Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:37][Si](CC)(CC)CC)([CH3:36])[CH3:35])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 94.1 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(5-triethylsilyloxy-5-methylhexyloxymethyl)androsta-5,7,16-triene (420 mg, 0.543 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (6 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (4 hours), worked up and purified by column chromatography (ethyl acetate:dichloromethane=4:1) to give the titled compound (220 mg, 94%) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](I)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:16][N:17](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:16]#[N:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C#N)c1
Temperature: 80 °C
Yield: 73 %

Procedure:
A mixture of t-butyl 3-bromo-5-iodobenzoate (1.91 g, 5 mmol), zinc cyanide (585 mg, 5 mmol), and tetrakis(triphenylphosphine)palladium(0) (300 mg, 5 mol %) in dimethylformamide (20 ml) was heated at 80° C. for 2 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (20 ml) and washed with water and brine. The organic phase was dried and evaporated. Chromatography with ethyl acetate/hexane (1:4) gave the title compound as a colourless oil (1.02 g, 73%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1.CC1(C)O[C:21](=[O:22])[CH2:20][C:18](=[O:19])[O:17]1>O>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]2[C:7](=[CH:6][CH:5]=1)[O:12][C:21](=[O:22])[C:20]([C:18]([OH:19])=[O:17])=[CH:9]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Solvent: O
Product: O=C(O)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
5-trifluoromethoxy-salicylaldehyde (286.0 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 189.1 mg of 6-trifluoromethoxy-3-carboxy-coumarin in a 50% yield.
Reaction SMILES: [NH2:1][C:2]1[C:9](C)=[CH:8][C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].[CH3:19]O>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:19]
Reactant: CO
Reactant: Cc1cn(-c2cc(C)c(N)c(C=O)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cn(-c2ccc(N)c(C(C)O)c2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
2-amino-3-methyl-5-(4-methylimidazol-1-yl)benzaldehyde (57 mg) was dissolved in methanol (1 ml) and sodiumborohydride (40 mg) was added thereto at 0° C. The mixture was stirred at room temperature for 6 hours and was distilled under reduced pressure to remove solvent. To the residue was added water. The mixture was extracted with chloroform. The extract was dried with Na2SO4 and distilled to give 34 mg (59%) of the title compound.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH2:16][OH:17].C(OCC)C>ClCCl>[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH:16]=[O:17]
Reactant: C/C(=C\c1ccccc1)CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(=C\c1ccccc1)CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Solid pyridinium chlorochromate (4.21 g, 0.02 mol) was added in one portion to a cooled (−10° C.) solution of (4E)-4-methyl-5-phenyl-4-penten-1-ol (2.25 g, 0.013 mol) in dry dichloromethane (50 ml) under nitrogen. After 30 minutes, the reaction was warmed up to room temperature. After 1 hour, diethyl ether (250 ml) was added to the reaction. After stirring for 10 minutes, the reaction was filtered through silica gel and the solid rinsed with diethyl ether. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1) followed by bulb-to-bulb distillation (82° C./0.002 mbar). 1.21 g (yield=53%) of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:28])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])=[C:14]([F:27])[CH:13]=3)[O:11][C:6]=2[C:5]([F:29])=[CH:4][C:3]=1[F:30].[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39].[Cl-].[NH4+]>CN(C)C=O>[C:23]([O:22][C:20]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:29])=[CH:4][C:3]([F:30])=[C:2]([NH:1][CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])[C:7]=3[C:8](=[O:28])[CH:9]=2)=[CH:13][C:14]=1[F:27])[CH3:19])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: C=CCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
828 mg (1.97 mmol) of 5-amino-2-[4-[N-(tert-butoxycarbonyl)-N-methylamino]-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 76 was dissolved in 40 ml of dimethylformamide under argon atmosphere, 160 mg of sodium hydride (60% oil dispersion) and 0.53 ml of 6-bromo-1-hexene were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. Additional 80 mg of sodium hydride (60% oil dispersion) and 0.27 ml of 6-bromo-1-hexene were added and the mixture was stirred for additional 1.5 hours. Art aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted three times with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to give 315 mg (32%) of 2-[4-[N-(tert-butoxycarbonyl)-N-methylamino]-3-fluorophenyl]-6,8-difluoro-5-(5-hexenylamino)-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CCN(CC)CC)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.[CH3:22][N:23]([CH3:29])[CH2:24][CH:25]([CH3:28])[CH2:26]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][CH:25]([CH3:28])[CH2:24][N:23]([CH3:29])[CH3:22])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CC(CCl)CN(C)C
Agent: Cl
Product: CCCC(=O)c1ccc(OCC(C)CN(C)C)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of 3-dimethylamino-2-methylpropyl chloride hydrochloride. The product is obtained as a colorless oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:45][CH:44]([OH:46])[CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CN(CCCCl)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol), 1-(3-chloropropyl)azetidin-3-ol (42.3 mg, 283 μmol, Eq: 3.0) and Cs2CO3 (123 mg, 377 μmol) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. LCMS showed complete reaction, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 62.1 μmol, 65.9%) as a light yellow semisolid. MS (M+H)+=644; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.36 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.35 (dd, J=8.9, 2.1 Hz, 1H), 6.55 (t, J=74.8 Hz, 1H), 5.75 (s, 2H), 4.43-4.63 (m, 3H), 3.66-3.76 (m, 2H), 3.55-3.65 (m, 2H), 2.88-2.99 (m, 2H), 2.51-2.61 (m, 2H), 2.03-2.17 (m, 3H), 1.65 (s, 9H), 0.92-1.02 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH2:38]([S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41])[CH3:39]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C:27]([N:46]3[CH2:45][CH2:44][N:43]([S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:48][CH2:47]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:35])([CH3:34])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-5-ethoxy-phenyl}-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 716.3 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[OH:18][NH:17][C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[C:2]=1[OH:1])=[NH:5]
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1cccc(Cc2c[nH]cn2)c1O
Yield: 45.9 %

