Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])[CH3:17].C(O)(C)C>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 83 %

Procedure:
The compound was prepared according to general procedure E with 4-hydroxybenzaldehyde (3.3 mmol) in dry acetone (15 ml), anhydrous K2CO3 (4.3 mmol), and ethyl-2 bromopropionate (3.6 mmol) at reflux for 2 h45. Isopropanol was added and evaporated by azeotropic distillation with ethyl-2-bromopropionate. 609 mg of pure compound were obtained (83% yield). 1H NMR (250 MHz, CDCl3): δ 1.10 (t, J=7.1 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H), 4.10 (q, J=7.1 Hz, 2H), 4.76 (q, J=6.8 Hz, 1H) 6.85 (d, J=8.7 Hz 2H), 7.70 (d, J=8.9 Hz, 2H), 9.74 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 14.0, 18.2, 61.4, 72.4, 115.1, 130.4, 131.8, 162.4, 171.1, 190.5
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.Br[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:3][O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: N#CCCCBr
Reactant: COCC1CCCN1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1CCCN1CCCCN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(methoxymethyl)pyrrolidine (300 mg, 2.61 mmol) and 4-bromobutyronitrile (0.31 mL, 2.99 mmol) in dry CH3CN (13 mL) was added K2CO3 (1.51 g, 10.94 mmol) at rt followed by KI (43 mg, 0.26 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (21 mL) and treated with LiALH4 (192 mg, 5.07 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Sat. aq. Rochelle's salt solution and EA were then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(2-(methoxymethyl)pyrrolidin-1-yl)butan-1-amine as a pale yellow oil. GC-MS-conditions 01: tR=2.1 min; [M+H]+=187.20.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][C:25]([OH:30])([CH2:27][C:28]#[CH:29])[CH3:26]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:29]#[C:28][CH2:27][C:25]([CH3:26])([OH:30])[CH3:24])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCC(C)(C)O
Product: COc1c(C)cnc(Cn2cc(C#CCC(C)(C)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine with 2-methylpent-4-yn-2-ol (H. Zhang et al., Tetrahedron Lett. 1999, 40, 7851) according to the general procedure A gave the title compound, as a solid. Mp=163-165° C. HPLC Rt=4.98 min.
Reaction SMILES: [Cl-].[NH4+].[NH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[O:22])=[C:16]([S:35][CH3:36])[CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)C.O.[Fe]>[NH2:3][C:4]1[C:9]([NH2:10])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:25]=3)=[O:22])=[C:16]([S:35][CH3:36])[CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CSc1cc(Oc2ccnc(N)c2N)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
A suspension of iron powder (4 equivalents, 78 mg, 1.4 mmol) and ammonium chloride (5.8 equivalents, 109 mg, 2 mmol) in ethanol (400 μL) and water (438 μL) was heated to reflux. 1-(4-(2-amino-3-nitropyridin-4-yl-oxy)-2-(methylthio)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (180 mg, 0.35 mmol) was added in portions and the mixture stirred at reflux for 24 hours. After cooling to room temperature, the slurry mixture was filtered and washed with ethanol. After removal of the solvent, the crude powder was dissolved into EtOAc, filtered to removed the precipitate, and evaporated to provide the title compound (100 mg, 59%) as a sticky dark oil. 1H-NMR (δ, ppm, DMSO-d6): 2.41 (s, 3H, CH3), 5.61 (s, 2H, NH2,Py), 6.06 (d, 1H, HPy,5, J=5.6 Hz), 6.79 (d, 1H, Harom, J=8.7 Hz), 7.01 (s, 1H, Harom), 7.26 (d, 1H, HPy,6, J=5.6 Hz), 7.58-7.69 (m, 4H, Harom), 8.12 (s, 2H, NH2,Py), 8.27 (s, 1H, NHurea1), 10.02 (s, 1H, NHurea3). LC-MS (m/z): 484 (M+H, 100).
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>ClCCl>[F:1][C:2]1([C:6]2[CH:7]=[N+:8]([O-:26])[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)COc1ccncc1C1(F)CCC1
Solvent: ClCCl
Product: [O-][n+]1ccc(OCC(F)(F)F)c(C2(F)CCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine (example 127a, 1.68 g, 6.74 mmol) in dichloromethane (40 ml) was added m-CPBA (3.49 g, 10.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was transferred into a separatory funnel and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the crude title compound (1.68 g, 94%) which was used without any purification for the next step; MS (ESI, m/z): 266.5 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:13](=[O:14])[O:12][CH2:11]2)(O)=[O:6]>CN(C)C=O>[Cl:3][C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:13](=[O:14])[O:12][CH2:11]2)=[O:6]
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)COC2=O
Temperature: 80 °C
Yield: 86 %

