Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30]C5C(C)=NC=CC=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:38][C:39]1[CH:44]=[C:43](O)[CH:42]=[C:41]([CH3:46])[N:40]=1>>[CH3:38][C:39]1[CH:44]=[C:43]([O:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]3[N:21]=[N:20][N:19]([CH:10]4[CH2:9][CH2:8][C:7]5[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=5[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:11]4=[O:18])[CH:23]=3)=[CH:25][CH:26]=2)[CH:42]=[C:41]([CH3:46])[N:40]=1
Reactant: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1
Reactant: Cc1cc(O)cc(C)n1
Product: Cc1cc(Oc2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)cc(C)n1

Procedure:
Prepared as for 6-fluoro-3-(4-{4-[(2-methylpyridin-3-yl)oxy]phenyl}-1H-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 2,6-dimethyl-4-hydroxypyridine.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12]CCCCCCBr.BrCCBr.C([O-])(O)=O.[Na+]>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[O:4]1[CH:5]=[CH:1][CH:2]=[C:3]1[C:7]([C:8]1[O:6][CH:11]=[CH:10][CH:9]=1)=[O:12]
Reactant: C1CCOC1
Reactant: BrCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: BrCCBr
Product: O=C(c1ccco1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
Preparation of 1-(2-Furyl)-7-hydroxy-1-heptanone (R=n-C6H12OH)—Magnesium turnings (8.20 g, 0.342 mol, 4.5 eq/halide) were covered with anhydrous THF (40 mL) and a solution of 1-(tetrahydropyran-2-yloxy)-6-hexyl bromide (20.1 g, 76.0 mmol in anhydrous 100 mL THF) was added dropwise once the reaction was initiated with 1,2-dibromoethane. The remaining halide solution was added dropwise and the mixture was allowed to stir at rt overnight. The resulting mixture was then added to a cooled solution of the Weinreb amide (10.3 g, 66.1 mmol in 100 mL anhydrous THF, 0° C.) via cannula. The resulting slurry was stirred (3 h) and then quenched with equal amounts of 1 N HCl and H2O. After warming to rt the mixture was separated and the aqueous layer was extracted with Et2O (2×). The combined organics were washed with sat'd. NaHCO3, brine, dried (Na2SO4), filtered, and evaporated to yield crude residue, which was then dissolved in MeOH (200 mL) with a small amount of TsOH and allowed to stir overnight. The reaction mixture was stirred with NaHCO3, evaporated, and the residue taken up in hexane. The hexane portion was washed with H2O (2×), brine, dried (Na2SO4), and concentrated to yield crude furyl ketone, which was distilled under vacuum (b.p. 164–167° C., 0.2 mm Hg) to give pure furyl ketone (6.95 g, 35.4 mmol, Yld. 53.6%). 1H NMR: δ 7.57 (dd, 1H, 3JH,H=1.7 Hz, 4JH,H=0.74 Hz, H-2), 7.17 (dd, 1H, 3JH,H=3.6 Hz, 4JH,H=0.76 Hz, H-4), 6.52 (dd, 1H, 3JH,H=3.6 Hz, 3JH,H=1.7 Hz, H-3), 3.63 (t, 2H, 3JH,H=6.6 Hz, H-12), 2.81 (t, 2H, 3JH,H=7.6 Hz, H-7), 2.13 (bs, 1H, OH), 1.72 (quintet, 2H, 3JH,H=7.4 Hz, H-8), 1.57 (quintet, 2H, 3JH,H=6.7 Hz, H-11), 1.39 (m, 4H, H-9 and 10). 13C NMR: δ 189.8, 152.7, 146.3, 117.0, 112.2, 62.8, 38.3, 32.5, 29.0, 25.5, 24.2.
