 (m, 1H), 5.271 (s, 2H), 4.942-4.761 (m, 2H), 3.922-3.781 (m, 2H), 3.282-3.169 (m, 4H), 2.343 (m, 2H), 2.127-1.977 (m, 8H). MS m/e 549.1 (M+H), RT=2.26 min
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:26]1([C:22]2[CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:5]4[CH:4]=[C:3]([OH:2])[N:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[N:6]=4)=[CH:15][CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3cccc(-c4ccccc4)c3)cc2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3cccc(-c4ccccc4)c3)cc2)nn1-c1ccccn1
Yield: 58 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 29 of Example C-3 was used in place of Compound 27 of Example C-1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:30][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ncccn3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ncccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.91 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyrimidinylthio)imidazole in 100 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.52 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyrimidinylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[CH2:10]([S:12]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:13])[CH3:11].[N-:23]=[N+]=[N-].[Na+].C(=O)([O-])O.[Na+]>>[CH2:10]([S:12]([C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)(=[NH:23])=[O:13])[CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCS(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Yield: 89 %

Procedure:
30.5 ml of oleum (20% SO3) was added carefully, on an ice bath, to 6.00 g (30.12 mmol) of (RS)-1-ethylsulfinyl-4-nitrobenzene. Then, under argon, 2.35 g (36.14 mmol) of sodium azide was added carefully, in portions and with stirring, and the mixture was then heated to 45° C. After 6 hours the mixture was cooled to room temperature and carefully poured onto ice. The mixture was alkalized with sodium hydrogencarbonate and was extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. 5.74 g (26.79 mmol; yield: 89%) of the product was obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(=O)C.[Pt](=O)=O>[CH2:6]([O:5][P:4]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)[NH:12][CH2:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccnc2ccc(C(F)(F)F)cc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1CCNc2ccc(C(F)(F)F)cc21
Yield: 64.6 %

Procedure:
8.32 g of 6-trifluoromethyl-quinoline-4-phosphonic acid diethyl ester is dissolved in 100 ml of glacial acetic acid, mixed with 1.0 g of platinum dioxide and hydrogenated at room temperature. After column chromatography, 5.44 g of 6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-phosphonic acid diethyl ester of melting point 94° C. is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CN(C=O)C>[C:13]([O:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: CC(=O)[O-]
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20° C. for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluting with CH2Cl2 -hexane to obtain 198 g of the title compound. ##STR35##
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([C:26](=O)[CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23]>C(O)(=O)C>[CH3:27][C:26]1[C:17]([CH3:16])([CH2:18][CH2:19][CH2:20][CH2:21][S:22]([O-:25])(=[O:24])=[O:23])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N+:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=[N+](c2ccccc2)c2ccccc2C1(C)CCCCS(=O)(=O)[O-]
Reaction time: 3 h

Procedure:
N,N-Diphenylhydrazine hydrochloride (0.01 mol, 2.2 g), 5-methyl-6-oxoheptanesulfonic acid (0.017 mol, 3.0 g) in glacial acetic acid (20 ml) were stirred at room temperature (˜20° C.) for an hour then at 100° C. for 3 hours (TLC check). The reaction mixture was cooled down and the solvent removed under vacuum. The residue was washed with diethyl ether and purified by flash column on silicagel. Yield: 2 g (56%). Structure confirmed by NMR spectrum.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[C:12]([CH3:23])[C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)C[C@@H]1C)CC3>>[CH3:23][C:12]1[CH2:13][CH2:14][CH2:15][C@@:16]2([CH2:17][OH:18])[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[OH:1]
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CCC1=O
Agent: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CCC1

Procedure:
Substituting 17β,19-dihydroxy-1α,17α-dimethyl-4-androsten-3-one and 17β,19-dihydroxy-4-methyl-4-androsten-3-one in lieu of the 17β,19-dihydroxy-1α-methyl-4-androsten-3-one above, results in the preparation of 1α,17α-dimethyl-4-androstene-17β,19-diol and 4-methyl-4-androsten-17β,19-diol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].C([Sn](=O)CCCC)CCC.[N:45]([Si](C)(C)C)=[N+:46]=[N-:47]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]3[N:45]=[N:46][NH:47][N:32]=3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(Cc4nn[nH]n4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of [5-(4′-cyanomethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.200 g, 0.44 mmol) in toluene (5 mL) was added dibutyltin oxide (0.011 g, 0.04 mmol), followed by azidotrimethylsilane (0.07 mL, 0.53 mmol), and the reaction was stirred at 100° C. for 5 hours, and then stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried and concentrated, and the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)C1CCC(Oc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Reaction time: 0.5 h

