Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:25]([CH2:36][CH:37]=[O:38])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2.[CH2:39](O)[CH2:40][OH:41].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH:25]([CH2:36][CH:37]3[O:41][CH2:40][CH2:39][O:38]3)[CH2:24]1)(=[O:21])=[O:22])=[CH:5]2
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1CC1OCCO1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
In toluene (10 mL) were dissolved 4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-(formylmethyl)piperazine (440 mg) and ethylene glycol (71 mg, followed by the addition of p-TsOH.H2O (15 mg). The resulting mixture was heated to 60° C. and stirred for 16 hours. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure to remove the solvent, whereby the title compound (460 mg) was obtained as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:34])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(Cc2ccncc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(pyridin-4-ylmethyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.0202 g, 0.0530 mmol) and ammonium acetate (0.0409 g, 0.530 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.13 mL, 0.13 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H25ClN6 (M+H)+: m/z=382.2; Found: 382.2.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([C:22](=[O:24])[CH3:23])[CH:21]=1.Cl>C(OCC)(=O)C.C(O)C.O1CCCC1.CCOCC>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([C:22](=[O:24])[CH2:23][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:21]=1
Reactant: COc1ccc(C2OCCO2)cc1C(C)=O
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(C2OCCO2)ccc1OC
Yield: 52.3 %

Procedure:
To dehydrated ether (15 mL) was added sodium hydride (940 mg, 23.5 mmol) under cooling with ice and stirring, and following this, diethyl carbonate (1.66 g, 14.1 mmol) was added, which was stirred for 30 minutes at room temperature. Next, 5′-(1,3-dioxolane-2-yl)-2′-methoxyacetophenone (2.08 g, 9.36 mmol), dehydrated tetrahydrofuran (20 mL) and ethanol (0.05 mL) were mixed and added dropwise slowly. After completion of the dropwise addition, the mixture was refluxed for 7 hours. After allowed to stand for cooling, the reaction mixture was poured slowly into a solution of 2 mol/L hydrochloric acid (20 mL) and ethyl acetate (30 mL) under cooling with ice and stirring. After separated the organic layer, the aqueous layer was extracted with ethyl acetate. Respective organic layers were combined, washed with water and saturated brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=3:1 v/v) to obtain 1.44 g (52%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[C:8]([C:6]1[CH:5]=[C:4]([CH2:12][O:13][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:3]([O:14][CH3:15])=[C:2]([NH2:1])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(N)cc(C(C)(C)C)cc1CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.03 g (3-amino-5-tert-butyl-2-methoxy-phenyl)-methanol and 2.4 g imidazole are dissolved in 20 ml of tetrahydrofuran and 2.75 ml trimethylsilyl chloride are added dropwise thereto. The mixture is stirred for 2 hours at ambient temperature, the solvents are eliminated in vacuo and the residue is divided between 10% aqueous potassium carbonate solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5 to 50:50).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]=5[C:36]5[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[C:50](Cl)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:29]2[CH2:30][CH2:31][C:32]([F:34])([F:35])[CH2:33][C:28]=2[CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:10][C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[N:2][N:1]5[C:50]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:20]=3)[CH2:26][CH2:25]2)=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2[nH]ncc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 521F (1.81 g) and triethylamine (0.85 mL) in dichloromethane (10 mL) was added trityl-chloride (1.06 g) and the reaction stirred at room temperature. After stirring for 16 hours the reaction was loaded onto silica gel (Reveleris 80 g) and eluted using a gradient of 0.1% to 1.5% methanol/dichloromethane over 40 minutes (flow=40 ml/min) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH2:13][C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[C:13]3[S:12][C:11]([NH:10][CH2:9][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:15][C:14]3=[O:16])[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18]