Reaction SMILES: C[C@@:2]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([OH:28])(=[O:27])=[O:26])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O-:5])=[O:4].[K].[OH-].[Na+]>O.C(O)C>[S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:13]1[N:12]([C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4])[CH:16]=[CH:15][N:14]=1)=[O:29])([OH:28])(=[O:26])=[O:27]
Reactant: CCCCCC[C@](C)(C(=O)[O-])n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC[C@H](C(=O)O)n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The potassium salt (22.5 g) was dissolved in a mixture of 200 mL H2O and 100 mL of ethanol. To this solution was added 1N NaOH (53 mL). The reaction was allowed to stir for 3 hours. Ethanol was then removed in vacuo, and the aqueous acidified to pH=1.5 with 5N HCl. This solution was extratced with 10% ethanol/ethyl acetate (3×200 mL). The organic was dried (Na2SO4) and concentrated in vacuo to give 8.65 g (46% for two steps) of (R)-[(2-sulfobenzoyl)amino-1H-imidazol-1-yl]-octanoic acid as a white solid. MS.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(C#C[Si](C)(C)C)c1
Yield: 62.6 %

Procedure:
Into a reaction flask were added tert-butyl (5-bromopyridin-3-yl)carbamate (3.0 g, 11.0 mmol), tetrahydrofuran (30 mL), and triethylamine (1.7 mL, 12 mmol). The reaction mixture was stirred under N2 bubbling for 5 min. (Trimethylsilyl)acetylene (1.60 g, 16.3 mmol), copper(I) iodide (84 mg, 0.44 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol) were then added. The resultant mixture was heated at 50° C. overnight. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (2.0 g, 63%). LCMS for C15H23N2O2Si (M+H)+: m/z=291.1.
Reaction SMILES: N1C=CN=C1.[C:6]1([P:12](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([OH:37])=[CH:34][CH:35]=2)[C:30]([CH:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[N:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[C:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][P:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:13])=[CH:34][CH:35]=2)[C:30]([CH:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[N:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1c1nn(C(=O)OC(C)(C)C)c2ccc(O)cc12
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1c1nn(C(=O)OC(C)(C)C)c2ccc(OP(=O)(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90 mg of imidazole and 250 μl of diphenylphosphinyl chloride are added to a solution of 140 mg of 3-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-5-hydroxyindazole-1-carboxylic acid tert-butyl ester in 15 ml of dichloromethane. The reaction medium is stirred at ambient temperature overnight. After dilution with 10 ml of dichloromethane and 10 ml of distilled water, the medium is separated by settling out. The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure in a rotary evaporator. The crude is taken up in a dichloromethane/methanol mixture and the solid is filtered off. After concentration under reduced pressure, the filtrate is purified by flash chromatography, eluent: cyclohexane/ethyl acetate 8:2 to obtain 200 mg of 3-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-5-(diphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, p-nitroaniline (138 g) was dissolved in a mixed solution of tetrahydrofuran (200 ml) and pyridine (140 ml) in a nitrogen atmosphere. Then, octadecanoyl chloride (333 g) was added dropwise into the three necked flask through the dropping funnel, over a time span of 20 minutes while stirring the reaction mixture. After the completion of the dropping, the reaction mixture was stirred for 2 hours. Then, a solid product was produced. The solid product was filtered and the filtrate was concentrated under a reduced pressure to provide crystals. The crystals were collected and recrystallized from ethanol. 4'-nitro-n-octadecaneanilide (364 g) was obtained. The yield thereof was 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: NCCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Cl)c3cccc1c23
Solvent: CCO
Product: Clc1ccc2c3c(cccc13)C(NCCCCCn1ccnc1)=N2
Yield: 76.8 %

Procedure:
A mixture of 4.4 g of 6-chloro-benz[cd]indole-2-thiol, 3.06 g of 5-(1H-imidazol-1-yl)pentanamine, 6.3 g of mercuric acetate and 150 ml of ethanol was reacted as described in Example 1, giving 5.2 g of the desired product, mp 132°-134° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)\[CH2:20][CH2:21][Cl:22])=[CH:14][CH:13]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:22][CH2:21][CH2:20]/[C:19](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:18](\[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1)/[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCC/C(=C(/c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCOc1ccc(/C(=C(\CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
