Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCCCC=1.[N+:26]([O-:31])([N+]([O-])=O)=[O:27].O>C(O)(=O)C>[N+:26]([C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:31])=[O:27]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc2oc(Br)c(-c3ccccc3)c2c1
Solvent: C1=CCCCC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 55 °C

Procedure:
A mixture of 20 g (0.063 mole) of 2-bromo-3-phenyl-5-benzofurancarboxylic acid and 1.25 1 of acetic acid is stirred and heated to 55° C. To this mixture is added 7.7 g (0.094 mole) of cyclohexene. To this mixture is added dropwise 8.7 g (0.094 mole) of dinitrogen tetroxide in 25 ml of acetic acid. After 5 hours the mixture is poured into cold water and the solid product is collected. Recrystallization from aqueous ethanol followed by recrystallization from a benzene-ethanol mixture provides 2-nitro-3-phenyl-5-benzofurancarboxylic acid, m.p. 271°-273° C.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1ccccc1)=C1SCS1

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (10 g) and aniline (3.6 ml) in methylene chloride (100 ml) was stirred at room temperature for 8 hrs. The reaction mixture was washed with 10% aqueous sodium hydroxide solution, dil-HCl and water and then evaporated to dryness. The residue solid was purified with ethyl acetate to give the titled compound as a white solid. (7.9 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6]
Reactant: COC(=O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a stirred solution of methyl 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (4.12 g, 10 mmol) in tetrahydrofuran (45 mL) and methanol (45 mL) was added lithium hydroxide hydrate (839 mg, 20 mmol) in water (18 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified using an SCX-2 cartridge eluting sequentially with methanol and 7 N methanolic ammonia. The product was triturated with THF (×5) and diethyl ether to give 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (3.51 g, 88%) as a white solid. To a solution of 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (76 mg, 0.19 mmol) in DMF (2 mL) was then added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride (Int 6, 93 mg, 0.19 mmol), followed by DMAP (11 mg, 0.1 mmol) and EDC (72 mg, 0.37 mmol). The mixture was allowed to stir at room temperature for 5 hours, and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (66 mg, 42%).
Reaction SMILES: ClC1C=CC=CC=1Cl.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH2:19][CH:20]=[C:21]4OC5C=CC=CC=5[CH:22]43)[C:17]2=[O:33])=[CH:12][CH:11]=1.C([C:36]1[C:42](=O)[C:41](Cl)=[C:40](Cl)[C:38](=[O:39])[C:37]=1C#N)#N>C(Cl)(Cl)Cl>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24](=[O:25])[C:23]34[C:37]5[CH:36]=[CH:42][CH:41]=[CH:40][C:38]=5[O:39][C:22]3=[CH:21][CH:20]=[CH:19][CH:18]4[C:17]2=[O:33])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N2C(=O)C3CC=C4Oc5ccccc5C4C3C2=O)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N2C(=O)C3C=CC=C4Oc5ccccc5C43C2=O)cc1
Yield: 36.2 %

Procedure:
15 ml of o-dichlorobenzene was added to a mixture of 0.50 g of 2-(4-methylphenyl)-3a,4,10b,10c-tetrahydro-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione and 0.75 g of DDQ. The mixture was refluxed for 4 hours. The reaction mixture was mixed with 50 ml of chloroform. The resulting mixture was washed with an aqueous 10% potassium carbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from methanol to obtain 0.18 g (yield: 36%) of 2-(4-methylphenyl)-1H-benzofuro-[3,2-d]isoindole-1,3(2H)-dione as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.9 g (18.0 mmol) of 3-bromo-4-hydroxybenzoic acid in 20 mL of 3:1 v/v CH2Cl2/CH3OH was treated with 10.8 mL of 2.0 M (trimethylsilyl)diazomethane solution in hexanes. The mixture was stirred at rt for 2 h, then concentrated to give 4.6 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 5.93 (bs, 1H), 7.05 (d, J=8.5, 1H), 7.92 (dd, J=2.1, 8.5, 1M), 8.19 (d, J=2.0, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:48])([F:47])[F:46].C(OCC)(=O)C.[ClH:55]>C(OCC)C>[ClH:55].[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:47])([F:46])[F:48]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 4-[[10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazine-carboxylic acid, tert-butyl ester of Example 6 (0.85 g, 1.29 mmol) was added in one portion to stirred ethyl acetate (10 mL) saturated with hydrogen chloride gas at 0° C. A precipitate formed after several minutes. The reaction mixture was stirred for 90 minutes under anhydrous conditions. The reaction was then warmed to room temperature and diluted with diethyl ether. The precipitated product was collected by filtration and dried under high vacuum to provide the desired title compound hydrochloride salt (0.65 g) as an off-white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Li+].[CH3:24][CH:25]([N-]C(C)C)C.CCI>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH2:24][CH3:25])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4.84 g, 16.2 mmol) in dry THF (60 ml) and HMPA (15 ml) at −78° C. under a dry argon atmosphere was added LDA drop wise (2 M solution in THF, 25 ml, 48.72 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3CH2I (10.13 g, 64.96 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. The reaction was quenched with aqueous citric acid, and the product was extracted with EtOAc (2×), the organic phase washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[O:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[O:33][C:32](=[O:34])[C:31]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:30]([OH:35])[CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Agent: Cc1nc(CCl)n(C)n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3cc(=O)n4c(C)csc4n3)C(=O)O2)cc1
Yield: 17 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 17%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OCCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1OCCCO2
Yield: 84 %

