Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:27]([F:30])([F:29])[F:28])[C:20]3[CH:19]=[C:18](C(O)=O)[CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10](C(O)=O)=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]1([C:7]2([C:27]([F:30])([F:28])[F:29])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2c(c1)C(c1ccccc1)(C(F)(F)F)c1cc(C(=O)O)ccc1O2
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)C1(c2ccccc2)c2ccccc2Oc2ccccc21
Reaction time: 8 h
Yield: 66 %

Procedure:
A 6 g sample of 9-phenyl-9-trifluOrOmethylxanthene2,7-dicarboxylic acid (XX) was stirred and refluxed in ml quinoline along with 11 g of copper powder, the emanating gas being measured by a wet-test meter. The theoretical amount of CO2 was evolved in two hours. The reaction mixture was cooled, filtered through a bed of Celite into 800 ml of water, acidified with 100 ml of concentrated hydrochloric acid, and left standing overnight. The supernantant liquid was decanted, and the residue was taken up in methylene chloride, and filtered through a bed of alumina. The solvent was stripped, the residue was stirred with methanol, and was filtered, yielding 3.1 g (66%) of a white solid. It was recrystallized from methanol; m.p. 89°-90°. The IR spectrum was sharp with no OH or CO bands. The NMR spectrum was confirmatory, with the following peaks: d 7.42; m 7.3-7.4; d 7.19, td 6.96, d 6.87 in 2:5:2:2:2 ratio. The compound was analyzed by mass spectrometry which showed the parent ion at 326, along with other Peaks, the strongest being at 257 (parent minus trifluoromethyl), and also at 249 (parent minus phenyl), and 199 (parent minus phenyl and minus difluorocarbene). The mass spectrum confirmed the molecular formula as C20H13F3O.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>C(Cl)Cl.CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Yield: 87.1 %

Procedure:
A solution of 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (0.2 g, 0.5 mmol), (prepared as described in Example 48), in a mixture of methylene chloride (5 ml) and DMF (2 ml) containing 10% palladium-on-charcoal (50 mg) was treated with hydrogen at 1.8 atmospheres pressure for 2 hours. The suspension was filtered and the catalyst was washed with methanol followed by methylene chloride. The volatiles were removed from the filtrate by evaporation. The residue was triturated with water. The resulting solid was washed with water and dried under vacuum over phosphorus pentoxide at 60° C. to give 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (140 mg, 89%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3ccc(F)cc3)C(C)(C)C2=O)cn1
Yield: 40 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-fluorobenzene. Yield 40%, white solid. 1H NMR (DMSO-d6, 400 MHz): .s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.53 (s, 2H), 5.18 (s, 2H), 7.13 (m, 2H) 7.43 (m, 2H), 7.81 (s, H), 8.18 (s, 1H). MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an 1050 of 0.08 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.CCCCCC.C([Li])CCC.[I:28]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C>[CH:14]1([CH2:13][O:12][C:3]2[C:4]([O:8][CH2:9][O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=2[I:28])[CH2:16][CH2:15]1
Reactant: II
Reactant: COCOc1cccc(Br)c1OCC1CC1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1cccc(I)c1OCC1CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
To 76 ml of diethyl ether solution containing 24.1 g (84 mmol) of 1-bromo-2-cyclopropylmethoxy-3-methoxymethoxybenzene obtained in Reference example 12-(a) was added dropwise 53.4 ml (84 mmol) of 1.58M n-butyl lithium hexane solution at −60° C. or lower under argon atmosphere. The mixture was stirred at the same temperature for further 30 minutes, raised to −30° C., and then, 50 ml of diethyl ether solution containing 21.3 g (84 mmol) of iodine was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then, gradually raised to room temperature. After completion of the reaction, to the reaction mixture was added 95 ml of 2% aqueous sodium thiosulfate solution, and the mixture was stirred for 1 hour. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 29.8 g of the title compound as a reddish oil substantially quantitatively.
Reaction SMILES: ClCl.[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][CH:5]1[CH2:20][CH:21]([CH3:23])[CH3:22].C([Cl:28])CCC>C(O)(=O)C.Cl>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][C:5]1([CH2:20][CH:21]([CH3:23])[CH3:22])[Cl:28]
Reactant: CC(C)CC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CCCCCl
Agent: Cl
Agent: ClCl
Solvent: CC(=O)O
Product: CC(C)CC1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Yield: 56 %

Procedure:
A solution of glacial acetic acid (50 ml.) and chlorine (0.40 g., 0.00565 mole) is added with stirred over a 10-minute period to a suspension of (1-oxo-2-isobutyl-6,7-dichloro-5-indanyloxy)acetic acid (1.6 g., 0.00485 mole) in glacial acetic acid (50 ml.) and concentrated hydrochloric acid (1 drop). During the addition the reaction vessel is heated on a steam bath. After the addition is complete, the mixture is stirred without heating for 30 minutes and then poured into ice water (200 ml.). The white solid thatseparates is collected by filtration, washed in water and dried to afford 1.0 g. (56% yield) of (1-oxo-2-isobutyl-2,6,7-trichloro-5-indanyloxy)acetic acid which after recrystallization from n-butyl chloride melts at 166° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH2:2][CH2:3][CH3:4].[C:14](Cl)([Cl:16])=[O:15]>C1(C)C=CC=CC=1>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]([Cl:16])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: CCCCNc1c(C)cccc1C
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)Cl)c1c(C)cccc1C

