Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.O1CCCCC1[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[CH:23][CH:22]=1.Cl>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:27]([C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)=[CH2:28])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(O)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of n-butyllithium (1.6 M solution in hexane, 41.6 mL, 1.1 eq) was added dropwise to a solution of 1,3-dibromobenzene (7.6 mL, 1.1 eq) in tetrahydrofuran (30 mL) at −78° C. After stirring 30 min at −78° C. 1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethanone (12.6 g, 57 mmol, 1 eq) in tetrahydrofuran (25 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with 1 N HCl (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude was dissolved in toluene (40 mL) and p-toluenesulfonic acid (50 mg) was added. The mixture was heated at 150° C. for 3 h. The solvent was removed under reduce pressure and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colorless oil (1.2 g, 10%);
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: CNOC
Reactant: Cc1cccc(C(=O)O)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a cooled mixture of 2-chloro-3-methyl-benzoic acid (1 g, 5.88 mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL, 23.52 mmol) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), evaporated to dryness and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 2-chloro-N-methoxy-3,N-dimethyl-benzamide (1.19 g) in 95% yield. ESMS m/z (relative intensity): 214 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:27](Cl)(=[O:29])=[O:28].[NH3:31].Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:27](=[O:29])(=[O:28])[NH2:31]
Reactant: O=C(Nn1cc(S(=O)(=O)Cl)c2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Reactant: N
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 8 %

Procedure:
A solution of 5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonyl chloride (0.14 g) in DCM (20 mL) is treated with a solution of aqueous ammonia solution (28%-5 mL) in water (15 mL) and stirred at rt for 24 h. The reaction mixture is acidified with 10 N aqueous HCl to pH ˜3 and extracted with DCM. The organic layer is washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane to afford 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid-[5-fluoro-3-sulfamoylindol-1-yl)amide (10 mg, 8%) as a solid. MS: 430 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 7.20-7.30 (m, 1H), 7.40-7.50 (m, 2H), 7.60-7.72 (m, 2H), 8.10 (s, 1H), 8.19-8.22 (d, 1H), 8.33-8.37 (d, 1H), 9.44 (s, 1H), 12.45 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[O:16])[CH2:4][CH3:5].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[CH2:17]([N:11]1[C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=[CH:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4.12 g (0.103 mol) of sodium hydroxide dissolved in 41 ml of water were added to a suspension of 20 g (0.103 mol) of 3-propylxanthine in 112 ml of methanol and the reaction mixture was stirred at 70° C. for one hour, then treated dropwise at the same temperature with 12.23 ml (0.103 mol) of benzyl bromide and kept between 70° and 80° C. for 4 hours. The mixture was cooled, filtered cold on a suction filter, and the product was washed with water on the suction filter and dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[CH:28]\[C:29]([NH:31][NH2:32])=[O:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:35](OC(OCC)OCC)C>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[CH:28]\[C:29]5[O:30][CH:35]=[N:32][N:31]=5)/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C(=O)NN
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/c1nnco1
Temperature: 120 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To (E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetohydrazide (118 mg, 0.25 mmol) obtained in Example 106, step 1 was added triethoxymethane (2.1 mL), and the mixture was stirred at 120° C. for 5 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 10/90) to give the title compound (compound 107) (18 mg, 16%).
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7]1)(=O)=O.O[C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]3[CH:44]=[CH:43][C:34]4[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=4[CH:32]=3)[CH:24]=2)=[C:18]([CH3:45])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:45][C:18]1[CH:17]=[C:16]([O:5][C@@H:6]2[CH2:10][CH2:9][N:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7]2)[CH:21]=[C:20]([CH3:22])[C:19]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]2[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=2)[CH:24]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Reactant: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCN(S(C)(=O)=O)C5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
(s)-1-(Methylsulfonyl)pyrrolidin-3-yl methanesulfonate 11c (41 mg, 0.17 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (70 mg, 0.17 mmol) and cesium carbonate (165 mg, 0.50 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction solution was heated to 80° C., and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 11d (71 mg, yield 75.1%) as a light yellow slime.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:29])[CH:17]([CH3:28])[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[C:21]([F:27])[CH:20]=1)C>>[F:25][C:23]1[CH:24]=[C:19]([CH2:18][CH:17]([CH3:28])[C:16]([OH:29])=[O:15])[CH:20]=[C:21]([F:27])[C:22]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1c(F)cc(CC(C)C(=O)O)cc1F
Yield: 69.9 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (35 mg, 0.15 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.04 g, 68%).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].CCN(CC)CC.Cl.[CH:13]1([CH:18]([NH2:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:13]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[NH:25][C:1](=[O:2])[CH3:3])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: NC(c1ccccn1)C1CCCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(c1ccccn1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
AcCl (0.10 g, 1.25 mmol) was added to a stirred suspension of Et3N (0.35 mL, 0.25 g, 2.5 mmol, 2.2 eq.) and (rac)-1-cyclopentyl-1-(2-pyridinyl)methylamine HCl salt (0.25 g, 1.14 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at rt for 2 h. The reaction mixture was washed with H2O (10%, 3×3 mL) and was dried over Na2SO4 and was concentrated under reduced pressure yielding the crude product (0.20 g) as a clear yellow oil which quickly crystallized. 1H NMR (300 MHz, CDCl3) δ ppm 8.53 (d, J=5.0 Hz, 1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 6.72 (br d, J=7.0 Hz, 1H), 4.93 (t, J=9.0 Hz, 1H), 2.37-2.20 (m, 1H), 2.00 (s, 3H), 1.80-1.10 (m, 8H); HPLC: Daicel Chiralpak AD-H, 80:20 v/v heptane-EtOH (+0.2% Et2NH), 1.0 mL min−1, 210 nm, Rt=9.5 min, Rt=19.2 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C.Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCCCBr)c(-c2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(OCCCBr)c(-c2ccccc2)c1
Reaction time: 1.5 h
Yield: 52 %

