Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.C([C@H]1CC[C@H](CCCOC2C=CC(C3N=CC(CCCCCCCCC)=CN=3)=CC=2)CC1)CCCCCCC.C([C@H]1CC[C@H](CCCOC2C=CC(C3N=CC(CCCCCCCCC)=CN=3)=CC=2)CC1)CCCCCCCC>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCCCC)CC3)cc2)nc1
Agent: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCCCCC)CC3)cc2)nc1
Agent: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCCCCCC)CC3)cc2)nc1
Product: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCCC)CC3)cc2)nc1

Procedure:
2-(4-[3-(trans-4-heptylcyclohexyl)-1-propyloxy]phenyl)-5-nonylpyrimidine; 2-(4-[3-(trans-4-octylcyclohexyl)-1-propyloxy]phenyl)-5-nonylpyrimidine; 2-(4-[3-(trans-4-nonylcyclohexyl)-1-propyloxy]phenyl)-5-nonylpyrimidine;
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)=[O:9])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cncnc1
Product: CCOc1ccc(NC(=O)c2cncnc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from pyrimidine-5-carboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.16 (s, 1H), 9.43 (s, 1H), 9.32 (s, 2H), 8.81 (d, J=9.3, 1H), 7.76 (d, J=3.0, 1H), 7.34-7.27 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18]O)([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18][Cl:24])([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCC1(CCO)CCN(c2nc3ccc(Cl)cc3s2)CC1
Product: CCC1(CCCl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A mixture of 2-[1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]ethanol (764 mg) and thionyl chloride (4 mL) were stirred at 60° C. for 1.5 hours. To the reaction solution was added ice and extracted with ethyl acetate. The organic layer was washed with sodium hydrogencarbonate and brine and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (739 mg). Yield: 92%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH2:14]=O.CO.[BH4-].[Na+]>O>[CH3:14][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
In a dried reaction flask, (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.774 g, 31.0 mmol) and formaldehyde solution (37%, 6.82 mL) were dissolved into methanol (124 mL) under a nitrogen protection. The mixture was stirred at room temperature for 1 hr. Sodium borohydride (3.518 g, 93.0 mmol) was added in portion under an ice bath. The mixture was stirred at room temperature for 3 hr. Water was added and the solution was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to produce a white solid (3.685 g) in 59.4% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[NH2:9][C:4]1[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(N)nc(N2CC=CCC2)n1

Procedure:
300 g. of 2-chloro-4,6-diamino-s-triazine, 180 g. of 1,2,5,6-tetrahydropyridine and 170 g. of sodium bicarbonate are mixed in 1700 ml. of n-butanol and heated to reflux for 18 hours. The mixture is cooled and filtered. The residue is digested three times with hot chloroform and ethanol and filtered. The filtrates are combined and concentrated, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine having a melting point of 200°-202° C.
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCOCC1>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=COCCCC
Reactant: CN(C=O)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 25 ml of 1,4-dioxane under stirring at 10–15° C., a solution of bis-trichloromethylcarbonate (28.3 g) in 50 ml of 1,4-dioxane is added dropwise in 90 min. The reaction mixture is kept under stirring at room temperature overnight, then the solvent is evaporated under reduced pressure. Toluene (50 ml) and water (200 ml) are added, the mixture is cooled at about 5–10° C. and the pH is corrected to about 7 by adding sodium hydroxide 15% aqueous solution (30 ml). After separation of the phases, the aqueous layer is extracted twice with toluene (50 ml×2) and the combined organic layers are washed with water (50 ml) and evaporated under reduced pressure. The obtained residue (32.3 g, containing, according to HPLC assay, 28.7 g of pure product, 81% molar yield) is used for the next step of the synthesis without any further purification.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:12]O>>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([SH:1])[CH:3]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccc(S)c1
Reaction time: 1 h

Procedure:
To a solution of 3-mercaptobenzoic acid (4.8 g, 31 mmol) in methanol (50 mL) at 0° C. was added a solution of hydrochloric acid in methanol (1M, 200 mL, 0.2 mol). The mixture was heated at reflux, stirred for 1 hour and concentrated under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed consecutively with saturated aqueous sodium hydrogen carbonate (100 mL), distilled water (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound as a colourless oil.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]([O:16]CC)=[CH2:15])=[CH:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.Cl>C1COCC1>[C:14]([C:11]1[N:10]=[CH:9][C:8]([CH:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]#[N:7])=[CH:13][CH:12]=1)(=[O:16])[CH3:15]
Reactant: C=C(OCC)c1ccc(C(C#N)CC2CC2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C#N)CC2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g, crude) in THF (10 mL) was added 4N HCl (10 mL) and stirred at room temperature for 2 h. The reaction mixture was adjusted pH to 6-7 by 4M aq.NaOH and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc: Petroleum ether=1:10) to give 2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (600 mg, yield: 60%) 1H NMR (CDCl3 varian 400): δ8.58-8.51 (m, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.75 (dd, J=8.0 Hz, 2.4 Hz, 1H), 3.92-3.85 (m, 1H), 2.61 (s, 3H), 1.88-1.79 (m, 1H), 1.71-1.65 (m, 1H), 0.75-0.67 (m, 1H), 0.49-0.45 (m, 2H), 0.10-0.03 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:15]1[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]#[N:31])[CH:29]=[CH:28][C:5]=43)[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1
Reactant: CN(C)C=O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccc(F)cc2F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C#N)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with zinc cyanide, and Tetrakis(triphenylphosphine)palladium(0) in DMF under microwave irradiation at 60 W for 30 minutes (Tmax=175° C.) to give 2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbonitrile. MS (ESI+) 405.1
Reaction SMILES: [C:1]1(=[CH:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]([C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1>C(OCC)(=O)C>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([S:23][C:1]2([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)C=C1CCCC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1

