Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Cl)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:16]2[CH2:18][CH2:17]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc2ccccc2c(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccccc2c(C2CC2)n1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 481 mg (2.17 mmol) 1-chloro-isoquinoline-3-carboxylic acid methyl ester, 235 mg (2.74 mmol) cyclopropylboronic acid, 100 mg (0.137 mmol) 1,1′-bis(diphenyl-phosphino)ferrocenedichloropalladium(II) and 950 mg (4.47 mmol) potassium phosphate in 20 mL dioxane was stirred at 110° C. for 12 h. The mixture was diluted with EtOAc, filtered over Celite and activated carbon and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=3/1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1F.O>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1[O:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:4]=1[F:3])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1Cl)Cc1ccc(F)cc1F
Temperature: -2.5 °C
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
Sodium hydride (0.101 g, 3.83 mmol, 95% in oil) was added to N,N-dimethyl formamide (20 mL) at −5 to 0° C. under nitrogen. The suspension was stirred for 10 minutes and to the resulting cooled mixture was added a solution of tert-butyl 2,4-difluorobenzyl(2-hydroxyethyl)carbamate (1.1 g, 4.21 mmol) in N,N-dimethylformamide (10 mL), maintaining the temperature at −5 to 0° C. during addition. The reaction mixture was stirred further for 20 minutes and then a solution of 3-chloro-4-fluoro-nitrobenzene (0.67 g, 3.83 mmol) in N,N-dimethyl formamide (10 mL), was added dropwise, maintaining the temperature in the range −5 to 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Water (300 mL) was then added to the reaction mixture and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 5-20% EtOAc in hexane to give the title compound (1.8 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:6]([F:16])[C:5]([C@H:17]([NH:20][CH2:21][C:22]2[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=[N:25][CH:26]=2)[CH2:18][CH3:19])=[CH:4][CH:3]=1.Cl.CCOC(C)=O.C(O)C>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:17]([NH:20][CH2:21][C:22]2[NH:23][CH:24]=[N:25][CH:26]=2)[CH2:18][CH3:19])=[C:6]([F:16])[C:7]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CC[C@@H](NCc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(C)=O
Product: CC[C@@H](NCc1cnc[nH]1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 56.9 %

Procedure:
To (6-Chloro-2-fluoro-3-{(R)-1-[(3-trityl-3H-imidazol-4-ylmethyl)-amino]-propyl}-phenyl)-pyridin-3-yl-methanone (0.208 g, 0.33 mmol) suspended in acetone (2 ml) treated with saturated HCl/EtOAc, ethanol added till all in solution stirred at ambient for 18 hours, concentrated then purified by Prep HPLC to give [(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl](1H-imidazol-5-ylmethyl)amine (0.07 g), MS: [M+H] 373
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:15][OH:16])[CH2:13][C:12](=[O:14])[CH2:11]2)[CH:5]=[C:4]([Cl:17])[N:3]=1.[BH4-].[Na+].Cl.C(O)C>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:15][OH:16])[CH2:11][CH:12]([OH:14])[CH2:13]2)[CH:5]=[C:4]([Cl:17])[N:3]=1
Reactant: Nc1nc(Cl)cc(NCC2(CO)CC(=O)C2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Cl)cc(NCC2(CO)CC(O)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-6-chloro-4-[[(1-hydroxymethyl-3-oxo-1-cyclobutyl)methyl]-amino]pyrimidine (2.21 g, 8.26 mmol) was dissolved in ethanol (80 ml) and sodium borohydride (0.31 g, 8.26 mmol) was added portionwise under ice-cooling. The mixture was stirred at room temperature for 30 minutes. The mixture was neutralized with hydrochloric acid-ethanol. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:7) to give white crystals (2.14 g, quantitative), m.p. 136-139° C. (ethyl acetate).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([O:21]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:21])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(Cl)cc3)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
