Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11]O)[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[ClH:13]>C(O)=O.O>[Cl:13][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: Cl
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O=CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CCl)C(O)=C1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
360 g of L-ascorbic acid in 1000 ml of formic acid are treated in a pressure vessel at 50° C with 145 g of hydrogen chloride gas in such a manner that the dosage velocity amounts to about 6.6 g per hour and the pressure amounts to about 0.4 to 0.6 atmospheres. Subsequently, the black mass obtained is evaporated at 60° C to a thick, pitch-like paste. This paste is stirred with about 2 liters of water at 60° C for 30 minutes. Subsequently, the water is evaporated off at 60° C under reduced pressure. The solid residue obtained is again dissolved in 2 liters of water, stirred at 60° C for 30 minutes and evaporated to dryness under reduced pressure at this temperature. This procedure is repeated once again. The residue is dissolved in 1.4 liters of water and extracted at room temperature 6 times with 1 liter of ethyl acetate each time. The combined ethyl acetate extracts are stirred with 20 g of active carbon for 15 minutes and subsequently filtered. The filtrate is freed from entrained water, dried over about 200 g of sodium sulfate, filtered and evaporated under reduced pressure at 40° C. The residue is dissolved in 600 ml of nitromethane at 80° C and filtered. The filter residue is back-washed with 100 ml of hot nitromethane (80° C). The combined nitromethane solutions are cooled to room temperature and the crystals obtained are filtered off. The crystals are dissolved at 80° C in 600 ml of nitromethane, treated with 5 g of active carbon and, after stirring for about 15 minutes at 80° C, filtered. The filter residue is washed with 100 ml of hot nitromethane (80° C). The combined nitromethane solutions are left to stand overnight at room temperature. The crystals obtained are filtered off and dissolved in 600 ml of nitromethane at about 70° C, treated with 5 g of active carbon and, after stirring for 15 minutes, filtered. The filter residue is washed with 100 ml of hot nitromethane (60° C). The combined nitromethane solutions are left to stand overnight at room temperature. The white crystals obtained are filtered off, dispersed in 100 mls of nitromethane and subsequently filtered. The thus-purified crystals are dried at 60° C under reduced pressure and further dried at 60° C for 48 hours under strongly reduced pressure (about 0.3 mmHg). There is obtained 6-chloro-6-deoxy-L-ascorbic acid of melting point 144° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5](Cl)=[C:4]([Cl:16])[N:3]=1.CCN(C(C)C)C(C)C.ClC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])=NC=1>CCO>[Cl:16][C:4]1[N:3]=[C:2]([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2Cl)n[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Temperature: 140 °C
Yield: 26.7 %

Procedure:
To a solution of 2,5,6-trichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39; 2.0 g, 8.2 mmol) in absolute EtOH (40 ml) were added DIEA (2.5 ml) and (15)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 1.2 g, 8.2 mmol) and the resulting solution was heated to 140° C. for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give an oil which was purified by Gilson (20-75% acetonitrile/H2O, 35 min) to give the titled compound as solid (762 mg). m/z: 383.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][CH:6]=[CH:5][N:4]=1)=O.[CH3:14][NH:15][NH2:16]>C(O)C>[CH3:14][N:15]1[C:9](=[O:11])[C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[CH:1]=[N:16]1
Reactant: CCOC(=O)c1cccnc1C=O
Reactant: CNN
Solvent: CCO
Product: Cn1ncc2ncccc2c1=O
Reaction time: 2 h

Procedure:
In ethanol (3 ml) was dissolved ethyl 2-formyl-3-pyridinecarboxylate (519 mg) followed by addition of methylhydrazine (267 mg), and the mixture was refluxed with stirring for 2 hours. This reaction mixtrue was concentrated to dryness and the residue was washed with diethyl ether-acetone and dried. Yellow powder, 391 mg. 1H-NMR (DMSO-d6) δ: 3.75(3H,s), 7.86(1H,dd,J=8.4&4.4Hz), 8.48(1H,s), 8.62(1H,d,J=8.4Hz), 9.14(1H,d,J=4.4Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=[N:21][NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1cccc(Cl)c1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=O)c1ccccc1)c1cccc(Cl)c1O
Temperature: 60 °C
Yield: 59.1 %

