Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)[CH:3]=1.[C:25](Cl)(=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1.C(N(CC)CC)C>ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)[CH:3]=1)=[O:34]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(C)(C)C)c(-c3ccnn3C)c2)c1
Temperature: 22 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
Tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (265 mg, 797.2 μmol), m-anisoyl chloride (168.0 μl, 1.5 eq) and triethylamine (266.7 μl, 2.4 eq) were taken up in 20 mL of dichloromethane in a round bottomed flask and stirred at 22° C. for 18 hr. The reaction was then concentrated and purified by column chromatography (40-75% ethyl acetate in hexane) to afford the title compound as a pale yellow oil in 73.9% yield LCMS m/z (%)=467 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 3.42 (q, J=5.56 Hz, 2H), 3.78 (s, 3 H), 3.88 (s, 3 H), 4.04 (t, J=4.80 Hz, 2 H), 6.28 (d, 1 H), 7.01 (d, J=9.09 Hz, 1 H), 7.10 (dt, J=4.55, 2.53 Hz, 1 H), 7.38-7.41 (m, 2 H), 7.43-7.45 (m, J=3.03 Hz, 1 H), 7.54 (d, J=2.02 Hz, 1 H), 7.66-7.71 (m, 1 H), 7.76 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1nc(OCC(F)(F)F)c2nc(Cl)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(OCC(F)(F)F)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
To a degassed suspension of 2-amino-4-(trifluoroethoxy)-6-chloro-pyrido[3,2-d]pyrimidine (24 mg, 0.1 mmol), 4-fluorophenyl boronic acid (21 mg, 0.15 mmol), and potassium carbonate (280 mg, 2.03 mmol) in a mixture of dioxane (15 ml) and water (5 ml) was added a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The mixture was refluxed for 45 minutes. The solvents were evaporated in vacuo, and the crude residue was purified by preparative TLC, using a mixture of methanol and dichloromethane (in a ratio of 10:90) as mobile phase, yielding the pure title compound, which was characterised by its mass spectrum as follows: MS (m/z): 339 ([M+H]+, 100).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]2[CH2:61][CH2:60][N:59]([CH2:62][C:63]([NH2:65])=[O:64])[CH2:58][CH2:57]2)=[CH:52][C:51]=1[O:66][CH3:67]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:49][C:50]4[CH:55]=[CH:54][C:53]([CH:56]5[CH2:61][CH2:60][N:59]([CH2:62][C:63]([NH2:65])=[O:64])[CH2:58][CH2:57]5)=[CH:52][C:51]=4[O:66][CH3:67])=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (127.4 mg, 0.368 mmol) and N,N-Diisopropylethylamine (0.257 mL, 1.47 mmol) in 3.2 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (113 mg, 0.318 mmol). After stirring at room temperature for 1 hour, 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (92 mg, 0.349 mmol) was added. The reaction mixture was heated at 65° C. overnight. The reaction was conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using DCM then 500:15:10 DCM:MeOH:7N NH3/MeOH as the eluant. The collected fractions afforded 2-(4-{4-[7-(3-tert-Butylsulfamoylphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxyphenyl)piperidin-1-yl)-acetamide as a yellow solid (23.0 mg, 11%). MP 250-252° C. LCMS (E/I+) 592.25 (M+H). 1H NMR (DMSO-d6)-9.02 (s, 1H), 8.55 (s, 1H), 8.37 (d, 1H, J=7.84 Hz), 7.99 (d, 1H, J=7.96 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.86 Hz), 7.63 (s, 1H), 7.23 (d, 1H, J=4.80 Hz), 7.21 (br s, 1H), 7.15 (br s, 1H), 7.01 (d, 1H, J=4.72 Hz), 6.95 (s, 1H), 6.92 (s, 1H), 3.88 (s, 3H), 2.97-2.90 (m, 2H), 2.88 (s, 2H), 2.49-2.41 (m, 1H), 2.22-2.11 (m, 2H), 1.84-1.72 (m, 4H), 1.12 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=c1cc(O)c2ccccc2n1-c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c(O)c2ccccc2n1-c1ccccc1