Procedure:
2-(3-Bromo-propoxy)-5-nitro-biphenyl (q, 530 mg, 1.57 mmol) was refluxed with stannous chloride hydrate (1.1 g, 4.8 mmol) in 5 mL ethanol and 3 mL concentrated HCl. After 1.5 hours, the solvent was evaporated and the mixture was basified with 2N NaOH. The mixture was then extracted with DCM, dried and evaporated, affording 250 mg 6-(3-bromo-propoxy)-biphenyl-3-ylamine (r) in 50% yield: 1H NMR (500 MHz, CDCl3): 7.3 (m, 5H), 6.7 (m, 3H), 4.2 (bs, 2H), 3.9 (m, 2H), 3.5 (m, 2H) and 2.1 (2H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC=CC=1.C[O-].[Na+]>[I-].[K+].CO>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:38][CH:37]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(OCc2ccccc2)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 52.6 %

Procedure:
To a mixture of 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate, 5.0 g of p-benzyloxyphenol, 50 mg of potassium iodide, 10 ml of benzene and 40 ml of methanol is added 1.19 g of sodium methoxide. The mixture is refluxed for 24 hours and the solvent removed under reduced pressure. To the residue is added acetone and hexane and the solids filtered off. The filtrate is dried (MgSO4) and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as eluent. The oil obtained is crystallized from hexane-methanol to give 5.6 g of crystals. Recrystallization from methanol-ethyl acetate gives crystals, mp 98°-101° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:58]([CH:61]2[CH2:63][CH2:62]2)(=[O:60])=[O:59])=[C:10]([CH2:12][N:13]([CH3:57])[C:14]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][C:40]=2[F:41])[C:37]([N:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:36][CH:35]=[CH:34]3)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[CH:19][C:18]=2[F:29])=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:45]([O:44][C:43]([N:42]([C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:16]3[C:14](=[O:15])[N:13]([CH3:57])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:58]([CH:61]4[CH2:62][CH2:63]4)(=[O:59])=[O:60])[NH:5][C:1](=[O:2])[O:27][CH2:26][C@H:25]([CH3:28])[C:20]4[C:21]([O:23][CH3:24])=[CH:22][C:17]3=[C:18]([F:29])[CH:19]=4)=[C:40]([F:41])[CH:39]=2)[CH:34]=[CH:35][N:36]=1)[C:50](=[O:51])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:49])([CH3:47])([CH3:48])[CH3:46]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)c(F)cc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc2c(F)cc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
Phosgene (87 mg, 0.176 mmol) was added dropwise to a solution of 25D (148 mg, 0.176 mmol) in acetonitrile (2.5 mL)/CH2Cl2 (2.5 mL) at 0° C. The mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene, and then the mixture was added to a solution of TEA (0.123 mL, 0.881 mmol) in CH2Cl2 (25 mL) at 40° C. over 5 h. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 15 min using a 12 g silica gel cartridge). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 25E (20 mg, 0.023 mmol, 13.11% yield).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1O[C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[K+].[Se-]C#N.[K+].C(O)CCC(C)C.O>COC(OC)(C)C.C(OCC)(=O)C>[CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])/[CH:3]=[CH:4]/[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: CC(C)CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#C[Se-]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 44.4 %

