Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:42]3[CH:41]=[CH:40][C:39]([F:38])=[C:44]([F:45])[CH:43]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and 3,4-difluorophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene as colorless crystals. APCI-Mass m/Z 648 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 480 (M+NH4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=O)[C:3]=1[N+:9]([O-:11])=[O:10].P(Br)(Br)([Br:14])=O.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C>[Br:14][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: Cc1ccnc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.8 %

Procedure:
The 4-methyl-3-nitropyridin-2(1H)-one (110 g, 0.71 mol) was suspended in dichloroethane (1 L). The solution of phosphorus oxybromide (317 g, 1.1 mol) in dichloroethane (1 L) was added dropwise thereto at the ambient temperature. The reaction mixture was refluxed for 12 hours. The mixture was allowed to cool to room temperature, poured into ice water, and neutralized with potassium carbonate. The organic layer was separated, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated to provide the title compound (yield 71.8%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([NH2:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>C(O)(=O)C.CCOCC>[C:2]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[CH:8][C:9]=1[NH:10][CH:16]=[CH:15][S:17]([F:20])(=[O:19])=[O:18])(=[O:3])[CH3:1]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: C=CS(=O)(=O)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(NC=CS(=O)(=O)F)c(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a mixture of 2-amino-4,5-dimethoxyacetophenone (18 g, 92 mmol) in 125 mL of glacial acetic acid was added in one portion ethenesulfonyl fluoride (11.4 g, 0.1 mol) under nitrogen. After stirring for 1 hour at room temperature the resulting yellow mixture was refluxed for 1 hour. The yellow crystalline solid was diluted with an equal volume of ether, filtered, washed with ether, and air dried. There was obtained the title compound (23.7 g, 85% yield) as a yellow solid, mp 142.5°-146.5° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13](O)=[O:14])[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([NH:30][CH2:27][CH2:28][CH3:29])=[O:14])[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Reactant: CCCN
Product: CCCNC(=O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(6-oxo-8-((3,4,5-trifluorobenzyl)oxy)-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl) acetic acid and propan-1-amine.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]=[CH:10][CH:11]=[CH2:12].O>C1(C)C=CC=CC=1.C(O)(=O)C>[C:1]1(=[O:8])[C:6]2[CH2:12][CH:11]=[CH:10][CH2:9][C:5]=2[C:4](=[O:7])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CC=C
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)C2=C1CC=CC2
Yield: 91 %

Procedure:
In toluene (30 ml) and acetic acid (10 ml), were dissolved 10.0 g (0.092 mol) of 1,4-benzoquinone, to which 10.0 g (0.18 mol) of 1,3-butadiene were added at -10° C. under stirring. Thereafter, the resultant mixture was gradually heated and stirred further for 3 hours at 40° C. The liquid reaction mixture was washed with water, and an organic layer was dried and concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) and ethanol (50 ml) were added to the residue, and the mixture was stirred for 1 hour at 40° C. After the liquid reaction mixture was concentrated under reduced pressure, the residue was dissolved in a liquid mixture of acetonitrile (100 ml) and water (30 ml). To the solution, were added 20.0 g (0,036 mol) of ceric ammonium nitrate at room temperature to stir the resultant mixture for 1 hour. The liquid reaction mixture was poured into water (200 ml) to make extraction with toluene (50 ml×2). The resulting organic layer was washed with water, dried and concentrated under reduced pressure to obtain 13.3 g of a crude product of the title compound (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.[H][H]>CN(C)C=O.[Ni]>[Br:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[NH:12][C:13](=[O:14])[C:15](=[O:16])[N:20]([OH:22])[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Agent: [Ni]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c3ccccc3c(Br)cc2n(O)c1=O
Yield: 65.1 %