Procedure:
A solution of 4-hydroxy-1-phenyl carbostyril (2.20g.; 0.0093 mole) in glacial acetic acid (10 ml.) was treated rapidly with concentrated nitric acid (2.5 ml. d 1.42) and the mixture heated on a steam bath for 21/2 mins. The red solution deposited a dark yellow solid on cooling which, after dilution with ethanol, was filtered off and washed well with ethanol, m.p. (AcOH -- EtOH) 167° - 169° C. (Found; C, 64.13; H, 3.70; N, 9.85; C15H10N2O4 requires; C, 63.83; H, 3.57; N, 9.92%).
Reaction SMILES: [C:1](=[O:36])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:11]2[C:6]1=[C:7]([OH:35])[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=2)[NH2:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1>[C:4]([O:35][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:36])[NH2:2])[C:17]1([O:19][C:17](=[O:18])[CH3:16])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])(=[O:3])[CH3:5]
Reactant: COC(OC)c1cc(O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(O)(O1)C2COC(N)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 196.1 %

Procedure:
To a solution of 11-benzyloxycarbonyl-6,9-dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (400 mg) in a mixture of pyridine (10 ml) and acetic anhydride (5 ml) was added 4-dimethylaminopyridine (10 mg). The mixture was stirred overnight at ambient temperature and evaporated in vacuo. The residue was subjected to silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol (50:1, v/v). The desired fractions were combined and then evaporated to dryness in vacuo to afford 11-benzyloxycarbonyl-8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (458 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([N:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:22]2)[N:3]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Cn1cnc2nc(Cl)nc(Cl)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3ncn(C)c13)CC2