Procedure:
Pseudomonic acid A (500 mgs) was dissolved in 2,2-dimethyoxypropane (50 ml) and treated with p-toluene sulphonic acid (few crystals). After 1 hour the solution was diluted with ethyl acetate, washed with brine and dried (MgSO4). The solution was evaporated in vacuo and the residue redissolved in water-methanol (1:1, 20 ml) and potassium bicarbonate (100 mgs, 1 eq) added. The solvents were removed in vacuo and potassium selenocyanate (432 mgs, 3 eq) and iso-hexylalcohol-water (9:1, 15 ml) added and reaction refluxed for 4 days. After filtering, the reaction mixture was diluted with ethyl acetate (20 ml) and extracted with aqueous sodium bicarbonate (3×20 ml). The aqueous extracts were combined and acidified with acetic acid under a layer of ethylacetate (20 ml). After stirring for ca. 1 hour the organic layer was separated and aqueous layer further extracted with ethylacetate (3×20 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated to an oil. Chromatography of the oil on silica (5 g) gave pure pseudomonic acid C (215 mgs, 45%).
Reaction SMILES: CO[C:3]1[CH2:4][C:5]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[BH4-].[Na+]>C(O)C>[C:5]12([CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:12][CH2:3][CH2:4]2
Reactant: COC1=Cc2ccccc2C2(CCC(=O)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC2(CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a partial solution of 5.10 g. (0.038 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen-4-one(r) (prepared as in Example 16A) in 105 ml. of 95% ethanol, 2.59 g. of sodium borohydride is added and the mixture stirred at room temperature for about 4 hours. Most of the solvent is removed under vacuum and water added to the residue. The material that precipitates is extracted with ether and the combined extracts washed with water and brine and evaporated to dryness. The residue is recrystallized once from Skellysolve B and then chromatographed over a column containing 500 ml. of silica gel with elution by 10% acetone:Skellysolve B. On the basis of TLC the less polar fractions are combined and recrystallized from benzene:cyclohexane to give a small amount of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), having a melting point of 144.5° to 146° C., and an NMR spectrum suggesting that the compound has the hydroxy substituent in the axial position.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:18][C:19]=3[CH:25]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 3, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storage at 4° C. overnight, the resulting precipitate was filtered off, washed with water and dried to obtain a yellow solid (27 mg, 48 μmol, 37%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]=; Rt=4.14 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reaction time: 17 h

Procedure:
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.4 ml) in 2 portions. The resulting suspension was stirred for 17 h. The solid was collected by filtration, washed with water and dried in vacuo.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.CC(C)([O-])C.[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:10]1[CH2:11][CH2:12][CH:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]1=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1NCCC1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(Cc2ccccc2)CCN1CCCCBr
Reaction time: 18 h

Procedure:
To a solution of 3-(phenylmethyl)-2-pyrrolidinone (0.23 g, 1.3 mmol) and 1,4-dibromobutane (0.57 g, 4.2 mmol) in DMF (5 ml) was added sodium t-butoxide (0.151 g, 1.6 mmol) and the solution stirred for 18 h. The solution was concentrated and the residues chromatographed over silica (20 g SPE, eluting first with cyclohexane then with DCM) to provide the title compound as a colourless oil containing a trace of DMF (0.25 g, 61%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:7][CH:8]=1)[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:15]
Reactant: CCC(CC)C(c1ccc(NC(=O)CCl)cc1)n1cncn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(CC)C(c1ccc(NC(=O)CN2CCN(C)CC2)cc1)n1cncn1
Yield: 35.8 %

Procedure:
A mixture of (±)-2-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide (0.0218 mol), 1-methylpiperazine (0.0436 mol) and K2CO3 (0.0436 mol) in CH3CN (150 ml) was stirred and refluxed for 4 hours. The mixture was cooled, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (8.13 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 3 g (35.8%) (±)—N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-4-methyl-1-piperazineacetamide (compound 15).
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].Cl>CO.O>[SH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S)C(=O)O
Temperature: 150 °C

Procedure:
To a solution of 6.0 ml of 0.5 M sodium methoxide in methanol was added 100 mg of 4-Mercapto-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester and 286 mg of L-alanine. The mixture was heated to 150° C. for 15 minutes using a CEM Discover microwave reactor. The resultant solution was acidified to pH 3 with 1N HCl, diluted with 10 ml water, and extracted with 20 ml of ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to 114 mg of product; MS (−): m/z 369.07 (M−1).