Procedure:
To a mixture of 1800 ml of thionyl chloride and 8.1 ml of N,N-dimethylformamide, 750 g (4.21 moles) of 5-carboxyphthalide are added under stirring. The mixture is heated slowly to reach an inner temperature of 60° C. in one hour, then it is kept at this temperature for another hour and finally it is brought to the reflux. After refluxing for 6 hours, about 600 ml of thionyl chloride are distilled off at a temperature of 80÷85° C., by replacing them by addition of toluene. Distillation is continued for a total of 2800 ml with concurrent replacement of the solvent by addition of 3800 ml of toluene. The mixture is slowly cooled and, at 80° C., the crystallization of the product begins. Cool to 10÷15° C. by continuing stirring for 15 hours. The hygroscopic product is filtered, washing with a total of 1500 ml of toluene, then it is dried under vacuum at 55° C. to give 710 g (86%) of 5-chlorocarbonylphthalide with a purity of 99% (HPLC).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][C:24]([N:1]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCOCCN1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and (1-adamantyl)acetyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>>[O:11]([C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nccc2[nH]cnc12
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: c1ccc(Oc2nccc3[nH]cnc23)cc1

Procedure:
In step (3) of Reaction Scheme VI, a 4-chloro-1H-imidazo[4,5-c]pyridine of Formula XLII is reacted with sodium phenoxide to provide a 4-phenoxy-1H-imidazo[4,5-c]pyridine of Formula XXXII-4. Phenol is reacted with sodium hydride in a suitable solvent such as diglyme (bis(2-methoxyethyl) ether) to form the phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XLII. The product can be isolated from the reaction mixture using conventional methods.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][C:15]=12)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][C:15]=12)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Yield: 87 %

Procedure:
A solution of Compound 467 (0.63 g, 1.58 mmol) and lithium hydroxide monohydrate (0.33 g, 7.90 mmol) in THF/water (10 mL, 4:1) was stirred from 0° C. to room temperature overnight. After evaporation of THF, the residue was acidified with 1N HCl to pH2 and extracted twice with 20% iPrOH/DCM. The combined organic extracts were evaporated to give Compound 471 (87% yield). LCMS (+ESI) m/z 385.0 [M+H]+.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:35])=[N:15][C:16]=3[NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7]1)C.[CH3:37][C:38]1[CH:39]=[N:40][NH:41][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:35][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:40]3[CH:39]=[C:38]([CH3:37])[CH:42]=[N:41]3)[CH:7]=[CH:8]2)=[C:16]([NH:20][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=1
Reactant: Cc1cn[nH]c1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carbonic acid (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA) (2.00 g, 3.97 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 mL) is added followed by 4-methyl-pyrazole (0.36 g, 4.37 mmol) and triphenylphosphine (0.16 g, 0.60 mmol). Tetrakis(triphenyl-phosphine)palladium(0) (0.23 g, 0.20 mmol) is then added and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 1:2). 1H nmr (CDCl3, 400 MHz); 8.10 (br s, 1H), 7.35-7.15 (m, 12H), 6.25 (m, 1H), 6.10 (m, 1H), 5.80 (m, 1H), 5.70 (m, 1H), 5.35 (m, 1H), 4.35 (t, 1H), 4.25 (m, 2H), 3.25 (m, 1H), 2.20 (m, 1H), 2.05 (s, 3H), MS (ES+) m/e 496 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][O:13][CH2:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH:15]1[NH:16][CH2:17][CH2:18][N:19]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:20]1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: COCC1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC1CN(c2ncc(C(=O)OC)cn2)CCN1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.74 mmol) in DCM (4.70 mL) was added to a stirred solution of 2-(methoxymethyl)piperazine (226 mg, 1.74 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35 mmol) in DCM (4.00 mL) at 25° C. under nitrogen. The resulting solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and diluted with MeOH. The resulting mixture was filtered. The filtrate was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (346 mg, 75%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][NH:25][C@@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN[C@@H](C(N)=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)[C@@H](C(N)=O)C1
Yield: 803.6 %

Procedure:
Molecular sieves (0.5 g) followed by aqueous formaldehyde (1 ml) were added to a stirred solution of (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (9) (0.102 g, 0.23 mmol) in DCM-AcOH (10:1 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (0.10 g, 0.463 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (20 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by preparative LCMS (standard basic conditions) to give the title product as a white solid (0.85 g, 80%): 1H NMR Spectrum: (DMSO d6) 1.87-1.92 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.43-2.47 (m, 1H), 2.71-2.80 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.03 (s, 1H), 7.23 (s, 1H), 7.26-7.30 (m, 2H), 7.47-7.54 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 459.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.[CH:15]1([C:18]([CH2:20]Br)=[O:19])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([C:18](=[O:19])[CH2:20][N:11]2[N:10]=[C:9]([O:8][CH3:7])[S:13][C:12]2=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(CBr)C1CC1
Reactant: COc1n[nH]c(=O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1nn(CC(=O)C2CC2)c(=O)s1
Reaction time: 20 h