Procedure:
A solution of 1.44 g of 2,6-dichloro-7-methylpurine, 1.63 g of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride and 1.5 g of triethylamine in 25 ml of methylene chloride was stirred at room temperature under nitrogen for 15 hours. The reaction mixture was washed with a 1N hydrochloric acid solution (3×150 ml), water (3×150 ml) and a brine solution (1×100 ml), and then dried over sodium sulfate. Removal of the solvent left a residue which was chromatographed on 150 g of silica gel, 1.3 g.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([C:9]([OH:11])=[O:10])[C:7]([CH3:13])([CH3:12])[S:6][C@H:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[CH3:2].[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1O)(=[O:22])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[O:10][C:9]([C@H:8]1[C:7]([CH3:13])([CH3:12])[S:6][C@@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]1[C:1](=[O:3])[CH3:2])=[O:11])(=[O:22])[CH3:21]
Reactant: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)[C@@H]2N(C(C)=O)[C@H](c3ccccc3)SC2(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A solution of (2S,4S)-3-acetyl-5,5-dimethyl-2-phenyl-4-thiazolidinecarboxylic acid [compound described in Reference Example 4 (b)] (102 g, 0.38 mol) in anhydrous DMF (500 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)-benzothiazoline (127 g, 0.38 mol) in anhydrous DMF (500 ml) at room temperature. N,N-Dimethylaminopyridine (5.58 g, 45.7 mmol) was added thereto under a nitrogen atmosphere at room temperature with stirring. After ice-cooling, diethyl azodicarboxylate (87 g, 0.50 mol) was added thereto. The mixture was stirred under ice-cooling for 15 minutes, at room temperature for one hour and further at an internal temperature of about 40° C. for three days. The reaction mixture was concentrated under reduced pressure, a 10% aqueous citric acid solution (1,000 ml) was added to the residue, and the whole was extracted with ethyl acetate (1,000 ml). The organic layer was washed with water (1,000 ml) and saturated brine (1,000 ml) successively and dehydrated with magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. A mixed solvent (ethanol/diisopropyl ether=200 ml/1000 ml) was added to the residue, the residue was dissolved by heating, and then the solution was allowed to stand at room temperature overnight. The precipitated crystals were filtered off and dried to give 34.7 g of the target compound. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=1/1) to give further 43.8 g of the target compound (total 43%).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.C(O[CH:18]=[C:19]([C:25]([CH3:27])=O)[C:20]([O:22]CC)=[O:21])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:27][C:25]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[N:12]=[CH:18][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ccc(OC(F)(F)F)cc1
Temperature: 76 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-Trifluoromethoxyphenylhydrazine hydrochloride (4.0 g) and ethyl 2-ethoxymethylene-acetoacetate (3.26 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added to a mixed solvent of water (10 ml) and ethanol (10 ml), and stirred at 76° C. for two hours. Sodium hydroxide (1.40 g) was added to the reaction solution and the mixture was further stirred at the same temperature for an hour. Ethanol was evaporated in vacuo, hydrochloric acid (1 mole/1) was added to the aqueous solution and the precipitated solid was recrystallized from ethyl acetate to give the titled compound (3.56 g).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:35]=[CH:34][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][Si](C)(C)C)=[CH2:20])=[C:15]([O:26][Si](C)(C)C)[C:14]=2[CH2:31][CH2:32][CH3:33])=[CH:9][CH:8]=1.[CH:36]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=1)[C:41]#[N:42])=[O:37].Cl>O1CCCC1.O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:34]=[CH:35][C:7]([CH:36]([OH:37])[C:38]3[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=3)[C:41]#[N:42])=[CH:8][CH:9]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[C:15]=1[OH:26])(=[O:21])[CH3:20]
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(CCC)c1O[Si](C)(C)C
Reactant: N#Cc1ccnc(C=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(O)c3cc(C#N)ccn3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 2.98 mL, 5.95 mmol) to a solution of 1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (3.00 g, 5.41 mmol) in tetrahydrofuran (0.1M) cooled to 0° C. After 15 minutes, warm reaction to room temperature. After 1 hour, cool the reaction to −78° C. Add a solution of 2-formyl-isonicotinonitrile (612 mg, 5.95 mmol) in tetrahydrofuran (10 mL) via syringe. After 1 hour, warm the reaction to room temperature. Add 10% hydrochloric acid (30 mL). After 5 minutes, pour the reaction into water and extract with ethyl acetate. Combine organics, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with methanol:dichloromethane followed by trituration with acetonitrile to yield the title product as a white solid (1.71 g, 76%): 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 4.50 (d, 1H), 5.16 (s, 2H), 5.84 (d, 1H), 6.46 (d, 1H), 7.41 (m, 4H), 7.51 (s, 1H), 7.55 (d, 1H), 8.76 (d, 1H), 12.74 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7](=[O:24])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=4)[NH:13][N:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:27][N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7](=[O:24])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=4)[NH:13][N:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:27][N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.8 %

Procedure:
A solution of tert-butyl (Z)-4-[(6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0462 g, 0.0812 mmol) in methylene chloride (1 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted five times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0277 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][CH3:10].Cl.[CH:12](O)=O>>[CH3:10][N:9]1[C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[N:1]=[CH:12]1
Reactant: CNc1cc(C)ccc1N
Reactant: O=CO
Agent: Cl
Product: Cc1ccc2ncn(C)c2c1
Yield: 57 %

Procedure:
A mixture of 6.60 g of 1-amino-4-methyl-2-(N-methylamino)benzene and a solution of 3.5 ml of formic acid in 50 ml of a 4N HCl was stirred at 100° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure and water was added to the residue. After washing with ethyl acetate, the aqueous phase was rendered alkaline with aqueous potassium carbonate followed by extraction with chloroform. The chloroform layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (40 g). Elution with ethyl acetate followed by recyrstallization from ethyl acetate-hexane gave 4.01 g (57%) of 1,6-dimethylbenzimidazole.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[C:8](=[O:14])[C:7]1=[O:15])C.O.[NH2:18][NH2:19]>C(O)C>[CH2:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([NH:18][NH2:19])=[O:16])[C:7](=[O:15])[C:8]1=[O:14])[CH3:13]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(CC)C(=O)C1=O
Solvent: O
Solvent: CCO
Product: CCN1CCN(CC(=O)NN)C(=O)C1=O
Yield: 77 %