Procedure:
Methyl chlorooxoacetate (45 μL, 0.48 mmol) was added in one portion to a stirred solution of ethyl 4-(4-aminophenoxy)cyclohexanecarboxylate (127 mg, 0.48 mmol) and pyridine (47 μL, 0.58 mmol) in DCM (5 mL) and the reaction mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was taken up in EtOAc (40 mL) and an aqueous solution of hydrochloric acid (1M, 20 mL) was added. The layers were separated and the organic layer was washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (152 mg, 91%) as a solid; 1H NMR (CDCl3) δ1.19 (3H, t), 1.39-1.45 (2H, m), 1.48-1.56 (2H, m), 1.97-2.03 (2H, m), 2.08-2.12 (2H, m), 2.23-2.31 (1H, m), 3.89 (3H, s), 4.07 (2H, q), 4.11-4.14 (1H, m), 6.80-6.84 (2H, d), 7.44-7.48 (2H, d), 8.66 (1H, s); MS m/e MR+ 350.
Reaction SMILES: [OH:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][O:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccccc1NO
Reactant: ClCc1nc2ccccc2s1
Product: CCOC(=O)c1ccccc1NOCc1nc2ccccc2s1
Yield: 52 %

Procedure:
The titled compound was prepared using similar procedure as that of Example-1 (step-2) using ethyl 2-(hydroxyamino)benzoate and 2-(chloromethyl)benzo[d]thiazole in 52% yield.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[S:13][C:14]4[C:24]5[C:19](=[CH:20][C:21]([CH:25]=O)=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]=4[N:16]=3)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>ClCCCl.CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[S:13][C:14]4[C:24]5[C:19](=[CH:20][C:21]([CH2:25][N:31]6[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]6)=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]=4[N:16]=3)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc2c(c1)CCc1nc(-c3noc(-c4ccccc4)c3C(F)(F)F)sc1-2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: ClCCCl
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc3c(c2)CCc2nc(-c4noc(-c5ccccc5)c4C(F)(F)F)sc2-3)C1
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a stirring solution of 2-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde (0.106 g, 0.249 mmol) in 1,2-dichloroethane (2.0 ml) at room temperature, was added azetidine-3-carboxylic acid (0.075 g, 0.746 mmol). The resulting pale suspension was stirred for 15 min after which tetraisopropyl titanate (0.222 ml, 0.746 mmol) was added dropwise. The reaction mixture turned light orange. Stirring was continued for 4 h after which sodium cyanoborohydride (0.023 g, 0.373 mmol) was added in one portion. After 90 min, the reaction mixture was diluted with MeOH and filtered through Celite. The filter cake was washed with MeOH (2×), and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (24 g Redisep® cartridge, eluting with 5%-MeOH in dichloromethane followed by 10% (10%-Ammonia-MeOH in dichloromethane) to yield 57 mg of the desired 1-((2-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)methyl)azetidine-3-carboxylic acid as an off white solid. The product had an LC ret. time=1.927 min. (condition: Start % B=0; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=254; Solvent Pair=MeOH/H2O/TFA; Solvent A=0.1% TFA in MeOH: H2O (10:90); Solvent B=0.1% TFA in; MeOH: H2O (10:90); Column 1=Waters Sunfire C18 5 um 4.6×30 mm); LC/MS M+1=512.08. 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (2H, d, J=7.48 Hz), 7.59-7.68 (3H, m), 7.53 (1H, d, J=7.70 Hz), 7.43 (1H, s), 7.38 (1H, dd, J=7.92, 1.54 Hz), 4.34 (2H, s), 4.16-4.23 (4H, m), 3.42 (1H, quin, J=8.36 Hz), 3.12-3.23 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23
Reactant: BrCc1ccccc1
Reactant: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCNCCO)c3ccc(Cl)c1c23
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCN(CCO)Cc3ccccc3)c3ccc(Cl)c1c23
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 14.5 g (32.3 mmol) of 5-chloro-2-[2-[(2-hydroxyethyl)]amino]-7-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one (5) and its 10-phenylmethoxy isomer (4), ~4:1 respectively by HPLC, 3.9 ml of α-bromotoluene, 6.5 g of potassium bicarbonate, and 140 ml of N,N-dimethylformamide was stirred at room temperature for 18 hr. The mixture was diluted with 500 ml of water and extracted with three 200 ml portions of dichloromethane. The combined organic extracts were washed with water, dried, and concentrated to an oil which was purified by chromatography on 600 g of silica gel (230-400 mesh). Elution with ethyl acetate:hexane (3:2) followed by concentration of product fractions gave the faster eluting component as a solid. Crystallization from acetonitrile afforded 3.55 g of pure isomer 9, mp 130°-134° C. Elution with ethyl acetate followed by concentration of product fractions afforded 9.2 g (66%) of slower eluting isomer 8 as a syrup which could not be crystallized.
Reaction SMILES: [C:1]([O:8]C)(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-])=[O:5].[NH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[NH2:11].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:1]([CH:2]1[CH2:3][C:4](=[O:5])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:14][CH:13]=2)[NH:11]1)([OH:8])=[O:7]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: NNc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)N1
Temperature: 100 °C
Yield: 89 %

Procedure:
50 parts of monomethyl maleate are added with stirring to 400 parts of water containing 70 parts of p-hydrazinobenzene sulphonate and 39 parts of sodium carbonate. The mixture is warmed until all reactants are in solution and the pH is adjusted by sodium carbonate to 9.2. The resulting solution is heated at 100° C for 9 hours. On completion of heating, the pH is adjusted to 3.8 by addition of hydrochloric acid and the 3-carboxy-1-(4'-sulphophenyl)-5-pyrazolidone thus formed is recovered and dried between 50°-100° C. The actual weight yield is 140 parts of strength 70% (determined by N.M.R.) which represents a yield of 89% of the theory.