Procedure:
A solution of 4-bromo-1-ethoxalylamino-2-nitronaphthalene (0.20 g, 0.5 mmol) in 20 ml of N,N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of a small amount of Raney-Ni. After the hydrogen uptake was complete, the mixture was filtered. The filtrate was evaporated to dryness and the residue was triturated with water and hot ethanol to give 100 mg (62%) of the title compound. M.p. >200° C. dec.; IR (KBr): 1690 cm-1 1; MS (m/e): 306 (M+, 2%), 308 ((M+2)+, 2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][C:20]1(C)OC(=O)CC(=O)[O:21]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:20](=[O:21])[CH:19]=[C:16]([OH:18])[CH:11]2[CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: N#Cc1ccc(N[C@@H](CC2CC2)C(=O)O)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C(=O)C=C(O)C2CC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)-3-cyclopropylalanine (2.05 g), Meldrum's acid (1.35 g) and 4-(N,N-dimethylamino)pyridine (1.56 g) in tetrahydrofuran (40 mL) was added N,N′-carbonyldiimidazole (1.66 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as pale-yellow crystals (yield: 844 mg, 34%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[CH2:22][C:23]#[N:24])[CH2:19]2>O>[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[CH2:22][CH2:23][NH2:24])[CH2:19]2
Reactant: N#CCC1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
0.051 Mole of lithium aluminum hydride is dissolved in 200 ml. of anhydrous ethyl ether at 0° C, under nitrogen. 0.0571 Mole of adamant-2-yl acetonitrile in 100 ml. of anhydrous ethyl ether is added dropwise with stirring and the mixture is allowed to warm to room temperature and stirred for one hour. 10 Ml. of water is added dropwise and the mixture then filtered. The filtrate is dried over potassium hydroxide pellets and then filtered. The filtrate is distilled to remove the solvent affording 2-(adamant-2-yl)ethylamine.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:43][C:44]1[C:52]2[C:51]([NH2:53])=[CH:50][C:49]([C:54]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:55]=3[CH:56]=[CH:57][NH:58]4)=[CH:48][C:47]=2[NH:46][N:45]=1>CN(C=O)C.C(Cl)(Cl)Cl>[F:43][C:44]1[C:52]2[C:47](=[CH:48][C:49]([C:54]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:55]=3[CH:56]=[CH:57][NH:58]4)=[CH:50][C:51]=2[NH:53][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[O:9])[NH:46][N:45]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]nc(F)c12
Reactant: Cc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]nc(F)c23)cs1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To 2-methyl-1,3-thiazole-4-carboxylic acid (24 mg) in DMF (0.375 ml) was added HATU (69 mg) followed by DIPEA (0.043 ml), and the solution stirred for 10 min at 20° C. To this was then added a solution of 3-fluoro-6-(1H-indol-4-yl)-1H-indazol-4-amine (67 mg) in DMF (0.375 ml) and the top was placed on the vial which had been pierced with a needle. The solution was stirred at 20° C. for 73 h, heated at 50° C. for 3 h, then left to stand for 3.5 days. A further portion of 2-methyl-1,3-thiazole-4-carboxylic acid (0.024 g) in DMF (0.375 ml) was treated with HATU (0.069 g) followed by DIPEA (0.043 ml). This solution was stirred for 15 min at 20° C. then added to the original reaction mixture. This was then stirred at 20° C. for a further 72 h then loaded onto a dried aminopropyl SPE cartridge (1 g) which had been preconditioned with chloroform. The material was left on the cartridge for 2 h, then the cartridge was eluted with methanol (3 column volumes) and the solvent blown off. This was purified directly by mass directed preparative HPLC (Method A). The residue was azeotroped with methanol (5 ml) to give the title compound (7 mg) as a beige solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:29]6[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=6)[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ccc(C(F)(F)F)cn4)CC3)C2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Example 4. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=535 [M+H]+.
Reaction SMILES: S(C)C.[CH:4]([NH:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C@H:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:24]=1)=O>C1COCC1>[CH3:4][NH:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C@H:12]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[CH:24]=1
Reactant: CN1CCc2cc(Cl)c(NC=O)cc2[C@@H](c2ccccc2)C1
Solvent: C1CCOC1
Solvent: CSC
Product: CNc1cc2c(cc1Cl)CCN(C)C[C@@H]2c1ccccc1
Reaction time: 8 h