Procedure:
A mixture of cyclopentylideneacetic acid (2 mmol) and p-(phenoxy)-thiophenol (2 mmol) was heated at 110° C. under nitrogen in the presence of piperidine (100 μL) for 24 hours. The residue was dissolved in ethyl acetate and washed with dilute hydrochloric acid. The organic layer was separated, dried and evaporated under reduced pressure to give crude 2-[-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetic acid, which can be used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC=CC=2)(=O)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[C:21](#[N:27])[CH2:22][CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC.CCOC(C)=O>[C:21]([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:19][CH3:20])#[N:27]
Reactant: C#CCCCC#N
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(C#N)ccc1C#CCCCC#N

Procedure:
This product was prepared from benzenesulfonic acid 4-cyano-2-methoxy-phenyl ester and 5-hexynenitrile following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (70 mg, 62%); 1H NMR δ (CDCl3): 7.52 (d, J=8.34 Hz, 1H), 7.21 (d, J=8.22 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.25 Hz, 2H), 2.58 (t, J=7.22 Hz, 2H), 1.99 (p, J=7.12 Hz, 2H); LCMS m/z: 224.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[N:5]=[CH:4][CH:3]=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[N:8]1[C:7]2[C:6](=[N:5][CH:4]=[CH:3][CH:2]=2)[NH:10][CH:9]=1
Reactant: Clc1ccnc2[nH]cnc12
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Product: c1cnc2[nH]cnc2c1

Procedure:
7-Chloro-3H-imidazo[4,5]pyridine (0.013 mole, 2 g) and uridine (0.014 mole, 3.4 g), were suspended in 32.3 ml of 0.01M potassium phosphate, pH 7.4. The enzyme catalysts purine nucleoside phosphorylase (970 units) and uridine phosphorylase (150 units) were added and the suspension mixed for two days at 37° C. The reaction was filtered and the filtrate lyophilized. The cake was extracted three times with acetone. These filtrates were combined and solvent removed in vacuo. The lyophilized powder was twice extracted with acetone and once extracted with methanol. These filtrates were combined with the extractions with methanol. These filtrates were combined with the extractions from above and solvent removed under vacuum. This powder was dissolved in 150 ml 30% n-PrOH/water (v/v) and chromatographed on a (7.5×90) cm column containing P-2 resin. Fractions containing product were pooled, dried in vacuo, resulting in 1.4 g of analytically pure 7-chloro-3-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine which had an Rf value of 0.25 on cellulose developed in (NH4)2SO4 :1M NaOAc:i-PrOH (79:19:2). M.p. 198° C.; UV λmax nm (ε×10-3) at pH 1 281, 284, 250; at pH 13, 279, 257; NMR (Me2SO-d6)δ 8.80 (s, 1H, H2), 8.34 (d, 1H, J=5.27, H5), 7.49 (d, 1H, J=5.26, H6), 6.07 (d, 1H, J=5.58, H1'), 4.5 (b, 1H, H2'), 4.1 (b, 1H, H3'), 4.0 (b, 1H, H4'), 3.5 (b, 2H, H5').
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:32][CH:16]([O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:33])=[O:3])=[CH:10][CH:11]=1)[CH2:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OC(C)CCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: CC(CCC#Cc1ccc(OC(F)(F)F)cc1)Oc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 e], [rac]-{6-[1-methyl-5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as brown crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C.C1COCC1>[F:20][C:18]1[CH:19]=[CH:12][C:13]([C:14]#[N:15])=[C:16]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][S:2]2(=[O:8])=[O:1])[CH:17]=1
Reactant: O=S1(=O)CCCCN1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1N1CCCCS1(=O)=O
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of 1,1-dioxo[1,2]thiazinane (8.84 g, 65.4 mmol) in DMF (20 mL) and THF (10 mL) was added portion-wise sodium hydride (1.65 g, 65.5 mmol, 95%). After stirring for 30 min, 2,4-difluorobenzonitrile (10.0 g, 72 mmol) was added and the mixture was stirred at 90° C. for 2.5 h. The mixture was cooled and concentrated and the residue was purified by flash chromatography eluting with 0%-10% EtOAc/hexane to give the title compound as white needles (1.37 g, 8% yield). 1H-NMR (500 MHz, CDCl3) δ: 7.70 (1H, dd, J=8.8, 5.8 Hz), 7.30 (1H, dd, J=8.8, 2.4 Hz), 7.15-7.12 (1H, m), 3.72 (2H, t, J=5.3 Hz), 3.33 (2H, t, J=6.1 Hz), 2.40-2.35 (2H, m), 2.05-2.01 (2H, m). LCMS [M+H]+ calcd for C11H12N2FO2S: 255.06. Found: 255.19.
Reaction SMILES: Cl.NO.[OH-].[Na+].O1CCOCC1.C[N:13]([CH:15]=[N:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)C>C(O)(=O)C>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[O:25][N:13]=[CH:15][N:16]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)N=CN(C)C)cc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ncno2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3.54 g (0.0510 mol) of hydroxylamine hydrochloride in a mixture of 10.2 mL (0.0510 mol) of 5 N NaOH, dioxane (50 mL), and 70% aq. acetic acid (100 mL), is added 6.79 g (0.0424) of N-[(dimethylamino)methylene]-4-methylbenzamide (prepared as described in J. Chem. Soc. Perkin. Trans. 1 1989, 589). The mixture is stirred at 90° C. for 1.5 h and the product is isolated from the cooled reaction mixture. MS 161 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CN1CCCC1=O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[N:11]=[C:4]2[CH:3]=[C:2]([O:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Reactant: COc1ccc(O)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2cc(N)n3nc(-c4ccco4)nc3c2)cc1