Procedure:
3 g (0.015 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl-)benzonitrile (prepared in example 1.1 above) are dissolved in 100 ml of methanol and 1.15 g (0.0165 mole) of hydroxylamine hydrochloride and 1.84 g of sodium acetate are added thereto. The resulting mixture is then heated at the reflux temperature for 20 hours. The methanol is evaporated under reduced pressure and the residue is taken up in 100 ml of water. The resulting aqueous solution is neutralized to pH 7 by addition of an aqueous sodium bicarbonate solution. The white precipitate thus formed is filtered off, dried under vacuum and recrystallized from methanol. 1.6 g of N,2-dihydroxy-3-(1H-imidazol-4-ylmethyl)-benzenecarboximidamide, identical to the product obtained in example 2.5 above, are obtained. Yield 46%.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.CN1CCNCC1.[C:20]1([CH:26]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:27][CH2:28][O:29][C:30]([C:32]2[C:33]([CH3:49])=[N:34][C:35]([CH3:48])=[C:36](C(O)=O)[C:37]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)=[O:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:20]1([CH:26]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:27][CH2:28][O:29][C:30](=[O:31])[C:32]2[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)=[CH:36][C:35]([CH3:48])=[N:34][C:33]=2[CH3:49])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc(C)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(-c2cccc(Cl)c2)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(C)n1
Temperature: 25 °C

Procedure:
447 mg (2.33 mmol) of WSC hydrochloride and 0.254 ml (2.29 mmol) of N-methylpiperazine in the ice bath were added to 952 mg (1.90 mmol) of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester in 40 ml of dichloromethane and stirred at room temperature for 2 nights. Saturated aqueous sodium hydrogencarbonate solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound as a by-product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].CN(C)[CH:19]=[O:20].O.Cl>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH:19]=[O:20])[S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3]1=[O:16]
Reactant: CN(C)C=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C=O)sc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine (300 mg; WO98/54190) was dissolved in phosphorus oxychloride (4 ml) and dimethylformamide (2 ml) was added. The mixture was then heated to 100° C. with stirring under nitrogen for 1 hour. The mixture was allowed to cool to ambient temperature and then added dropwise to vigorously stirred hot water (˜50° C.), containing a small amount of 2M hydrochloric acid. The mixture formed was allowed to cool to ambient temperature and filtered to give the title compound as a brown solid (210 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]=12.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[N:18]1[N:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]2=[C:16]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cnn3cccnc23)cc1
Temperature: 85 °C