Procedure:
To a suspension of 31.5 g. of N-butyl-2,6-dimethylaniline in 400 ml. of toluene is added 50 ml. of phosgene. The solution is heated to reflux and refluxed for 30 minutes. The solvent is then allowed to distill off (ca 350 ml.) and then cooled. The solution is evaporated in vacuo to a light oil which is then dissolved into hexane, filtered and the hexane evaporated off in vacuo to give a milky oil which is then distilled to give 2,6-dimethyl-N-butylphenylcarbamoyl chloride (b.p. 105° C./0.1 mm)
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:49])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:49])=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@@H](C)N3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@@H](C)N3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 2-({2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (278 mg, 0.397 mmol) in dioxane (10 mL) and a 2M aqueous NaOH solution (2 mL) was heated at 80° C. for 6 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a pink solid (172 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=5.68 Hz, 3H), 2.27 (s, 6H), 2.59 (d, J=15.57 Hz, 1H), 2.80 (d, J=4.58 Hz, 3H), 3.07 (d, J=14.28 Hz, 1H), 3.24-3.46 (m, 2H), 3.80 (s, 3H), 4.71-4.85 (m, 1H), 6.29 (dd, J=3.02, 1.74 Hz, 1H), 6.85-7.07 (m, 3H), 7.26-7.43 (m, 1H), 7.54 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.55 (dd, J=4.40, 1.65 Hz, 1H), 8.64 (s, 1H), 10.15 (s, 1H), 11.30 (s, 1H). ESIMS (M+H)+=547.43; Optical rotation +11.0 (1 mg/mL MeOH, rt).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][CH2:16][C:17]1[S:18][C:19]([CH3:27])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1)=O)(C)(C)C>>[CH2:25]([O:24][C:22]([C:20]1[N:21]2[CH:13]=[N:15][CH:16]=[C:17]2[S:18][C:19]=1[CH3:27])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1nc(CNC(=O)OC(C)(C)C)sc1C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C)sc2cncn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A 30 ml portion of trifluoroacetic acid was added to 9.0 g of 2-(N-t-butoxycarbonylamino)methyl-4-ethoxycarbonyl-5-methylthiazole, and the mixture was then stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, an aqueous saturated sodium hydrogencarbonate solution was added so as to adjust the pH of the solution to about 8. Then, 150 ml of dichloromethane was added, and a mixture of 28.4 ml of formic acid and 14.2 ml of acetic anhydride which had been beforehand reacted with each other at 50° C. for 30 minutes was then added at room temperature with vigorous stirring, followed by stirring for additional 1 hour. The organic layer was separated, and the aqueous layer was further extracted four times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. To the resulting unpurified 4-ethoxycarbonyl-2-(formylamino)methyl-5-methylthiazole, 30 ml of toluene and 14 ml of phosphorus oxychloride were added, followed by stirring at 100° C. for 1 hour. After cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was then diluted with dichloromethane. Afterward, an aqueous potassium carbonate solution was added so as to adjust the pH of the solution to about 8. The organic layer was separated, and the aqueous layer was further extracted five times with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 5.43 g of 3-ethoxycarbonyl-2-methylimidazo[5,1-b]thiazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccccc1OCCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
The above oil of 4-[2-(2-fluorophenoxy)ethyl]piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 12 mmol) in dichloromethane (60 mL) was mixed with trifluoroacetic acid (10 mL) and was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was treated with a saturated solution of NaHCO3. The aqueous solution was extracted with dichloromethane and the organic layer was concentrated to give 1-[2-(2-fluoro-phenoxy)ethyl]piperazine as a white solid (2.25 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ 2.40 (b, 4H), 2.67 (m, 6H), 4.13 (t, 2H), 6.92 (m, 1H), 7.11 (t, 1H), 7.18 (m, 2H).
Reaction SMILES: C[C@@H]1O[C@@H](O[C@@H:9]2[C:14]3=[C:15](O)[C:16]4[C:28](=O)[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5OC)[C:20](=O)[C:17]=4[C:18](O)=[C:13]3[CH2:12][C@@:11](O)(C(C)=O)[CH2:10]2)C[C@H](N)[C@@H]1O.[ClH:39].C(O)(=O)C.[NH2:44][NH:45][C:46]([NH2:48])=[S:47]>C(O)C>[ClH:39].[N:44](=[C:20]1[C:17]2[C:16](=[CH:15][C:14]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[CH:18]=2)[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2)[NH:45][C:46]([NH2:48])=[S:47]
Reactant: NNC(N)=S
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=S)NN=C1c2ccccc2Cc2cc3c(cc21)CCCC3
Yield: 187.5 %