Procedure:
A mixture of intermediate (5) (0.25 mol) and KOH (1 mol) in water (650 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled, acidified with HCl, the resulting precipitate was filtered off, washed with water, and dried, yielding 48 g of 8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid (intermediate 6).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
A solution of triphenylphosphine (160 mg, 0.61 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (109 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid (150 mg, 0.51 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (112 mg, 1.12 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% diethyl ether then 1/1 diethyl ether/ethyl acetate then 1/3 diethyl ether/ethyl acetate) to afford 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide (15 mg, 8%) as a pale yellow foam: mp 48-52° C.; EI-HRMS m/e calcd for C22H23N3OS (M+) 377.1562, found 377.1564.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][C:35]1([CH3:52])[O:39][CH:38]([CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[CH2:37][O:36]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:44]([CH2:43][CH2:42][O:41][CH2:40][CH:38]2[CH2:37][O:36][C:35]([CH3:52])([CH3:34])[O:39]2)[C:45]2[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC1(C)OCC(COCCNc2ccc(F)cc2)O1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccc(F)cc2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.115 ml) and DMF (0.005 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in anhydrous dichloromethane (5 ml). The reaction was stirred at room temperature for 1.5 h then [2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(4-fluoro-phenyl)-amine (0.078 g) as a solution in dichloromethane (0.5 ml), DMAP (0.002 g) and DIPEA (0.080 ml) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with further dichloromethane and extracted with saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (1:1, 2:1 and 4:1 v/v), to give the title compound as a colourless gum (0.037 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=[C:20]1[CH2:24][CH2:23][S:22][CH:21]1[C:25]([O:27][CH3:28])=[O:26]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:20]2[CH2:24][CH2:23][S:22][C:21]=2[C:25]([O:27][CH3:28])=[O:26])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Reactant: COC(=O)C1SCCC1=O
Product: COC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CCS1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and methyl 3-oxotetrahydrothiophene-2-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)-4,5-dihydro-thien-3-yl]ureido}-benzoate, m.p. 161°-163° C.,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:32]([C:28]3[S:27][CH:31]=[CH:30][N:29]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: O=Cc1nccs1
Product: COC(=O)c1cc(N)c2nc(-c3nccs3)nn2c1