Procedure:
Water (160 mL) was added dropwise at room temperature to a mixture of 4-ethoxycarbonylphenylboronic acid (50 g, 0.26 mol), 3-bromopyrazolo[1,5-a]pyrimidine (56.25 g, 0.28 mol), Pd(ddpf)Cl2.CH2Cl2 (4.25 g, 5.21 mmol), and Cs2CO3 (169.42 g, 0.52 mol) in 1,4-dioxane (1 L). The reaction mixture was then heated 85° C. for 4 h. The reaction mixture was cooled, poured into water and extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of petroleum ether: EtOAc (100:10 to 3:1) to deliver the title compound (64 g, 93%) as a yellow solid.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[NH2:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:2][CH3:1])[N:7]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cncc(N)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a stirred solution of methanol (89 μL; 2.2 mmol) in dioxane (1 mL) was added sodium hydride (53 mg; 2.2 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4) and filtered. The crude product was purified using the Biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (11% yield).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1.[Zn]>[CH2:18]([C:12](=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: O=CC=Cc1ccccc1
Reactant: CCCCC(Br)C(=O)OCC
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCCCC(=CC=Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Yield: 38.7 %

Procedure:
In a 500 ml three necked flask was placed 7.0 g Zn dust and 0.7 g Cu powder in 150 ml dry toluene. To this suspension was added a solution of 13.2 g (0.1 mol) cinnamaldehyde and 22.3 g (0.1 mol) ethyl 2-bromohexanoate in 100 ml toluene. The reaction was refluxed overnight under nitrogen, cooled to room temperature and washed two times with 140 ml of 20% acetic acid and two times with 150 ml water. The organic phase was dried over magnesium sulfate and the solvent removed by rotary evaporation. Distillation of the crude product (24.9 g) resulted in isolation of 10.0 g ethyl 2-butyl-5-phenyl-pentadienoate. BP: 135-138 @ 0.1 mm Hg UV (CH2C12): λmax 315, ε=33,280, K=129.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]2=[O:8])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 3.5 g 1H-Pyrimidine-2,4-dione and 3 g 1-Fluoro-4-nitro-benzene and 13.8 g Cs2CO3 in 60 mL DMF was heated to 80° C. for 12 h. This solution was poured on to 200 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:11]([CH3:19])=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[Li+].[OH-].O.Cl>C1COCC1.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:11]([CH3:19])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OC)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)O)c2C)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
Part B: To a stirred solution of ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylate (8.00 gram, 0.0198 mol) in THF (80 mL) is added LiOH (0.59 gram, 2 molar equivalents) and water (80 mL). The resulting mixture is stirred for 16 hours at 80° C. After cooling to room temperature, HCl (2N solution, 12.3 mL) is added to give an oily precipitate. After addition of water and extraction with ethylacetate, the ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue is crystallised from diisopropyl ether and dried to give 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid (4.04 gram, 87% yield) as a pale grey solid. Melting point: 189–191° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=O.[NH2:27][C:28]([NH2:30])=[O:29]>C(O)C>[OH:29][C:28]1[N:30]=[C:5]([C:7]2[CH:8]=[C:9]([P:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:3][N:27]=1
Reactant: NC(N)=O
Reactant: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Solvent: CCO
Product: Oc1nccc(-c2cccc(P(c3ccccc3)c3ccccc3)c2)n1
Yield: 90 %

Procedure:
10 mmol of 4 are dissolved in 100 ml of aqueous ethanol and mixed with 25 mmol of urea. It is refluxed for 7 h, the solvent is removed and the colorless solid is washed with water. Recrystallization from chloroform gives 20 in a yield above 90%. ESI MS, m/z (%): 366.3703 (100) [M+H]+. 31P{1H} NMR (101.2 MHz, 25° C., DMSO-d6): 5-7.45.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3ccccc3)ccc2F)c1
Temperature: 80 °C

Procedure:
[3-(5-Bromo-2-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (78) (209 mg, 0.55 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude reside was purified by column chromatography using 20% EtOAc in heptane to give the title compound.