6.9 g of E-1-[4-(2-benzyloxyethoxy)phenyl]-4-chloro-1,2-diphenyl-but-1-ene was dissolved in the mixture of ethyl acetate (60 ml) and ethanol (60 ml). Palladium on carbon (5%, 0.7 g) was added and the solution was stirred vigorously under a hydrogen atmosphere at room temperature until there was not any starting compound left (thin layer chromatography). Palladium on carbon was filtered off through siliceous earth and the filtrate was evaporated to dryness. The residue was crystallized several times from the mixture of ethanol and water.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:25])[N:15]=1.ClC1C(Cl)=C([Li])C(C(F)(F)F)=C(Cl)N=1.[CH3:40][O:41][C:42]1[C:49]([O:50][CH3:51])=[C:48]([O:52][CH3:53])[CH:47]=[C:46]([CH3:54])[C:43]=1[CH:44]=[O:45]>C(OCC)C.C1(C)C=CC=CC=1.O>[CH3:40][O:41][C:42]1[C:49]([O:50][CH3:51])=[C:48]([O:52][CH3:53])[CH:47]=[C:46]([CH3:54])[C:43]=1[CH:44]([C:18]1[C:17]([C:21]([F:24])([F:22])[F:23])=[C:16]([Cl:25])[N:15]=[C:14]([Cl:13])[C:19]=1[Cl:20])[OH:45]
Reactant: FC(F)(F)c1cc(Cl)c(Cl)nc1Cl
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: [Li]CCCC
Agent: [Li]c1c(Cl)c(Cl)nc(Cl)c1C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(C)c(C(O)c2c(Cl)c(Cl)nc(Cl)c2C(F)(F)F)c(OC)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
17 ml (25 mmol) of n-butyllithium (1.5 mol/l hexane solution) was dropwise added at 0° C. to a solution having 3.6 ml (25 mmol) of diisopropylamine dissolved in 60 ml of diethyl ether, followed by stirring for 45 minutes. The solution was cooled to −78° C., and a solution having 6.0 g (24 mmol) of 2,3,6-trichloro-5-trifluoromethylpyridine dissolved in 8 ml of diethyl ether was added, followed by stirring for 25 minutes to prepare 2,3,6-trichloro-5-trifluoromethyl-4-pyridyllithium, and then a solution having 5.0 g (24 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 12 ml of toluene was added, followed by stirring for 1 hour. 30 ml of water was added to the mixture to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain (2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol (melting point 131 to 135° C.).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C:23]([C:30]1[N:34]=[C:33]([CH3:35])[O:32][N:31]=1)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:19])[F:20])=[CH:8][C:9]([C:12]([NH:22][C:23]([C:30]3[N:34]=[C:33]([CH3:35])[O:32][N:31]=3)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)C(C)(N)c1noc(C)n1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: CCOC(=O)C(C)(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2(F)COC2)cn1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and ethyl 2-amino-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147a) as starting materials and isolated (283 mg, purity: 86%, 57%); MS (ESI, m/z): 491.5 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]3[CH2:30]CC[CH2:27]3)[N:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]([CH3:30])[CH3:27])[N:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1nn(C2CCCC2)c2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)n1nc(C(=O)c2cccc(O)c2)c2ccccc21
Yield: 37.6 %

Procedure:
A mixture of [3-(benzyloxy)phenyl]-(1-cyclopentyl-1H-indazol-3-yl)methanol (0.11 g, 0.19 mmol.), ammonium formate (0.071 g, 1.17 mmol) and 10% palladium on carbon (0.09 g) in 10 mL ethanol was heated at reflux for 18 hours. The reaction was filtered (celite) and the cake washed with excess ethanol. The filtrate was concentrated in vacuo. The crude product was purified by HPLC [column: silica gel 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane, gradient elution, 1:9 to 1:1 over 15 min) to give the title compound (0.020 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=O)[C:12]([N:14]([CH3:16])[CH3:15])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)C.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:14]([CH3:15])[CH3:16]
Reactant: CN(C)C(=O)C(=O)c1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 5-bromo-N,N-dimethyl-α-oxo-1H-indole-3-acetamide (from step (a), 19.85 g, 67.3 mmol) in tetrahydrofuran (100 ml) was added dropwise to a slurry of lithium aluminium hydride (7.66 g, 0.2 mol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere, maintaining the temperature below 5° C. The yellow green slurry was then warmed to ambient temperature and then brought to gentle reflux. Reflux was maintained for 5 hr after which time the reaction mixture was cooled to 0° C. and isopropyl alcohol (150 ml) and IMS (150 ml) were added sequentially. The grey slurry was then warmed to ambient temperature, before 1N NaOH (100 ml) was added. The reaction mixture was then filtered through a celite (trade mark) pad and the pad washed consecutively with demineralised water (100 ml) and IMS (100 ml). The filtrate was then concentrated under reduced pressure until all alcohol had been removed and then the aqueous residue was extracted with ethyl acetate (2×200 ml). The combined organic extracts were then evaporated in vacuo to give a brown oil. This was triturated with a mixture of hexane and ethyl acetate (1:1) (30 ml) to give the subtitle compound (13.4 g, 75%) as a cream solid. m.p. 82-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1I)=[O:4].