2-(4-chloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (1.0 g, 3.16 mmol) obtained in step 2 was dissolved in 10 ml of toluene, aluminum chloride (2.11 g, 15.8 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (745 mg, 2.59 mmol) in a yield of 82%.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CN1CCNCC1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of acryloyl chloride (102.0 g, 1.13 moles) in methylene chloride (100 ml) was added dropwise into a solution of N-methyl piperazine (86.0 g, 0.86 moles) in methylene chloride (450 ml) over a period of one hour. During the addition, the temperature of the N-methyl piperazine/methylene chloride solution was kept below 25° C. After the addition was complete, the reaction mixture was stirred at room temperature for two hours. The reaction mixture was neutralized with 260 g of 17% sodium carbonate solution. The organic layer containing the crude product was separated from the aqueous layer via a separatory funnel. The aqueous layer was washed well with methylene chloride. Combination of the organic phases and rotoevaporation of the solvent yielded 100.0 grams of crude product. Distillation of the crude product yielded a fraction (74°-78° C.,/5 mm Hg) that was >98.0% pure by G.C. analysis. 13C NMR and IR analysis gave spectra consistent with the title compound.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[F:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=3[C:22]3[C:17]2=[C:18]([CH3:30])[CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[F:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=3[C:22]3[C:17]2=[C:18]([CH3:30])[CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=1
Reactant: Cc1cccc2c3c(n(Cc4ccc(F)cc4)c12)CCCC3=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc2c3c(O)cccc3n(Cc3ccc(F)cc3)c12
Temperature: 75 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Pyridinium bromide perbromide (0.0800 g, 0.25 mmol) is added to a solution of 9-(4-fluorobenzyl)-8-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one in THF (0.4 mL) and DMF (0.3 mL) and the mixture is heated to 75° C. After stirring for 8 h, THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium sulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.0391 g, 0.45 mmol), lithium carbonate (0.0358 g, 0.48 mmol) and DMF (1.2 mL) is heated at 120° C. for two hours. The DMF is then removed under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (30 mL) using ethyl acetate/heptane (10/90) to give 0.0321 g (52%) of the title compound; MS (ESI+) for C20H16FNO m/z 306.1 (M+H)+; IR (drift) 3545, 1588, 1508, 1453, 1408, 1336, 1316, 1269, 1234, 1227, 1203, 819, 791, 743, 720 cm−1; 1H NMR (CDCl3) δ2.63, 5.36, 5.72, 6.58, 6.85, 6.96, 7.15-7.22, 8.25. Anal. Calcd for C20H16FNO: C, 78.67; H, 5.28; N, 4.59. Found: C, 74.98; H, 5.05; N, 4.37.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH:19](Br)[CH3:20].C(C(C)=O)C>C(OCC)(=O)C.CCCCCC>[Br:18][CH2:19][CH2:20][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: CC(Br)Br
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCBr)cc1
Reaction time: 24 h

Procedure:
A mixture of 100 g. of methyl p-hydroxybenzoate, 200 g. of anhydrous potassium carbonate, 400 g. of dibromoethane and 1500 ml. of methyl ethyl ketone is refluxed under vigorous stirring for 24 hours, at the end of which time the reaction is essentially complete, as demonstrated by t.l.c. using an ethyl acetate-hexane mixture (60:20) as gradient. The solid is separated by filtration, and the filtrate is evaporated to dryness under vacuo. The oily residue is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate and evaporated to dryness under vacuo, to yield methyl 4-(2-bromoethoxy)benzoate.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:34])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)[CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Cl.O1CCOCC1>>[F:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)[CH2:22]3)[CH2:18][CH2:17]2)=[O:34])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21)[C@@H]1C[C@H](F)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-2-(3-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate from Step 3 (63 mg, 0.130 mmol) and 4 N HCl in 1,4-dioxane (0.487 mL, 1.948 mmol) to give a colorless solution. The reaction was stirred at room temperature overnight, and the solvent was then removed in vacuo. The residue was purified using a 12 g silica gel cartridge eluted with a gradient of 0-2.5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (4S)-4-fluoro-N-{(3aR,4S,6aS)-2-[3-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-prolinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.31 (d, J=7.5, 1H), 7.33 (dd, J=10.1, 5.7, 1H), 7.06 (d, J=7.6, 1H), 6.90 (s, 1H), 6.75 (dd, J=8.3, 2.1, 1H), 5.30-5.12 (m, 1H), 4.30 (dt, J=14.4, 7.3, 2H), 3.72-3.55 (bs, 1H), 3.50-3.43 (m, 1H), 3.32 (ddd, J=21.0, 13.1, 0.8, 1H), 3.23 (dd, J=9.9, 8.0, 1H), 3.13 (dd, J=9.5, 8.2, 1H), 2.99 (dd, J=9.7, 4.1, 1H), 2.96-2.84 (m, 1H), 2.76-2.67 (m, 1H), 2.66-2.52 (m, 2H), 2.26 (dddd, J=39.3, 14.8, 7.9, 4.3, 1H), 2.07 (td, J=12.3, 6.8, 1H), 1.93 (dtd, J=13.1, 7.9, 5.2, 1H), 1.60 (ddd, J=16.0, 12.6, 7.8, 1H), 1.38 (ddd, J=13.2, 7.7, 6.7, 1H); MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].S(OC)(OC)(=O)=O.S(OS(OC)(=O)=O)(OC)(=O)=O.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:1]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)(=[O:4])=[O:2])=[CH:26][CH:25]=1