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (example 10c, 38.1 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one as a light brown solid: 52.3 mg (72.4%), MS: m/e 452 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccn1
Temperature: 0 °C
Yield: 15.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.38 g, 0.019 mole) was added slowly dropwise to a stirred and chilled (15°-20° C.) solution of 2-(3-chlorophenyl)-3-H-imidazo[4,5-b]pyridine-3-acetic acid (4.70 g, 0.016 mole) in 50 ml of dimethylformamide. The reaction mixture was stirred at ambient temperature for 1/2 hr., then warmed to 60°-65° C. for 5 hrs. This acylchloride solution was added dropwise under nitrogen to a stirred and chilled (15°-20° C.) solution of 2-aminopyridine (1.76 g, 0.019 mole), triethylamine (1.89 g, 0.019 mole), and 30 ml of dimethylformamide. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was poured into 400 ml of ice water and extracted with ethyl acetate (3×). The ethyl acetate layers were washed with 5% potassium hydroxide (2×50 ml), water (2×50 ml), dried, and filtered. The residue was treated with isopropyl alcohol and excess ethereal hydrogen chloride to give solid which was recrystallized twice from isopropyl alcohol-isopropyl ether and once from isopropyl alcohol. The solid was collected by filtration, washed with cold isopropyl alcohol, then isopropyl alcohol-water, and dried under high vacuum for 2 days to give 0.92 g (15.8%) of title compound, mp 165°-66° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:6])[CH:2]=[CH2:3].CC1C=CC=C([N+]([O-])=O)C=1C(OCC=C)=O>C(O)C>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc([N+](=O)[O-])c(C(=O)OCC=C)c1
Agent: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CCO
Product: C=CCOC(=O)c1ccc(N)c(C(=O)OCC=C)c1

Procedure:
The above nitro compound was reduced by the method described in example 6, for the reduction of allyl 2-methyl-6-nitrobenzoate, except that the solvent was ethanol, to give allyl 3-allyloxycarbonyl-4-aminobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](OC(=O)C)(=[O:11])[CH3:10]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromoaniline (22.0 g, 12.8 mmol), acetic anhydride (13.06 g, 12.8 mmol) and a catalytic amount of DMAP in CH2Cl2 (100 mL) was stirred at 0° C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous NaHCO3 solution and concentrated. The residue was triturated with hexanes/CH2Cl2, the solid was filtered and rinsed with hexanes to give aa (25.4 g, 92.8%). HPLC Rt=1.523 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:3]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 17.8 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-(acetamido)phenylboronic acid 77 mg, sodium carbonate 69 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 31 mg, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, 4-(acetamido)phenylboronic acid 39 mg and sodium carbonate 22 mg were added, and it was stirred at 95° C. for 14 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Ethanol 2.0 mL and 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 6.0 mol/L hydrochloric acid 0.50 mL, water 3.0 mL and ethyl acetate 4.0 mL were added to the reaction mixture. The organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 40-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(4-(acetamido)phenyl)-2-(4-fluoroanilino)benzoic acid 14 mg of a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: O=Cc1cccc(Br)c1
Solvent: CCO
Product: COC(=O)c1cc(F)ccc1N=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of 2-amino-5-fluoro-benzoic acid methyl ester (15 g, 89 mmol) and 3-bromo-benzaldehyde (16.4 g, 89 mmol) in ethanol (200 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-fluoro-benzoic acid methyl ester (15.3 g, 52%) as a white solid: LC/MS m/e calcd for C15H11BrFNO2 M+: 336.2, observed: 336.2.