Procedure:
A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow solid (0.100 g, 59%): mp 202-203° C.; 1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>C(N(CC)CC)C.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:47][Si:48]([CH3:50])([CH3:49])[C:51]#[C:52][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#C[Si](C)(C)C)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.5 g) in triethylamine (5 mL) were added trimethylsilylacetylene (0.2 mL), tetrakis(triphenylphosphine)palladium (0) (81 mg) and copper (I) iodide (27 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The insoluble material was removed by filtration. The filtrate was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1-2/1) to give 4-(2-trimethylsilylethynyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.4 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added tetra(n-butyl)ammonium fluoride (0.15 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.33 g).
Reaction SMILES: CN(C=O)C.Cl[N:7]([C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1)[C:8]([CH3:10])=[O:9].O.O.[S:19]1([C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[NH:22]1)(=[O:21])=[O:20].[Na]>O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:7][C:8](=[O:9])[CH2:10][N:22]2[C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[S:19]2(=[O:20])=[O:21])[CH:15]=1
Reactant: CC(=O)N(Cl)c1cc(C)on1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To 2.31 liters of DMF is added 479 grams (2.75 moles) of 3-(chloroacetamino)-5-methylisoxazole followed by 669 grams (2.9 moles) of sodium saccharin dihydrate. The mixture is heated to 100°C. and this temperature is maintained for 2 hours. The cooled reaction mixture is poured into 8 liters of water, filtered and the wet cake is recrystallized from 15 liters of ethanol to give 658 grams (74.8%) of 2,3,dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide, mp 218°-220°C.; I.R. and NMR spectra are consistant with the structure.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:52])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:53][C:54]1[O:55][C:56]([CH3:62])=[C:57]([C:59](O)=[O:60])[N:58]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:52])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[C:59]([C:57]1[N:58]=[C:54]([CH3:53])[O:55][C:56]=1[CH3:62])=[O:60])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)c(C)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
(S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.025 g), 2,5-dimethyl-oxazole-4-carboxylic acid (0.010 g), HBTU (0.027 g) in DCM (3.0 mL), DIEA (0.019 g) was added. The reaction mixture was stirred at room temperature for 2.0 hours, poured onto a silica gel column and eluted with 1% MeOH, 1:1 hexanes-EtOAc to provide (S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.0139 g).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@H]2O)[C@@H]1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OS(C)(=O)=O)[C@@H]1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-L-glucofuranoside as a colorless oil, 669 mg, 95% yield, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16](C(O)=O)=[C:15]3[N:10]([N:11]=[C:12]([O:20][CH3:21])[CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:29][C:16]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][C:12]([O:20][CH3:21])=[N:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C(=O)O)c(-c3cccc(F)c3)nn2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Br)c(-c3cccc(F)c3)nn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylic acid (2.0 g) in anhydrous DMF (20 ml) was added n-bromosuccinimide (1.78 g) and the resulting solution stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (800 ml) and washed sequentially with water (10×100 ml) and sat. brine (25 ml), dried (Na2SO4), and concentrated to give the title compound as a buff solid (2.1 g, 93%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CC[N:21]([CH:25]([CH3:27])[CH3:26])C(C)C.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CCOC(C)=O.CN(C=O)C>[CH:25]1([NH:21][C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:18])[CH2:27][CH2:26]1
Reactant: COCCNc1cc(C(=O)O)c2ccccc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNc1cc(C(=O)NC2CC2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a DMF (0.1 M) solution of 3-{[2-(methyloxy)ethyl]amino}-1-naphthalenecarboxylic acid (1 eq.) from the previous step, Hunig's base (3 eq.) and cyclopropylamine (1.5 eq.) was added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting reaction solution was stirred at RT for 48 h. The now reddish solution was diluted with EtOAc and washed sequentially with 1 N aq. NaOH, water and brine. The organic extract was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24](O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(Cl)Cl>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]([F:7])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Product: FC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.27 mL (2.0 mmol) of (Diethylamino)sulfur trifluoride (DAST) in 2 mL of CH2Cl2 was cooled to −78° C. To this was added a solution of 1-benzyl-4-(3-Phenyl-2-hydroxypropyl)piperidine (Example 228, Step 2) in 2 mL of CH2Cl2. The mixture was stirred and warmed to rt. After 20 min, 10 mL of H2O were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give 1-benzyl-4-(3-phenyl-2-fluoropropyl)piperidine. Removal of the benzyl protecting group was achieved under standard conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28]
Reactant: O=C(CBr)c1cccnc1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cccnc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromoacetylpyridine hydrobromide (G. B. Barlin, L. P. Davies, S. J. Ireland, M. M. L. Ngu, Aust. J. Chem., 1989, 42, 1735).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][CH2:12][C:13]([F:24])([F:23])[C:14]([F:22])([F:21])[C:15]([F:20])([F:19])[CH:16]([F:18])[F:17])(=[O:10])[CH:8]=[CH2:9]>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:9][CH2:8][C:7]([O:11][CH2:12][C:13]([F:23])([F:24])[C:14]([F:21])([F:22])[C:15]([F:20])([F:19])[CH:16]([F:17])[F:18])=[O:10])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: C=CC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Product: O=C(CCN1CCOCC1)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Yield: 97 %

