Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]2)[C:11]=1[CH3:12]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.00 g, 4.10 mmol) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate to give (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[CH:12]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:5][CH:4]=1.[N:25]([O-])=O.[Na+]>C(O)(=O)C>[NH2:25][C:12]1[C:11]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:10][C:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)=[N:14][C:13]=1[NH:15][CH3:16]
Reactant: O=N[O-]
Reactant: CNc1cc(N2CCOCC2)nc(SCc2ccc(OC)cc2)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1nc(SCc2ccc(OC)cc2)nc(N2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.6 %

Procedure:
2-(4-methoxybenzylsulfanyl)-4-methylamino-6-morpholinopyrimidine (5.0 g, 14.4 mmol) was dissolved in acetic acid (50 ml), and an aqueous solution (10 ml) of sodium nitrite (1.49 g, 21.6 mmol) was added drop-wise under water cooling and stirred at room temperature for 5 hours. After distilling away acetic acid under reduced pressure and dissolving the residue in ethyl acetate, washing was performed in the order of 2N—NaOH solution and water, then dried with MgSO4 and the solvent was distilled away under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), 1.0 g of Pd/C was added and catalytic hydrogenation was performed under normal pressure for 4 hours. Celite was used to filter off Pd/C and the filtrate was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain 1.28 g (25% yield) of 5-amino-2-(4-methoxybenzylsulfanyl)-6-methylamino-4-morpholinopyrimidine. Melting point: 79.5 to 84° C. MS m/z: 361 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[N:19]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (750 mg) and THF (dry) (10 mL) were added (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (632 mg), ADDP (958 mg) and tri-n-butylphosphine (1.442 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). The product was crystallized from EtOAc-hexane to give the title compound (1132 mg).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[N:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[OH:18][CH:15]1[CH2:14][CH2:13][N:12]([C:9]2[N:8]=[CH:7][C:6]([C:5]3[N:4]=[N:3][N:2]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:1]=3)=[CH:11][N:10]=2)[CH2:17][CH2:16]1
Reactant: OC1CCN(c2ncc(-c3nnn[nH]3)cn2)CC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Temperature: 80 °C

Procedure:
A mixture of 1-[5-(1H-tetrazol-5-yl)pyrimidin-2-yl]piperidin-4-ol (550 mg, 2.224 mmol), triethylamine (0.62 mL, 4.45 mmol), ethyl bromoacetate (371 μL, 3.34 mmol) in THF (77.4 mL) was heated at 80° C. for 1 h. The solvent was evaporated, diluted with water (5 mL) and slurried with Et2O (5 mL). The mixture was filtered and washed with water followed by Et2O. The solid was dried under high vacuum to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH3:13].O>CO>[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[OH:19])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(C=O)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(C(O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.3 %

Procedure:
To a solution of indole (6.00 g) in methanol (60 ml) were added sodium hydroxide (2.25 g) and 4-ethylbenzaldehyde (7.56 g), and the mixture was stirred at room temperature for 3 days under argon atmosphere. Added thereto was water, and methanol was evaporated under reduced pressure. The residue was extracted with diethyl ether, and the extract was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-70:30) to give 4-ethylphenyl-(1H-indol-3-yl)methanol (2.10 g) as a colorless solid. APCI-Mass m/Z 234 (M+H−H2O).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:21])[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[C:12](=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:22])[NH:14]2
Reactant: Cc1cccc2c1C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c[nH]c(C=C2C(=O)Nc3cccc(C)c32)c1CCC(=O)O
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (300 mg) suspended in ethylene glycol (5 mL) was heated in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (1 pellet) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and purified on a silica gel column to give 115 mg (44% yield) of 3-[2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]2[CH2:17][O:18][CH:24]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCCNC(C)=O)OCC
Reactant: OCC(CO)Oc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NCCCC1OCC(Oc2ccc(OCc3ccccc3)cc2)CO1

Procedure:
2-(4-Benzyloxyphenoxy)propane-1,3-diol (98 mg, 0.36 mmol), N-(4,4-diethoxybutyl)acetamide (73.06 mg, 0.36 mmol) and p-toluenesulfonic acid (61.89 mg, 0.36 mmol) were stirred in 6 ml of toluene at 60° C. for 2 h and concentrated. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 30.8 mg (22%) of cis-N-{3-[5-(4-benzyloxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide, M+H+: 386.15 and 29.8 mg (22%) of trans-N-{3-[5-(4-benzyloxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide, M+H+: 386.19.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>CN(C)C=O>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: CN(C)CCN
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CN(C)CCNc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1[N+](=O)[O-]