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.ClCCl.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[Cl:28].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:28][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:18]=1[NH:17][C:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)=[O:12])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
A 3.5 g portion of 4-nitrophenyl chlorocarbonate was added at 0° C. to a 30 ml dichloromethane suspension of 3 g of methyl 4-amino-3-chlorobenzoate and 4 ml of pyridine and stirred at room temperature for 2Hours. The reaction solution was diluted with chloroform and washed with 1 M hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, water and saturated brine in that order, and the organic layer was dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was recrystallized from hexane-ethyl acetate to obtain 4.23 g of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate as a pale brown powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5]2.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([O:19][C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-bromo-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (434 mg, 1.7 mmol), tert-butyl acrylate (1.23 mL, 8.5 mmol) and (i-Pr)2EtN (0.9 mL, 5.1 mmol) in DMF (25 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (38 mg, 0.17 mmol) and P(o-tol)3 (103 mg, 0.34 mmol) then heated to 110° C. for 22 h. The hot mixture was filtered through a pad of celite and washed with ethyl acetate (50 mL). The filtrate was diluted with H2O (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, then brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting brown solid was then triturated with a diethyl ether followed by filtration to yield the white solid product. Yield 178 mg (35%); 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.52 (d, J=16.1 Hz, 1H), 6.52 (d, J=15.8 Hz, 1H), 2.80 (s, 2H), 1.49 (s, 9H), 1.09 (s, 6H); ESI MS m/z 303 [C17H22N2O3+H]+
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:22][O:23]C1C=C(C=CC=1OC)N.BrC1N=C(Br)C2N(C=CN=2)C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:23][CH3:22])[C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(Nc2nc(Br)cn3ccnc23)cc1OC
Agent: Brc1cn2ccnc2c(Br)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(Br)cn3ccnc23)cc(OC)c1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Preparation of 6-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (2) A mixture of 3,4-dimethoxyaniline (18.0 g, 118 mmol), 6,8-dibromoimidazo[1,2-a]pyrazine (25.0 g, 90.4 mmol), and N,N-diisopropylethylamine (11.7 g, 90.4 mmol) in DMF (500 mL) was stirred at 120° C. overnight. After this time, the reaction was cooled to room temperature and concentrated to approximately 100 mL under reduced pressure. The dark brown reaction mixture was poured into ice-cold water (300 mL) and stirred for 10 min. The resulting brown precipitate was filtered and the filter cake washed with water (100 mL). The filter cake was dried under vacuum and recrystallization from methanol (˜800 mL) to afford 6-bromo-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (2) (23.3 g, 74%) as a light brown needle-shaped solid: 1H NMR (300 MHz, DMSO-d6) 9.81 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.62 (s, 1H), 7.53 (dd, J=8.7, 2.4, 1H), 6.94 (d, J=8.7 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H); ESI MS m/z 349.2 [M+H]+; HPLC, 6.92 min, >99% (AUC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N:13](OCCCC)=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])/[C:7](=[N:13]\[OH:14])/[CH2:6]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C/C(=N/O)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40° C. was added n-butyl nitrite (0.8 mL, 6.25 mmol) followed by conc HCl (0.6 mL). The reaction was stirred 30 min, precipitated solid was collected by filtration, air-dried and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 (br.s, 2H) 3.86 (s, 3H) 6.99 (dd, J=8.54 Hz, 2.2 Hz, 1H) 7.12 (d, J=1.71 Hz, 1H) 7.66 (d, J=8.55 Hz, 1H) 12.45 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)=O>C1COCC1>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH2:9][OH:8])[CH2:12]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of lithium aluminium hydride (1.41 g) in THF (15 mL) at 0° C. was added piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a solution in THF (10 mL) and the mixture stirred at room temperature for 3 h. The reaction was cooled to 0° C. and quenched by addition of aqueous ammonium chloride and the mixture filtered through celite. The filtrate was diluted with ethyl acetate, washed with water, separated and dried (MgSO4). The solvent was evaporated to give 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.25 g). To a solution of this alcohol (422 mg) in THF (8 mL) was added sodium hydride (94 mg; 60% dispersion in mineral oil). After 15 min iodomethane (0.49 mL) was added and the reaction stirred for 18 h. The mixture was then diluted with ethyl acetate and washed sequentially with water, brine, separated and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg). To a solution of 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (204 mg) in DCM (3 mL) was added 2M hydrogen chloride in diethyl ether and the mixture stirred for 18 h. The solvent was evaporated to give the desired amine (168 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available propionyl chloride the title compound is obtained as colorless solid.