Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[F:12][S:8]([F:13])([F:9])([F:10])([F:11])[C:6]1[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[CH:3]=[C:2]([O:1][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:7]=1
Reactant: BrCCOC1CCCCO1
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(OCCOC2CCCCO2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 700 mg) and 2-(2-bromo-ethoxy)tetrahydropyran (670 mg) were dissolved in DMF (15 ml), and sodium hydride (77 mg) was added. After stirring at RT for 2 h, the mixture was heated to 50° C. for 4 h and left to stand over the weekend. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The crude product was purified using silica gel (100 g, n-heptane/EA 4:1). 813 mg of the title compound were obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h

Procedure:
Combine 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (3.108 kg, 6.17 mol) and acetonitrile (14.56 kg) and adjust the temperature to about 0° C. Add N-methyl-4-aminopiperidine (0.775 k, 1.1 eq.). Diisopropylethylamine (1.595 kg) was added aver about 29 minutes at temperature of about 6 to 12° C., the temperature was adjusted to about 20 to 25° C. and the reaction mixture was stirred overnight. The solid was collected by filtration, rinsed with acetonitrile (4.47 kg) and dried under at stream of nitrogen for 1 hour, then in a vacuum oven at 40° C. for 2 days to give the title compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=C)[CH:11]=[C:10]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1.[Mn]([O-])(=O)(=O)=[O:27].[K+]>O.O1CCOCC1>[Cl:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:27])[CH:11]=[C:10]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metaperiodate (701 mg, 3.28 mmol) was suspended in water (10 mL) and sonicated until a clear solution was obtained. 2-Chloro-4-(1-ethoxyvinyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (486 mg, 1.64 mmol) in 1,4-dioxane (20 mL) and potassium permanganate (39 mg, 0.25 mmol) were added and the mixture was stirred at rt for 30 min. The mixture was filtered, precipitate was washed by dioxane and DCM. DCM an solid sodium bicarbonate (s) were added to the filtrate. The mixture was extracted with DCM (×2). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with DC ti give the title compound as a solid, 385 mg (79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=383.0 (M+H)+
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[CH3:21])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1COCC1.CO.O[Li].O>O>[Cl:20][C:16]1[C:15]([CH3:21])=[C:14]([S:11]([NH:10][C:5]2([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2cccc(Cl)c2C)CCCC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)NC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
methyl-1-(3-chloro-2-methylphenylsulfonamido)cyclopentanecarboxylate (550 mg, 1.65 mmol) was charged and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After the stirring for 12 hours, the resultant solution was vacuum-evaporated, adjusted with 2N—HCl to pH 5-6, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed so as to obtain 1-(3-chloro-2-methylphenylsulfonamido)cyclopentanecarboxylic acid (516 mg, 1.62 mmol, 98%).
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:39])([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[N:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:27][N:26]=3)[CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[CH2:8])CCC.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CCO.O>[CH3:39][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[N:10][C:9]([C:7](=[O:6])[CH3:8])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: C=C(OCCCC)c1ccc(-c2ccc(C(C)(c3ccc(OCc4ncccn4)cn3)C(C)C)cc2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C(C)(c3ccc(OCc4ncccn4)cn3)C(C)C)cc2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydrochloric acid (100 mL of a 1.0 M solution in EtOH) was added to a stirred solution of 7b (15.8 g, 30.9 mmol) in EtOH (25.0 mL) at 0° C. After approximately 15 min, a second portion of hydrochloric acid (150 mL of a 2.0 M aqueous solution) was added, and after another 15 min, a third portion of hydrochloric acid (100 mL of a 6.0 M aqueous solution) was added. After an additional 10 min, the reaction was warmed to rt and aged for 30 min. The reaction was diluted with water, recooled to 0° C. and neutralized by the addition of solid sodium bicarbonate. The resulting mixture was saturated with solid sodium chloride and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 7c m/z (ES) 454 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.80 (d, 2H, J=4.8 Hz), 8.42 (d, 1H, J=3.0 Hz), 8.16 (d, 1H, J=8.7 Hz), 8.08 (d, 2H, J=8.5 Hz), 7.98 (d, 1H, J=8.9 Hz), 7.56 (d, 2H, J=8.5 Hz), 7.27 (m, 1H), 7.24 (dd, 1H, J=3.0, 8.7 Hz), 7.18 (d, 1H, J=8.9 Hz), 5.34 (s, 2H), 3.10 (m, 1H, J=6.7 Hz), 2.94 (s, 3H), 1.73 (s, 3H), 0.88 (d, 3H, J=6.7 Hz), 0.83 (d, 3H, J=6.8 Hz).