Procedure:
Me2S in THF (13.25 ml) was added dropwise to the product obtained in Example III (2.55 g, 0.008 mol) dissolved in 30 ml of THF with stirring and cooling in an ice bath. The ice bath was removed and the mixture was heated to reflux for 3.5 hours. The mixture was left to stand at room temperature overnight. Ethanolic HCl was added dropwise to the mixture with cooling (ice bath) and stirring until a pH of 1.5 was reached. The mixture was heated to reflux for one hour and then the solvent was removed. The residue was stirred with ether and 1N NaOH. The dried ether solution was evaporated in vacuo. The residue was crystallized from isopropyl ether, m.p. 98°-100° C. [α]26D +67.3 (DMF, c=1).
Reaction SMILES: [OH-].[K+].[CH:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)(=[O:15])[CH3:14]>CO>[CH3:21][C:16]1([C:13](=[O:15])[CH:14]=[CH:3][CH:4]=[CH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:20][CH2:19][CH2:18][O:17]1
Reactant: O=CC=Cc1ccccc1
Reactant: CC(=O)C1(C)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)C=CC=Cc2ccccc2)OCCO1
Reaction time: 4 h

Procedure:
4.0 g of a 15% strength by weight potassium hydroxide solution were added dropwise to a solution of 26.4 g of cinnamaldehyde and 26.0 g of 2-acetyl-2-methyl -1,3-dioxolan in 100 ml of methanol in the course of 10 minutes at from 20° to 25° C., and the mixture was stirred for a further 4 hours at from 20° to 25° C. Thereafter, the solvent was distilled off, the residue was taken up in 200 ml of tert-butyl methyl ether and the solution was washed with water and dried over sodium sulfate After the solvent had been distilled off, the crude product was distilled at from 150° to 155° C. and at 0.04 mbar.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1)(=[O:3])[CH3:2].[CH3:14][Mg]I.CCOCC>C1COCC1>[OH:3][C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1)([CH3:14])[CH3:2]
Reactant: CCOC(=O)c1coc(C(C)=O)n1
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C(C)(C)O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a flask containing a solution of ethyl 2-acetyloxazole-4-carboxylate (2.0 g, 10.9 mmol) in THF (50 ml), 3M solution of MeMgI in ether (5.0 ml, 13.11 mmol) was added at 0° C. The resulting mixture was stirred at RT for 5 h. The mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc. The organic layer was concentrated and purified with flash chromatography. Yield 1.0 g. 1H-NMR (400 MHz; CDCl3): δ 1.59 (s, 3H), 1.66 (s, 6H), 2.70 (s, 1H), 4.39 (q, 2H), 8.17 (s, 1H).
Reaction SMILES: C1(S(N=N[C:12]2[CH:13]=[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH:15]=[C:16]([Br:18])[CH:17]=2)(=O)=O)C=CC=CC=1.[K].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].O>CS(C)=O>[Br:18][C:16]1[CH:15]=[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH:13]=[C:12]([S:34][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(=O)N(C)c1cc(Br)cc(N=NS(=O)(=O)c2ccccc2)c1
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
0.22 g (0.00055 mol) of N-[3-[2-(phenylsulphonyl)-diazenyl]-5-bromophenyl]-N-methylacetamide was dissolved in 15 ml of dimethyl sulphoxide, treated with 0.185 g (0.000825 mol) of 4-nitrothiophenol potassium salt and stirred at 40° C. for 18 hrs. The reaction mixture was poured into 300 ml of water, extracted with diethyl ether, the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4, filtered and the filtrate was freed from solvent. The residue was chromatographed on silica gel with 1% MeOH in dichloromethane. There was obtained 0.217 g (100%) of N-[3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-N-methylacetamide as a yellow oil. MS (EI): me/e=382, 380 (C15H13BrN2O3S+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>Cl[Ti](Cl)(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:28]([C:27]3[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=3)=[O:29])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=C(c1ccc(F)c(F)c1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A slurry of 3.23 g (10 mmol) of 2-[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]benzo[b]thiophene in 50 mL of 1,2′dichloroethane was treated with 1.76 g (10 mmol) of 3,4-difluorobenzoyl chloride at 0° C. The mixture was protected from light and 4.4 mL (40 mmol) TiCl4 was added dropwise. The reaction was stirred at 0° C. for 5 h at which time it was quenched by carefully pouring it into 400 mL of saturated aqueous NaHCO3. To this was added EtOAc (200 mL), and the two layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give a crude oil which was purified by chromatography (SiO2; 2% MeOH in CHCl3) to afford 1.7 g (3.7 mmol; 37%) of the ketone as a viscous oil.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[N:12]=[C:11]([CH3:20])[C:10]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C)nc2cccc(C)c2c1N