Procedure:
A solution of 1-(4-fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (100 mg) in dimethylformamide (2 ml) was shaken with 2-dimethylaminoethylamine (0.3 ml) at 70° C. for 2 hours. Volatiles were removed and the residue was partitioned between dichloromethane and water. The organic phase was dried and concentrated. The product with the molecular weight of 459.51 (C25H25N5O4); MS (ESI): 460 ([M+H]+), was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:36])[C@@H:10]([NH:23][C:24](=[O:35])[CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:44]1([C:50](Cl)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][C:24]([NH:23][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:35])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate and triethylamine (0.50 g) in chloroform (30 ml) was added triphenylmethyl chloride (1.37 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (5S)-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-6-oxohexylcarbamate (1.62 g) as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.Cl.[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][NH:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: C1CC2CNC1CN2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)cc21
Yield: 43.4 %

Procedure:
A solution of 0.52 g (2.0 mmole) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.37 g (2.0 mmole) of 2,5-diazabicyclo(2.2.2)octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 0.90 ml (6.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 25 ml of acetonitrile was heated under reflux for 21 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from ethanol to give 0.30 g of the title compound, mp 270°-272°.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)C)(C)(C)C.Cl.O1CCOCC1>ClCCl>[ClH:23].[Cl:23][C:18]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:12][CH2:13]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CN(CCN1CCN(c2cccnc2Cl)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCN1CCN(c2cccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
Dissolve {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (4.900 g, 13.807 mmol) in dichloromethane (100 mL). Slowly add 4N HCl in dioxane (20.711 mL, 82.845 mmol). Stir at room temperature for 18 hr. Concentrate and wash the resulting solid with diethyl ether to afford the title preparation (7.500 g, 99% yield). MS ES: m/z=255 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][C:23]([CH3:26])=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])[N:10]=2)[CH:7]=1.[Br-].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:20])=[CH:12][C:11]=1[C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3cn4cc(Br)cnc4n3)c2)o1
Reactant: OB(O)c1ccccc1
Agent: [Br-]
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3cn4cc(-c5ccccc5)cnc4n3)c2)o1

Procedure:
Compound 31 was synthesized using N-(3-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-4-chlorophenyl)-5-methylfuran-2-carboxamide (I-14) as the bromide and phenylboronic acid using a suzuki coupling protocol described in the synthesis of I-11. The residue was redissolved in methanol and precipitation yielded the compound 1H NMR (400 MHz, DMSO-D6) δ 10.33 (s, 1H), 9.38 (d, J=2.1, 1H), 8.99 (d, J=2.0, 1H), 8.71 (d, J=2.5, 1H), 8.62 (s, 1H), 7.95 (dd, J=2.4, 8.7, 1H), 7.80 (d, J=7.8, 2H), 7.52 (dt, J=7.8, 14.7, 5H), 7.34 (d, J=3.3, 1H), 6.35 (d, J=3.3, 1H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:19]([CH3:20])[CH3:18])=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: CNC
Solvent: CCO
Product: COc1ccc(Nc2nc(N(C)C)ncc2I)cn1
Temperature: 140 °C
Yield: 80 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (150 mg, 0.414 mmol), dimethylamine (2.0 M solution in tetrahydrofuran) (0.044 mL, 0.827 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N4-(6-methoxypyridin-3-yl)-N2,N2-dimethylpyrimidine-2,4-diamine (123 mg, 0.331 mmol, 80% yield). 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H); 8.18 (s, 1H); 7.84 (dd, J=8.92, 2.48 Hz, 1H); 6.75 (d, J=8.92 Hz, 1H); 6.65 (s, 1H); 3.94 (s, 3H); 3.09 (s, 6H). m/z (ESI, +ve ion) 371.9 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@:9]1([C:42]([F:45])([F:44])[F:43])[CH2:24][N:12]2[C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=[C:11]2[N:10]1[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28](C(OC(C)(C)C)=O)[CH:27]=1>C(Cl)Cl>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH2:25][N:10]2[C:11]3=[N:16][C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:14][C:13](=[O:23])[N:12]3[CH2:24][C@@:9]2([CH3:8])[C:42]([F:44])([F:45])[F:43])=[CH:27]1
Reactant: CC(C)(C)OC(=O)n1cc(CN2c3nc(N4CCOCC4)cc(=O)n3C[C@@]2(C)C(F)(F)F)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1c[nH]c2ccccc12
Reaction time: 8 h
Yield: 46.2 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution of 200 mg of 2-methylpropan-2-yl 3-{[(2S)-2-methyl-7-(morpholin-4-yl)-5-oxo-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-1(5H)-yl]methyl}-1H-indole-1-carboxylate in 3 ml of methylene chloride. After an overnight period at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure. After purification by preparative LC MS (method D), the acetonitrile is concentrated and then the aqueous phase is extracted with ethyl acetate. The organic phase is successively washed with a saturated aqueous solution of sodium bicarbonate, twice with water and once with a saturated aqueous solution of sodium chloride. The resulting organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue it taken up with water and then lyophilized. 75 mg of (2S)-1-(1H-indol-3-ylmethyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are thus obtained in the form of a pinkish-coloured lyophilisate, the characteristics of which are the following:
Reaction SMILES: N#N.[CH:3]1([C:6]2[S:7][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:11](O)=[O:12])[N:10]=2)[CH2:5][CH2:4]1.CN(C=O)C.C(Cl)(=O)C([Cl:28])=O>C1(C)C=CC=CC=1>[CH:3]1([C:6]2[S:7][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:11]([Cl:28])=[O:12])[N:10]=2)[CH2:5][CH2:4]1
Reactant: O=C(O)c1nc(C2CC2)sc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1nc(C2CC2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-cyclopropyl-5-phenyl-thiazole-4-carboxylic acid (90 mg, 0.37 mmol) in toluene (2.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.11 mL, 1.25 mmol) and the resulting yellow solution was stirred at rt for 2 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-cyclopropyl-5-phenyl-thiazole-4-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>CCO>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[NH:7][N:6]=2)[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: COc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reaction time: 12 h