Procedure:
55 g of potassium carbonate are added to a solution of 26.4 g of 5-methoxy-3H-[1,3,4]-thiadiazol-2-one in 700 ml of dioxane and the reaction mixture is heated to 60°. Then 35 g of bromomethyl cyclopropyl ketone are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. The residue is stirred with diisopropyl ether and filtered with suction. 41 g of crystals of the title compound having a melting point of 98-100° are thus obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C1C=CC(Cl)=CC=1)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.[K].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 60.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxymethyl-4-methanesulfonyloxypyrrolidine (23.7 g: ca. 50 mmole) in dimethylformamide (50 ml), potassium phthalimide (10.2 g: 55 mmole) is added in a nitrogen atmosphere, and the mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a stirring mixture of ice water (500 ml) and ethyl acetate (500 ml). The organic layer is successively washed with water (4 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from a mixture of n-hexane and toluene. The solid is filtered off and the filtrate is purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.41 g). Yield: 61%. Colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:19][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 148.2 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 20.4 g (0.2 mol, 2.0 eq.) of 1-hexanol were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8 mL). Subsequently, the resultant was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 33.1 g of 4-hexyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7](=[O:15])[C:6]=2[CH:16]=1.II>CC(C)=O>[CH3:6][C:5]1([CH3:14])[CH:4]=[C:3]([CH3:2])[C:16]2[C:2](=[CH:3][CH:4]=[C:5]3[C:6]=2[C:7](=[O:15])[O:8][C:9]2[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1]1
Reactant: Nc1ccc2c(c1)c(=O)oc1ccccc12
Agent: II
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1ccccc13
Temperature: 105 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
In a pressure tube, 8-aminobenzo[c]chromen-6-one (Reference Compound No. 1-1-(2), 8.81 g, 41.7 mmol) was dissolved in acetone (300 ml . . . ), then iodine (4.24 g, 16.7 mmol) was added thereto, then the pressure tube was sealed, and then the reaction mixture was stirred at 105° C. for 2 days. After cooling down, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (4.83 g) as a yellow solid. (Yield 40%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=[CH2:15]>COCCOC>[Cl:12][CH2:13][C:14](=[CH2:15])[CH2:16][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=C(CCl)COc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 4-cyanophenol (11.9 g; 0.1 mol) in 1,2-dimethoxyethane (100 mL) was slowly added to a stirred and cooled (0° C.) suspension of NaH (4.0 g; 0.1 mol; 55% dispersion) in 1,2-dimethoxyethane (250 mL). The reaction mixture was refluxed for 1 hour and then allowed to cool to room temperature. 3-Chloro-2-chloromethyl-propene (20 g; 0.16 mol) was added in one portion and the reaction mixture was stirred at 45° C. for 40 hours. The reaction mixture was partitioned between DCM and NaHCO3 (satd.) and the organic layer collected, dried, concentrated and purified using column chromatography (DCM:MeOH; 50:1) to give the sub-title ompound in a 66% yield.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([O-:15])=[O:14].[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>O1CCOCC1>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:34][CH2:33][C:32]([O:36][CH3:37])=[O:35])[CH:20]=[C:19]2[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(Cc3cccnc3)c2c1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 1.25 h
Yield: 74.5 %

Procedure:
Benzyltrimethylammonium hydroxide (0.8 ml of 40% solution in methanol) was added to a stirred mixture of 5-nitro-3-(3-pyridylmethyl)-1H-indole (7.34 g) and methyl acrylate (3.0 g) in dioxan (140 ml) and the resulting solution was stirred for 75 minutes and then evaporated. The residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from ethyl acetate/hexane to give the title compound (7.33 g), m.p. 101°-102° C. Found: C,63.85; H,4.86; N,12.37. C18H17N3O4 requires: C,63.71; H,5.05; N,12.38%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[S:7][C:8]([C:10]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[S:7][C:8]([C:10]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1cc2cc(OC)c(OC)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3ccccc3C(=O)O)sc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of methyl 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoate (650 mg, 1.75 mmol) in MeOH (9 mL) and THF (20 mL) was added 2N NaOH (9 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with 1N HCl and diluted with water. The resulting suspension was filtered and the solid was dried under vacuum to afford 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid (550 mg, 88%). LC-MS (ES-API); rt 9.22 min; m/z calculated for C18H15NO5S [M+Na]+ 380.1, found 380.0.