Reaction SMILES: [Na][Na].[C:3]([CH2:11][C:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([OH:22])=[O:21])=O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH2:25][NH2:26]>CO.O>[C:20]([C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=1[C:12]1[CH:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:26][N:25]=1)([OH:22])=[O:21]
Reactant: O=C(O)C1=C(C(=O)CC(=O)c2ccccc2)CCCC1
Reactant: NN
Agent: Cl
Agent: [Na][Na]
Solvent: O
Solvent: CO
Product: O=C(O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1

Procedure:
To a slurry of 31.6 g of the disodium salt of 2-benzoylacetyl-1-cyclohexenecarboxylic acid in 150 ml of methanol is added 12 g of concentrated hydrochloric acid, followed by 12 g of hydrazine hydrate. The reaction mixture is refluxed for 2 hours, cooled to 5°, acidified to pH 3, and diluted with 150 ml of water. The solid is collected and recrystallized from acetic acid-water to give 11.4 g of 3-(2-carboxy-1-cyclohexen-1-yl)-5-phenylpyrazole, m.p. 207-209°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl ethyl (5-nitropyridin-2-yl)propanedioate (4.10 g, 13.2 mmol) in a mixed solution of TFA/DCM (4 mL/20 mL) was stirred for 5 hours at room temperature. The mixture was concentrated under reduce pressure. The residue was dissolved with DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated to give title compound. 1H-NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:15]2[CH:25]=[C:19]3[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]3[C:17](=[O:26])[N:16]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Cl)c(C(F)(F)F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-chloro-3-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][NH2:13].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:13][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNc1cc(C(=O)O)cc(Cl)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (25 g, 130.2 mmol) in 52 mL water was added 60 mL of 40% methylamine in water. Reaction heated to reflux at 100° C. After 16 h, reaction was cooled to rt. Reaction was acidified with 1N HCl (200 mL) and extracted with EtOAc (300 mL×4). The combined organics were washed with brine (150 mL), dried over Mg2SO4, filtered, and concentrated in vacuo to give 24.2 g (100%) of 2-chloro-6-(methylamino)isonicotinic acid as a brown solid. LC/MS [M+H]+ 187.0.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)O1.C(=O)([O-])[O-].[K+].[K+].[CH:29]1([NH:32][C:33](=[O:53])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([N:41]3[C:50](=[O:51])[C:49]4[C:44](=[CH:45][CH:46]=[C:47](I)[CH:48]=4)[N:43]=[CH:42]3)[CH:35]=2)[CH2:31][CH2:30]1>CN(C=O)C.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:29]1([NH:32][C:33](=[O:53])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([N:41]3[C:50](=[O:51])[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([C:9]5[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=5)[CH:48]=4)[N:43]=[CH:42]3)[CH:35]=2)[CH2:31][CH2:30]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(I)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCNCC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a nitrogen flushed flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.04 g), potassium carbonate (0.869 g), and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride (0.11 g) was added a solution of N-cyclopropyl-3-(6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (1.0 g) in DMF (14 ml). The reaction mixture was stirred for 16 hours at 80° C. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine, dried (magnesium sulfate) and concentrated. The resulting solid was dissolved in 4N HCl in dioxane (5 ml) and methanol (5 ml) and stirred at room temperature for 2 hours. The precipitate was collected by filtration and washed with ethyl acetate and diethyl ether. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 20% methanol/ethyl acetate+1% aqueous ammonia solution gave N-cyclopropyl-4-methyl-3-[4-oxo-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-3(4H)-yl]benzamide (AZ12267331) (0.393 g) as a light brown solid; NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.69 (m, 2H), 2.15 (s, 3H), 2.43 (m, 2H), 2.85 (m, 1H), 2.94 (t, 2H), 3.40 (s, 2H), 6.45 (s, 1H), 7.53 (d, 1H), 7.74 (d, 1H), 7.86 (s, 1H), 7.90 (d, 1H), 8.05 (d, 1H), 8.12 (s, 1H), 8.29 (s, 1H), 8.49 (d, 1H); Mass Spectrum: M+H+ 401.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24]OS(C)(=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24][N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1sc2ccccc2c1-c1ccccc1
Reaction time: 0.08 h

Procedure:
NaH (60% in mineral oil, 15 mg, 0.377 mmol) was added in one portion to a mixture of 9H-purin-6-ylamine (47 mg, 0.345 mmol) in DMF (3 mL) at RT. After 5 min stirring, a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester from Example 26 (100 mg, 0.314 mmol) in DMF (2 mL) was added dropwise and stirring at RT was continued for 30 min. The reaction mixture was then quenched by addition of water and a solid formed. The precipitated was collected by filtration and was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) and triturated from diethyl ether affording 166 as a white solid (52 mg, 46%). LCMS: RT 3.99 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 8.15 (1H, s), 8.06 (1H, s), 7.98-7.92 (1H, m), 7.64-7.59 (4H, m), 7.57-7.46 (2H, m), 7.42-7.37 (2H, m), 7.27 (2H, s), 5.63 (2H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:11]([O:12][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: CCCCBr
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1ccc(C=CC(=O)OC)cc1OC

Procedure:
4.16 g (20.0 mmol) ferulic acid methyl ester was dissolved in 115 ml 2-butanone. 2.09 ml (22.0 mmol) n-butyl bromide and 11.06 g (80 mmol) potassium carbonate were added. The reaction suspension was then heated at reflux temperature for 20 hours. The reaction mixture was filtered. The filtrate was concentrated by evaporation. The crude product was recrystallised from 42 ml isopropyl alcohol yielded 4.85 g (92%) (4-butoxy-3-methoxycinnamic acid methyl ester as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.S(=O)(=O)(O)O.[Br:15]Br.[OH-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:15])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)nc(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
20 g(0.164 mole) of 2-amino-4, 6-dimethylpyridine was added into a mixture of 69 ml of water and 16.1 g(0.164 mole) of sulfuric acid and the resulting solution was cooled to 0° C., and thereto was added 8.45 ml(0.164 mole) of bromine gradually at 0° C. The resulting solution was stirred for 30 minutes, adjusted to pH 9 to 10 with aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 18.25 g of the title compound(yield 55%) and 5.4 g of dibromo compound(yield 11.8%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([NH2:11])=[O:10].[C:13]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])#[CH:14].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:16]([Si:15]([C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:17]
Reactant: C#C[Si](CC)(CC)CC
Reactant: CC(C(N)=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1ccccc1C(C)C(N)=O)(CC)CC
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-iodophenyl)propanamide I13 (12.4 g, 45.2 mmol), ethynyltriethylsilane (9.72 mL, 54.2 mmol), PdCl2(PPh3)2 (0.634 g, 0.904 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.262 g, 0.904 mmol) and CuI (0.172 g, 0.904 mmol) in DMF (46 mL) was stirred under a nitrogen atmosphere at 70° C. for 4 hours. The volatiles were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf, 0-30% EtOAc in cyclohexane) to give the title compound I14 as an orange oil (8.9 g, 68%). LCMS-B: rt 3.845 min; m/z 288 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](N)CC3)c[nH]c12