Procedure:
Daunorubicin hydrochloride (0.4 g.) is dissolved in ethanol (60 cc.) containing 2.5% of acetic acid, and thiosemicarbazide (0.135 g.) is then added. The resulting mixture is heated for 12 hours to 45°C. with stirring, then evaporated to dryness under reduced pressure, and the residue is taken up in water (50 cc.). The resulting solution is lyophilised to give 4-methoxy-5- (or 12-) oxo-6,9,11-trihydroxy-7-(2,3,6 -O-tridesoxy-3-amino-1-L-lyxohexosyl)-9-[1-(thiosemicarbazono)ethyl]-12- (or 5-) (thiosemicarbazono)-5,7,8,9,10,12-hexahydro-naphthacene hydrochloride (0.476 g.) in a yield of 89%.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26]>>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([N:7]1[CH2:8][CH:4]2[CH:5]([CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3]2)[CH2:6]1)=[O:26]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: Cc1ccoc1C(=O)O
Product: Cc1ccoc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. For C20H20N4O2, 348.16; m/z found 349.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added 5-bromo-2-nitropyridine 111-1 (2.3 g, 11.4 mmol), 1-(piperazin-1-yl)ethanone 111-2 (1.6 g, 12.8 mmol), triethylamine (4.8 mL, 34.2 mmol) and DMSO (5 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone 111-3 as a light yellow solid. MS m/z 251.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Temperature: 25 °C

Procedure:
A stirring solution of 53.4 g (0.23 mol) of 1-tert-butoxycarbonyl-3-methylindazole, prepared as in Part B, in 1.0 L of CCl4 is heated to reflux, and then a mixture of 45.1 g (0.25 mol, 1.1 equiv) of N-bromosuccinimide and 5.7 g (23.5 mmol, 0.1 equiv) of benzoyl peroxide is added portionwise over 5 min as a solid. The resulting solution is heated at reflux for 4.5 h, then cooled to RT. The reaction mixture is filtered through a pad of Celite to remove the precipitated succinimide, and the solvent is removed in vacuo. Purification of the crude material by gradient silica gel flash column chromatography using hexane/EtOAc 15/1 to hexane/EtOAc 3/1 as eluent afforded 43.2 of the title compound as a white solid: 1H NMR (CDCl3, 300 MHz) δ8.20 (d, 1H, J=7.8), 7.88 (d, 1H, J=7.8), 7.60 (dd, 1H, J=7.3, 7.3), 7.41 (dd, 1H, J=7.3, 7.3), 4.91 (s, 2H), 1.77 (s, 9H); ;TLC Rf =0.56 (EtOAc/Hexane 1/5).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[NH:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[O:11]=[C:8]1[CH2:7][CH2:6][CH:5]([N:12]2[CH2:13][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:15]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 1,4-dioxaspiro[4.5]decan-8-one with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H followed by acidic deprotection of the ketal afforded the product.
Reaction SMILES: [NH:1]([C:29]([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:46][C:47]1[C:52](O)=[C:51]([F:54])[C:50]([F:55])=[C:49]([F:56])[C:48]=1[F:57].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[NH:1]([C:29]([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C@H:2]([C:26]([O:28][C:52]1[C:47]([F:46])=[C:48]([F:57])[C:49]([F:56])=[C:50]([F:55])[C:51]=1[F:54])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g (2.51 mmol) of Fmoc-Asn(Trt)-OH are dissolved in 15 ml of tetrahydrofuran. 0.51 g (2.76 mmol) of pentafluoro-phenol is added, the solution is cooled to 0° and then 0.57 g (2.76 mmol) of dicyclohexyl-carbodiimide is also added in solid form. It is stirred at 0° for 30 minutes, at room temperature for 2 hours and again at 0° for 30 minutes. The dicyclohexylurea which has crystallized out is filtered off, and the filtrate is evaporated to dryness and triturated with 40 ml of diisopropyl ether. The powdery residue is filtered off, dried and recrystallized from methylene chloride/petroleum ether. Fmoc-Asn(Trt)-OPfp is obtained; m.p. 154°-156°, [α]D20 =-7.8° (THF).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19].C(N(CC)CC)C.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:28][SH:29]>N1C=CC=CC=1>[CH2:32]([O:31][C:27]([CH2:28][S:29][C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19])=[O:30])[CH3:33]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CSC1=C(C=O)CCc2c(C(=O)OCC)sc(SC)c21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.00 g), triethylamine (1.44 g) and pyridine (25 ml), ethyl thioglycolate (1.37 g) was added at 0° C., followed by stirring at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure; the residue was poured over water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water in that order and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:7 to 1:5, v/v) to yield ethyl 4-ethoxycarbonylmethylthio-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.07 g, 81.0%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 102-103° C.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH:11]1[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:18]2[N:15]3[C:16](=[O:17])[CH:11]([NH:10][C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:12][N:13]([S:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])(=[O:36])=[O:35])[CH:14]3[CH2:21][N:20]([CH:22]([CH3:24])[CH3:23])[C:19]2=[O:25])=[CH:28][CH:29]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using cyclohexanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=668.14 (calculated, monoisotopic); measured value (M+H)+: 669.11