Reactant: O=S(=O)=O
Reactant: Clc1ccccc1
Agent: COS(=O)(=O)OS(=O)(=O)OC
Solvent: COS(=O)(=O)OC
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
When the components are passed once through the reactor at a rate giving a residence time of from 1 to 3 minutes, the conversion rate is 57%. This can be increased to 91% conversion by continuously pumping the effluent reaction mixture back to the fixed bed of the reactor to give an average residence time of approximately 15 minutes. No advantage is gained, we have found, by first converting sulfur trioxide and dimethyl sulfate to reactive dimethyl pyrosulfate and then reacting the latter with chlorobenzene. Precipitating the product in chlorobenzene instead of aqueous sulfuric acid gives bis(4-chlorophenyl) sulfone having a purity of >99.5%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:17])O1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]3[CH:39]=[CH:38][NH:37][C:34]3=[N:35][CH:36]=2)=[C:27]([F:40])[CH:26]=1>>[F:40][C:27]1[CH:26]=[C:25]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:17])=[O:18])[CH:30]=[CH:29][C:28]=1[C:31]1[N:32]=[C:33]2[CH:39]=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1
Reactant: CC(C)CS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)ccc1-c1cnc2[nH]ccc2n1
Product: CC(C)CS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc3[nH]ccc3n2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 490 using N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isobutylsulfonamide and 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): mass calcd. C22H21FN4O2S, 424.14; m/z found, 425.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.78 (d, J=2.6, 1H), 8.20-8.11 (m, 1H), 7.73-7.65 (m, 2H), 7.46-7.37 (m, 1H), 7.34-7.29 (m, 2H), 7.26-7.19 (m, 2H), 6.87-6.79 (m, 1H), 6.59 (s, 1H), 2.97 (d, J=6.6, 2H), 2.31-2.13 (m, 1H), 1.05 (d, J=6.7, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Mg]Br)(C)C.C1COCC1.[N+:19]([C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH:24]=[O:25])([O-:21])=[O:20]>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:22]([N+:19]([O-:21])=[O:20])=[C:23]([CH:24]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[OH:25])[CH:26]=1
Reactant: Clc1ccc(I)cn1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1ccc(Cl)nc1
Temperature: -45 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0 eq.) in 10 mL anhyd. THF was stirred at −40° C. to −50° C. After five minutes, 2.2 mL of 2.1 M iPrMgBr/THF (4.6 mmol, 1.1 eq.) were added drop wise over 1 minute and the reaction mixture is maintained at −40 to −50° C. for 30 minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was then added and the reaction was maintained at −50° C. After 1 hour, the reaction was allowed to warm to −10° C., and quenched with 50 mL saturated brine after a further fifteen minutes. The crude product was extracted with EtOAc, dried on Na2SO4 and concentrated by rotary evaporation to yield desired product. MS: (M+H)/z=298.9
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:10]([CH:11]=O)[C:9]=1[SH:19])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:20]=[C:21]1[C:29]([CH3:31])([CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:32]>CC(=O)CC>[C:1]([O:6][CH2:7][C:8]1[C:9]2[S:19][C:21]3([C:29]([CH3:31])([CH3:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]3[CH3:32])[CH:20]=[CH:11][C:10]=2[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCc1cc([N+](=O)[O-])cc(C=O)c1S
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CCC(C)=O
Product: C=C(C)C(=O)OCc1cc([N+](=O)[O-])cc2c1SC1(C=C2)N(C)c2ccccc2C1(C)C
Yield: 72.7 %

Procedure:
In 120 ml of 2-butanone were dissolved 14.1 g of 3-methacryloxymethyl-5-nitrothiosalicylaldehyde and 8.7 g of 2-methylene-1,3,3-trimethylindoline and the mixture was refluxed in a nitrogen atmosphere for 20 hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 15.9 g of 8-methacryloxymethyl-6-nitro-1',3',3'-trimethylspiro[2H-1-benzothiopyran-2,2'-indoline] as light yellow crystals (Yield 73%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](=[NH:31])OCC>C(O)C.C(Cl)(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: COc1ccc(COc2cccnc2N)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(COc2cccnc2NC(=N)Cc2ccccc2C)cc1