Reactant: COCC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(=O)COC)CC3)c[nH]c12

Procedure:
Starting from cis-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A183) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].CC(N(C)C)=O.Cl[CH2:23][C:24]1[CH:32]=[C:30]([CH3:31])[CH:29]=[C:27]([CH3:28])[C:25]=1[CH3:26]>C1COCC1.CS(C)=O.C(OC)(C)(C)C.CCCCCC>[CH3:23][C:24]1[CH:32]=[C:30]([CH3:31])[CH:29]=[C:27]([CH3:28])[C:25]=1[CH2:26][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:15]
Reactant: Cc1cc(C)c(C)c(CCl)c1
Reactant: OCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(CC(O)COCCOCCOCCO)c(C)c1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
95% Sodium hydride (40.85 g, 1.6 moles) was placed into a 3 L flask under argon and THF (1.2 L) at −10° C. was added. Dry tetraethylene glycol (500.0 g, 2.57 moles) was added slowly. The pot temperature was maintained below 15° C. during the addition. Once the NaH had reacted, a homogeneous solution resulted. 18C6 (3.9 g) and dimethyl-acetamide (DMAC, 500 mL) was added. Chloroisodurene (TMB-Cl, 98.6 g, 0.58 mole) dissolved in THF (500 mL) was added to pot over about 4 h. The reaction mixture was stirred for about 17 h at about 40° C. under argon. The reaction was monitored by tlc on silica gel plates, eluting with 10% MeOH/CH2Cl2 vs TMB-Cl. The reaction was complete; the TMB-Cl was consumed. The solvent was removed in vacuo; the resulting oil was extracted with CH2Cl2 (700 mL) and water (300 mL). The CH2Cl2 layer was separated, dried over MgSO4, filtered through fluted filter paper and concentrated in vacuo to leave an oil. A column was prepared with 600 g of silica gel and hexane as needed. The crude product was placed onto column with hexane and a minimum of t-butylmethyl ether (TBME, 100 mL) to make a clean transfer. The column was eluted with hexane (4 L) and then as follows: (2 L) 10% TBME/hexane; (2 L) 20% TBME/hexane; (4 L) TBME/hexane; (3 L) 40% TBME/hexane, and (2 L) TBME. Like fractions containing product were combined and concentrated in vacuo to give 140.2 g (73%). The product was characterized by nmr. 1H NMR [400 MHz, DMSO (d6)] □6.81 (s, 2H), 4.56 (t, 1H), 4.45 (s, 2H), 3.57-3.45 (m, 14H), 3.41 (t, 2H), 2.28 (s, 6H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]N(C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[C:4]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:46]=[C:44]([NH:43][C:33]2[CH:34]=[CH:35][C:36]([N:37]3[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]3)=[C:31]([O:30][CH3:29])[CH:32]=2)[N:45]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(F)cc1Cl
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(F)cc1Cl

Procedure:
The title compound was prepared from crude ethyl 2-(2-chloro-4-fluoro-benzoyl)-3-dimethylamino-acrylate (50 mg, 0.17 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (51 mg, 0.14 mmol) using in analogous manner the procedure described in example 28b). Obtained as a yellow solid (14 mg, 21%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[C:11]([OH:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:8]([F:26])[CH:7]=1>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:12][C:11]1[CH:10]=[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])[C:8]([F:26])=[CH:7][C:6]=1[Cl:5]
Reactant: CN=C=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.51 g of methyl isocyanate and subsequently one drop of triethylamine are added at room temperature while stirring to a solution of 2.00 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 20 ml of methylene chloride. The reaction mixture is stirred for one hour and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether-n-hexane (2:1) as the eluent. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl methylcarbamate, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 7.24 ppm (d,1H), 6.34 ppm (s,1H), 5.21 ppm (q,1H), 3.54 ppm (d,3H), 2.88 ppm (d,3H).