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:69]1[C:73]2([CH2:78][CH2:77][CH:76]([NH2:79])[CH2:75][CH2:74]2)[O:72][CH2:71][CH2:70]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:79][CH:76]1[CH2:77][CH2:78][C:73]2([O:69][CH2:70][CH2:71][O:72]2)[CH2:74][CH2:75]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Reactant: NC1CCC2(CC1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.5 g, 1.5 mmol), palladium acetate (0.033 g, 0.15 mmol), BINAP (0.093 g, 0.15 mmol), cesium carbonate (0.733 g, 2.25 mmol) and 1,4-Dioxa-spiro[4.5]dec-8-ylamine (0.706 g, 4.5 mmol) in toluene (8 mL) was degassed with N2 then heated to 110° C. for 8 h. The reaction was diluted with ethyl acetate filtered through a Celite pad and purified by silica gel chromatography (0-40% hexane/ethylacetate) to give the title compound in 50% yield. MS (m/z): 378.1 [M+H]; HPLC retention time: 5.12 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: OC[CH2:3][S:4]([CH:7]1[NH:10][C:9](=[O:11])[CH:8]1[CH:12]([O:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])[CH3:13])(=O)=O>C(#N)C.O.C(Cl)Cl>[CH3:3][S:4][CH:7]1[NH:10][C:9](=[O:11])[CH:8]1[CH:12]([O:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])[CH3:13]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)NC1S(=O)(=O)CCO
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CSC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.17 g (16.7 mmol) of methyl mercaptan Na salt are added at 0° C. to a solution of 4.48 g (11.1 mmol) of 4-(2-hydroxyethylsulphonyl)-3-[1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-azetidin-2-one in 11 ml of acetonitrile and 11 ml of H2O and the mixture is stirred at 0° C. during the course of 20 minutes. The reaction mixture is diluted with 100 ml of methylene chloride and 25 ml of H2O and the aqueous phase is extracted three times with 25 ml each of methylene chloride after separating off the organic phase. The purified organic phases are dried over MgSo4 and filtered, and the solvent is removed in vacuo, 3.80 g of title compound being obtained as a slightly yellowish non-crystalline compound. NMR spectrum in CDCl3 : δ=1.45 (d, J=7 Hz, 3 H), 2.12 (s, 3 H), 3.3 (dd, J=Hz, J=2 Hz), 4.70 (d, J=2 Hz, 1 H), 5.12 (m, 1 H), 5.20 (s, 2 H), 6.45 (wide s, 1 H), 7.50 (d, J=8.5 Hz, 2 H), 820 (d, J=8.5 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCCN=C=O
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Product: CCCCNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Yield: 46.7 %

Procedure:
A mixture of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (1.56 g.) and n-butyl isocyanate (0.99 g.) in anhydrous acetonitrile (30 cc.) is heated at the reflux temperature for 2 hours. The solution obtained is treated with decolourising charcoal at the reflux temperature, filtered hot, after which it is cooled to a temperature of about 20° C. The product which crystallises is filtered off and washed with acetonitrile (4 cc.). After drying, 2-(7-chloro-1,8 naphtyridin-2-yl)-3-n-butylaminocarbonyloxy-isoindolin-1-one (0.96 g.), melting at 152° C. and then at 174° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](C(O)=O)=[CH:7]2)([O-])=O.[H-].[Na+].CI.O>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
The ethyl ester of 5-nitroindole-2-carboxylic acid (0.300 g, 1.28 mmol) was dissolved in anhydrous DMF (6 mL) and NaH (0.078 g, 60%, 1.92 mmol) was added. The reaction was stirred at RT for 20 min, then MeI (160 μL, 2.56 mmol) was added and stirring was continued for 3 h. The reaction was quenched with the addition of aqueous NaHCO3 (˜1%) while stirring vigorously. The brown solid formed (0.096 g) was filtered and dried in air overnight. The N-methyl nitro derivative (196 mg, 0.79 mmol) was then dissolved in DMF (4 mL), H2O (400 μL) and SnCl22H2O (888 mg, 3.95 mmol) were added, and the mixture was stirred at 60° C. for 3 h. The mixture was then partitioned between 10% aqueous NaHCO3 and EtOAc and stirred vigorously. The aqueous layer was re-extracted with EtOAc and the combined EtOAc layers were washed with brine, dried over anhydrous MgSO4 and concentrated to dryness. The residue was purified by flash column chromatography, using 1:1 ration EtOAc/hexane as the eluent, to obtain the pure 5-aminoindole derivative (118 mg) of example 27.