Procedure:
The title compound, MS m/e (%): 276.1 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and thiazole-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)Cl>[Br:15][CH2:9][C:8](=[O:10])[C:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:12]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)Oc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)CBr
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
110.2 g (0.5 mol) of 3-(4-chlorophenoxy)-3-methyl-butan-2-one were dissolved in 500 ml of methylene chloride, and 83 g (0.52 mol) of bromine were added dropwise at room temperature in a manner such that continuous decoloration occurred. When the addition had ended, the mixture was subsequently stirred for 30 minutes, the organic phase was washed twice with 300 ml of water and twice with 300 ml of saturated sodium bicarbonate solution and was dried over sodium sulphate and distilled. 105.9 g (70% of theory) of 1-bromo-3-(4-chlorophenoxy)-3-methyl-butan-2-one of boiling point 115° to 118° C./0.1 mm Hg were obtained. ##STR759##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][NH:11][CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: CCCC1CNCC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of 210 mg (0.425 mmol) of tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-naphthalen-2-ylmethoxy-5-propyl-piperidine-1-carboxylate in 18 ml of methanol was treated with 12 ml of 1N hydrochloric acid and stirred at 50° C. overnight. Subsequently, the solution was evaporated under reduced pressure, the residue was taken up in warm toluene and again evaporated, the product beginning to separate out. There were obtained 153 mg (84% of theory) of (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-naphthalen-2-ylmethoxy-5-propyl-piperidine as a colourless solid. MS: 252 (M-naphthylmethyl)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.C(Cl)(Cl)Cl.[Br:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:19][C:11]1[S:10][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([CH3:1])[N:7]=2)=[N:13][CH:12]=1
Reactant: Cc1cc(Nc2nccs2)nc(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2ncc(Br)s2)nc(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask were added 50 mg of (2,6-dimethyl-pyrimidin-4-yl)-thiazol-2-yl-amine (23-2), chloroform (3.0 mL) and 47 mg of N-bromosuccinimide. The reaction was allowed to stir at room temperature for 2 hours. The chloroform was diluted with ethyl acetate and washed with saturated sodium bisulfite solution. The ethyl acetate was dried (MgSO4) and the solvent removed under high vac to give the desired product. The title compound was used as is. 1H-NMR (400 MHz, DMSO-d6) 11.05 (1H, s), 7.53 (1H, s), 6.69 (1H, d), 6.69 (1H, s), 2.54 (3H, s), 2.35 (3H, s). MS(M+1)=285.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[C:7](=[O:21])[NH:6][C:5]2([CH:24]1[CH2:26][CH2:25]1)[C:22]#[CH:23].FC(F)(F)C(O)=O.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:21])[NH:6][C:5]2([CH:24]1[CH2:26][CH2:25]1)[C:22]#[CH:23]
Reactant: C#CC1(C2CC2)NC(=O)N(Cc2ccc(OC)cc2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: C#CC1(C2CC2)NC(=O)Nc2ccc(Cl)cc21
Yield: 71 %

Procedure:
A solution of 1.4 g (4.11 mmol) of 6-chloro-4-cyclopropyl-4-ethynyl-3,4-dihydro-1-(p-methoxybenzyl)quinazolin-2(1H)-one in 5 mL of CH2Cl2 was treated with 10 mL of trifluoroacetic acid (Aldrich) under N2 overnight at r.t. The reaction was concentrated by rotovap under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water, brine, dried over MgSO4 and the solvents removed to give an oil which was flash chromatographed on SiO2 using 95:5 CHCl3 --CH3OH to give a foam. Trituration of this material with ether gave 720 mg (80%) of the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>O1CCCC1.CCCCCC>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution (10 mL) of 2-bromothiophene (1.0 g) in tetrahydrofuran was cooled to −70° C., and a 1.6 mol/L solution (4.2 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 30 min, tributyltin chloride (2.1 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil (2.4 g) containing the title compound was used for the next step without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]([OH:23])=O)([O:3]C(C)(C)C)=O.CN(C(O[N:32]1N=N[C:34]2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.COC(=O)[C@@H](C)N>ClCCl.CN(C=O)C>[CH3:34][C@@H:33]1[C:1](=[O:3])[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[C:21](=[O:23])[NH:32]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: COC(=O)[C@@H](C)N
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1NC(=O)C2CNCCN2C1=O
Reaction time: 0.75 h

Procedure:
To a solution of N,N′-diboc-piperazine-2-carboxylic acid (2 g, 6.06 mmol) in 50 mL of dichloromethane and was added TBTU (2.138 g, 6.66 mmol) and diisopropylethyl amine (1.3 mL, 7.26 mmol). The reaction was stirred for 45 min. In the meantime, a suspension of D-alanine methyl ester hydrochloride (1.249 g, 12.11 mmol) and diisopropylethylamine (3.27 mL, 18.76 mmol) in 20 mL of dichloromethane and 5 mL of DMF was stirred and finally added to the reaction mixture. The reaction was left stirring at room temperature overnight. UPLC-MS analysis showed the expected product (peak at 0.72 min, m/z=416 (M+1), 360 (M−t-Bu+1). The reaction was diluted with dichloromethane and extracted with sat. NaHCO3, dried (Na2SO4), and the solvent removed. The crude (4.242 g) was taken to the next step without further purification.