Procedure:
With ice cooling and stirring, 9.6 g of morpholine was added dropwise to 28.6 g of 2,2,3,3,4,4,5,5-octafluoropentyl acrylate. The mixture was stirred for one hour at room temperature, after which it was directly distilled for purification. There was obtained 36.2 g of 2,2,3,3,4,4,5,5-octafluoropentyl 3-morpholinopropionate (boiling point 84° C./13 Pa, yield 97%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6](O)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1.O=P(Cl)(Cl)[Cl:21].CC(=O)OCC>[N+](C)(C)(C)C.[Cl-].CC#N>[Cl:21][C:6]1[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=2[F:1])=[CH:10][N:9]=[C:8]([S:11][CH3:12])[N:7]=1
Reactant: CSc1ncc(Oc2ccc(F)cc2F)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
The title compound of step 1 (5.30 g, 19.63 mmol), POCl3 (18.06 g, 117.78 mmol), (Me)4NCl (3.23 g, 29.47 mmol) in dry CH3CN (60 mL) was refluxed for 12 h. The mixture was poured into ice-water (50 mL) and subjected to EA extractive work up. Concentration under vacuum gave impure title compound (4.0 g), which was carried on to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1>CC(O)=O.O.[Fe]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=2)=[CH:14][CH:13]=1)=[O:17])=[O:29]
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)NC(=O)Nc1ccc(Sc2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Iron powder (1.77 g, 31.63 mmol) was added in portions to a mixture of 6n (3 g, 6.32 mmol) in AcOH (90 mL) at 80° C. The reaction mixture was refluxed for 30 min and then cooled to room temperature and diluted with water. The precipitated solid was collected by filtration. The solid was dissolved in an excess of ethyl acetate and filtered. The filtrate was dried and concentrated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-hexane 2:3) to give 7d, yield 62%. 1H NMR (400 MHz, DMSO-d6): δ 11.92 (br, s, 1H), 10.73 (br, s, 1H), 8.75 (s, 2H), 7.68 (m, 2H), 7.57 (m, 2H), 7.25 (m, 1H), 6.79 (m, 1H), 6.59 (m 2H); EI-MS m/z 443 [M]+, 445 [M+2]+; HRMS calculated for C18H12BrN5O2SNa [M+Na]+: 465.9943, found: 465.9938. Anal. (C18H14BrN5O2S) C, H, N.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([O-:19])=[O:18].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[C:11]=1[OH:16])([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(Nc1ccccc1)c1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 42.1 %

Procedure:
2-Phenylaminocarbonylphenol (5.00 g, 23 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (2.20 g, 25.5 mmol). The addition of sulfuric acid (30 mL/3 M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. THe organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(2.50 g, 42%). 1H NMR (CD3COCD3): δ 8.15 (d,1H), 8.09 (d,1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:22])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methylphenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow oil (0.405 g), which was subsequently deprotected.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[OH-:20].[Na+]>C(O)(=O)C>[O:13]([CH2:12][C:4]1[NH:3][C:2](=[O:20])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(COc2ccccc2)nc2nccnc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(COc2ccccc2)nc2nccnc12

Procedure:
A mixture of 4.0 g (0.016 mole) of 4-amino-2-(phenoxymethyl)pteridine and 400 ml of 5% aqueous sodium hydroxide is brought slowly to 95° C. and maintained at this temperature for 2 hours. After cooling, the solution obtained is acidified with acetic acid to pH 5.5. The precipitate formed is isolated by filtration. It is purified by recrystallization from ethanol. Yld: 2.8 g (70%), m.p. 220°-221° C.