Procedure:
To a solution of 5-methoxy-1H-pyrazol-3-amine (890 mg, 7.8 mmol) in absolute EtOH (20 ml) were added triethylamine (3.3 ml, 23.6 mmol), 2,4,5-trichloropyrimidine (1.4 g, 7.8 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound as an oil which crystallized upon standing (1.8 g). m/z: 261.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][C:26]([F:28])([F:27])[CH:23]([C:20]1[CH:21]=[CH:22][C:15]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)=[N:18][C:17]=3[C:16]=2[CH:19]=1)[OH:24]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C=O)cc1-2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C(O)C(F)(F)F)cc1-2
Yield: 6 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbaldehyde (0.354 g, 1.04 mmol) was dissolved in THF (7 mL) and treated with (trifluoromethyl)trimethylsilane (0.154 mL, 1.04 mmol) followed by TBAF (1M, 0.02 mL, 0.02 mmol). Stirred the resulting reaction mixture at ambient temperature for 2 h. Concentrated in vacuo and re-dissolved in DMF and purified by reverse phase HPLC to give 25.6 mg (6% yield) of 329. LC/MS(ESI+): m/z 411 (M+H). 1H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.10 (s, 1H), 7.41 (d, J=8.4, 1H), 7.10 (d, J=8.3, 1H), 6.80 (s, 1H), 5.80 (dt, J=13.1, 6.5, 1H), 5.21 (d, J=6.7, 1H), 4.39 (t, J=4.9, 2H), 3.45 (t, J=4.9, 2H), 1.55 (d, J=6.5, 6H)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: COCCOCCl
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(Br)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 0.96 g) was added to a solution of 4-bromo-2-trifluoromethyl-phenol (5.0 g) in dry THF (200 ml) and the mixture was stirred for 30 minutes. 1-Chloromethoxy-2-methoxy-ethane (2.85 ml) was then added and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure. The residue was taken into water and tert-butyl methyl ether, the organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford 4-bromo-1-(2-methoxy-ethoxymethoxy)-2-trifluoromethyl-benzene (6.4 g) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:1]=[C:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: O=C(O)CCC/C=C\CC1C=CCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCC/C=C\CC1C=CCCC1=O
Reaction time: 0.17 h

Procedure:
A solution of 15.8 g. of 7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid (as obtained by ether-pentane extraction as described above) in 300 ml of acetone was stirred with ice-bath cooling as 30 ml of standard Jones reagent was added dropwise. The resultant mixture was stirred for 10 min at 0° and then quenched by the addition of several ml of isopropyl alcohol. After stirring for another 10 min at 0° the solvents were removed by evaporation in vacuo. The residue was dissolved in water and extracted several times with ether. The combined ether extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to yield 13.0 g of crude 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acid as a yellow oil.