Procedure:
Ethyl 4-(4-methoxybenzylamino)-2,5-dimethylquinoline-3-carboxylate (Example 12a, 0.563 g, 1.54 mmol) was dissolved in TFA (8 mL) and the resultant solution was stirred at room temperature for 15 minutes, TFA was then removed under vacuum to give the crude ethyl 4-amino-2,5-dimethylquinoline-3-carboxylate product, which was dissolved in EtOH (4 mL). To this solution was added NaOH (4.0 N, 3.86 mL) and the reaction mixture was stirred at 100° C. for 1 hr. Water (25 mL) was added, and the solvent was decanted away from insoluble material then acidified with AcOH to pH 5.5. The precipitate was collected by filtration to give the title compound (300 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.78 (s, 3H), 2.88 (s, 3H), 7.30 (d, J=7.2 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.65 (m, 1H), 7.8-8.0 (br, 1H), 12.2-12.9 (br, 2H). MS 217 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25](OS(C)(=O)=O)[CH2:24]2)[S:21][CH:22]=1)=[O:17])[C@@H:11]([CH3:14])[CH2:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C)C=O>[C:32]([S:34][CH:25]1[CH2:26][N:23]([C:20]2[S:21][CH:22]=[C:18]([C:16](=[O:17])[NH:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C@@H:11]([CH3:14])[CH2:12][CH3:13])[N:19]=2)[CH2:24]1)(=[O:35])[CH3:33]
Reactant: CC([O-])=S
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.55 g, 3.15 mmol) (obtained as described in Reference Example 38(5)) in dimethylformamide (78 ml) was added potassium thioacetate (2.16 g, 18.9 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methyl-butylcarbamoyl]-1,3-thiazol-2-yl}azetidine (910 mg, yield 61%) as a pale brown oil.
Reaction SMILES: O1C(C2C=C3C(=CC=2)NC(=O)C3)=CN=C1.COC(OC)(N(C)C)C.[CH3:25][N:26]([CH3:44])[C:27](=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][CH:41]=[N:40][CH:39]=3)[CH:36]=2)[NH:31][C:30]1=[O:43])[CH3:28].[S:45]([NH2:55])(=[O:54])([C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=1)=[O:46]>>[CH3:44][N:26]([CH3:25])[C:27](=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][CH:41]=[N:40][CH:39]=3)[CH:36]=2)[NH:31][C:30]1=[O:43])[CH3:28].[O:42]1[C:38]([C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30](=[O:43])[C:29]3=[C:27]([NH:53][C:50]2[CH:49]=[CH:48][C:47]([S:45]([NH2:55])(=[O:54])=[O:46])=[CH:52][CH:51]=2)[CH3:28])=[CH:39][N:40]=[CH:41]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(=C1C(=O)Nc2ccc(-c3cnco3)cc21)N(C)C
Agent: COC(C)(OC)N(C)C
Agent: O=C1Cc2cc(-c3cnco3)ccc2N1
Product: CC(Nc1ccc(S(N)(=O)=O)cc1)=C1C(=O)Nc2ccc(-c3cnco3)cc21

Procedure:
3-(1-Dimethylaminoethylidene)-5-(oxazol-5-yl)-1,3-dihydroindol-2-one was prepared from 5-(oxazol-5-yl)-1,3-dihydroindol-2-one and N,N-dimethylacetamide dimethyl acetal according to Procedure H. Condensation of 3-(1-dimethylaminoethylidene)-5-(oxazol-5-yl)-1,3-dihydroindol-2-one and sulfanilamide according to Procedure J provided the title compound: mp>250° C.; 1H NMR (DMSO-d6): δ 2.51 (s, 0.8H, DMSO), 2.61 (s, 3H), 6.97 (d, J=8.2 Hz, 1H), 7.37 (s, 2H), 7.40 (dd, J=8.0, 1.5 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.83 (d, J=8.5 Hz, 2H), 8.34 (s, 1H), 10.85 (s, 1H), 12.33 (s, 1H); APCI−MS m/z 395 (M−H)−. Anal. Calcd for C19H16N4O4S.0.1 C2H6OS.0.6 H2O: C, 55.56; H, 4.32; N, 13.50; S, 8.50. Found: C, 55.53; H, 4.32; N, 13.27; S, 8.58.