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. p-methoxy-phenol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 322 M+H+ (100%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.FC(F)(F)C(O)=O.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[CH:27]=1.C(N(CC)CC)C>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[CH:27]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CCCCn1ccc(CN)cc1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1=O

Procedure:
A mixture of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (170 mg, 0.51 mmol) and 4-aminomethyl-1-butyl-1H-pyridin-2-one trifluoroacetate (150 mg, 0.51 mol) is stirred in dimethylformamide (2.7 mL) at room temperature in the presence of triethylamine (0.33 mL) for 18 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified via semi-preparative HPLC (Prodigy ODS3 column, 5% acetonitrile/95% water/0.01% trifluoroacetic acid to 100% acetonitrile at 10 mL/min) to give (4Z)-6-iodo-4-({[(1-butyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as an peach colored solid (25 mg, 10% due to substantial loss of material during HPLC malfunction).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][C:20]([C:24](O)=[O:25])=[CH:19][C:18]=4[CH:27]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][N:29]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][C:20]([C:24]([NH:41][C:40]5[CH:39]=[CH:38][C:37]([CH2:36][N:29]([CH:30]6[CH2:35][CH2:34][O:33][CH2:32][CH2:31]6)[CH3:28])=[CH:43][CH:42]=5)=[O:25])=[CH:19][C:18]=4[CH:27]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)C=C(C(=O)O)CCO4)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCO4)cc2)CC1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a solution of 7—(4—(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.12 g), 4—(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.08 g) and 1-hydroxybenzotriazole(0.05 g) in dimethylformamide (15 ml) was added 1-ethyl-3—(3-dimethylaminopropyl)carbodiimide hydro-chloride (0.1 g), under ice-cooling. Under nitrogen atmosphere, the mixture was cooled to room temperature. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.14 ml), and the mixture was stirred over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7—(4—(4-methylpiperazin-1-yl)phenyl)-N-(4—((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 124) (0.15 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH2:16][OH:17])([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@:9]([CH2:16][O:17][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC[C@@](CO)(NC(=O)OC(C)(C)C)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@](CO[Si](C)(C)C(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1.3 g of (S)-2-tert-butoxycarbonylamino-2-hydroxymethylpent-4-enoic acid were dissolved in 10 ml of dimethylformamide. 1.44 g of imidazole and 1.7 g of tert-butyl-dimethylsilyl chloride were added thereto. The mixture was stirred at room temperature for 14 h and then partitioned between 150 ml of water and 200 ml of diethyl ether. The aqueous phase was extracted twice with 100 ml of diethyl ether each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was taken up in 20 ml of THF and 60 ml of methanol. 11 ml of a 1 M potassium carbonate solution were added, and the mixture was stirred at room temperature for 2 h. Then 150 ml of a saturated sodium chloride solution were added, and the pH of the solution was adjusted to 2 with 1 M HCL solution. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the crude product was employed without further purification in the next reaction.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][OH:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
3,4-Methylenedioxyphenylacetic acid (18.0 g) was added portionwise over 30 minutes to a stirred, ice-cooled suspension of lithium aluminium hydride (4.0 g) in ether (400 ml) and the mixture was stirred at room temperature for two hours, quenched by the cautious addition of saturated aqueous ammonium chloride solution and filtered. The filtrate was washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated to give the title compound as a pale yellow oil (15.01 g, 90%), which was characterised by its 1H n.m.r. spectrum.