Yield: 5.3 %

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (4.6 g, 20 mmol) and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, convened to the free base by washing with aqueous sodium bicarbonate, and purified by flash chromatography (chloroform/methanol) to obtain the product as a gum (0.38 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6](=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CCCCNC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-butylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-butylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with butylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2([CH3:31])[CH2:29][CH2:28][O:27][C:26]2=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:26](=[O:30])[C:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])([CH3:31])[CH2:29][CH2:28][OH:27])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Reactant: CC(C)(C)c1cc(N)no1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)c2ccc(Cl)cc2)no1
Reaction time: 0.25 h
Yield: 4.5 %

Procedure:
To a solution of 5-tert-butyl-isoxazol-3-ylamine (0.280 g; 2.00 mmol) in methylene chloride (5 mL) was added dropwise trimethylaluminum (1.0 mL of a 2.0 M solution in toluene; 2.00 mmol). The mixture was stirred 15 minutes and 3-(4-chloro-benzenesulfonyl)-3-methyl-dihydrofuran-2-one (0.440 g; 1.60 mmol) added. The mixture was stirred 18 hours and carefully quenched with 10% aqueous citric acid, aqueous sodium tartrate and chloroform. The organic layer was dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.030 g of the desired product. 1H NMR (CDCl3) δ 9.4 (bs, 1H), 7.76 (d, 2H), 7.52 (d, 2H), 6.49 (s, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 2.58 (m, 1H), 2.25 (m, 1H), 1.65 (s, 3H), 1.3 (s, 9H). MS (ESI): m/e 415, 417 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CC#N>[CH3:39][O:38][N:37]([CH3:36])[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)=[O:11]
Reactant: CSc1nccc(C(=O)O)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CON(C)C(=O)c1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a slurry of 2-methylsulfanyl-pyrimidine-4-carboxylic acid (10.0 g, 59.2 mmol) in CH3CN (300 mL) is added in sequence: 1-hydroxybenzotriazole hydrate (9.59 g, 71.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.6 g, 71.0 mmol), N,O-dimethylhydroxylamine hydrochloride (8.66 g, 88.8 mmol), and triethylamine (Et3N) (24.9 mL, 178 mmol). The resulting slurry is stirred overnight at ambient temperature. After 16 hours, the reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate (300 mL) and the layers separated. The aqueous layer is extracted with ethyl acetate (3×250 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo and the resulting residue is purified over silica (100% EtOAc) to afford 10.1 g (89% yield) of the desired product as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=4.9 Hz, 1H), 7.15 (br s, 1H), 3.77 (br s, 3H), 3.38 (br s, 3H), 2.61 (s, 3H); MS (ESI) m/z 214 (M+1).
Reaction SMILES: C(O)C.[Na].[CH2:5]([O:7][C:8](=[O:23])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=1[C:18]([CH:20]1[CH2:22][CH2:21]1)=O)[CH3:6]>C(OCC)(=O)C>[CH2:5]([O:7][C:8]([C:9]1[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=2[C:18]=1[CH:20]1[CH2:22][CH2:21]1)=[O:23])[CH3:6]
Reactant: CCOC(=O)COc1cccc(O)c1C(=O)C1CC1
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(O)c2c1C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
To an anhydrous ethanol (2 ml) was added sodium (50 mg) at 0° C. under argon atmosphere. After 10 minutes, (2-cyclopropanecarbonyl-3-hydroxy-phenoxy)-acetic acid ethyl ester (380 mg) was added to the reaction mixture and the reaction mixture was stirred overnight at 0° C. The reaction was quenched with 2 N hydrochloric acid (5 ml) and stirred for 30 minutes yielding a white precipitate. The mixture was diluted with ethyl acetate (10 ml), washed with water (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate yielding 3-cyclopropyl-4-hydroxy-benzofuran-2-carboxylic acid ethyl ester (298 mg) as a white solid. FAB-MS: m/z 246 (M+); 1H-NMR (CDCl3): δ 0.99-1.05 (2H, m), 1.17-1.24 (2H, m), 1.45 (3H, t, J=7.26 Hz), 2.26-2.35 (1H, m), 4.45 (2H, q, J=7.26 Hz), 6.27 (1H, s), 6.71 (1H, dd, J=0.99 Hz, 8.25 Hz), 7.09 (1H, dd, J=0.99 Hz, 8.25 Hz), 6.41 (2H, d, J=8.25 Hz), 7.29 (1H, dd, J=8.25 Hz, 8.25 Hz).