Procedure:
As described for example 112a, (4-ethyl-2,3-dioxo-piperazin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) and the resulting mixture heated under reflux for 16 h. The precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 77%). MS: m/e=215.4 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[C:15]([CH2:17]Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([CH2:17][N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[CH:14]=[CH:13][N:12]=1
Reactant: CC(=O)N1CCNCC1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetylpiperazine (1.0 equiv) was mixed with compound 2-chloro-4-(chloro-methyl)pyridine (1.0 equiv) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N:13]=O.[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[CH3:16].O>C1(C)C=CC=CC=1.[Pd]>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[N:13]=[C:22]1[C:21]1[CH:24]=[CH:25][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CCOc1ccc(C=O)cc1
Reactant: CNc1ccc2ccccc2c1N=O
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nc3c4ccccc4ccc3n2C)cc1
Reaction time: 1 h

Procedure:
A solution of 11.16 g (0.06 mole) of 2-methylamino-1-nitrosonaphthalene in 800 cc of toluene is hydrogenated at room temperature and at the atmospheric pressure in the presence of 3 g of Palladium-on-carbon. After one hour, when the theoretical amount of hydrogen has been consumed, 9 cc (0.06 mole) of 4-ethoxy benzaldehyde are added and the obtained reaction mixture is heated to the reflux temperature under an inert atmosphere for about 3 hours. The water which forms during the reaction distillates as binary azeotrope with toluene and is separated through a Dean-Stark apparatus. Then further 1.5 g of 5% Palladium-on-carbon are added and reflux is prolonged for two additional hours. Filtration of the hot solution followed by concentration of the filtrate to dryness under vacuum affords a residue which has been purified by cristallization from ethyl acetate. Yield 14.5 g (80%) M.p. 138°-9° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Yield: 102.6 %

Procedure:
A solution of 4-chloro-3-nitro-pyridine (2.0 mmol, 0.32 g), triethylamine (3.0 mmol, 0.42 mL) and piperazine-1-carboxylic acid tert-butyl ester (2.5 mmol, 0.47 g) in dioxane (2 mL) was irradiated using microwave for 8 minutes at a temperature of 150° C. The reaction mixture was concentrated in vacuo, and the resulting residue was purified using flash column chromatography on silica gel (eluent: ethyl acetate) to provide 4-(3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (633 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 6.87 (d, J=6.0 Hz, 1H), 3.68-3.56 (m, 4H), 3.32-3.18 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)[CH3:3].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].C[C:17]([O:20]C)(C)C>>[CH3:1][N:2]([CH2:4][C-:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:17]=[O:20])[CH3:3].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: CN(C)C[c-]1cccc1
Reactant: COC(C)(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: CN(C)C[c-]1cccc1C=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Charge an inertized reactor with 39.6 g of 1-[(dimethylamino)methyl]-ferrocene and 360 ml of MTBE. Distill about 160 ml of MTBE (4V) at atmospheric pressure. Cool the solution to −10° C. and slowly add 98.2 ml of a solution of t-BuLi in heptane (titer 16%). Stir the reaction mixture at −10° C. for 2 hours and then at 0° C., slowly add 25.2 ml of DMF. Continue stirring the reaction mixture at 20° C. for 2 hours then at 5° C., slowly add 135 ml of 1.5N aqueous HCl. Continue stirring the reaction mixture at 5° C. for 30 min, then at 20° C. for 30 min. Leave the reaction mixture to settle and withdraw the aqueous phase then the MTBE phase. Counter-extract the aqueous phase with 125 ml of MTBE. Filter the combined MTBE phases on activated charcoal then concentrate to 120 ml under vacuum. Add 80 ml of isopropanol then distill 420 ml of solvent to constant volume, under vacuum, by regular addition of isopropanol. At the end of distillation, dilute the reaction mixture to 280 ml with isopropanol. 39.9 g of the expected compound is obtained in solution in isopropanol.