Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>C1COCC1>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CN(C)CCN
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 430 mg (1.35 mmol) of benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated with a 5-fold excess of N,N-dimethyl-ethylenediamine and the mixture was stirred at room temperature for 2 hrs. The THF was removed under vacuum. After dilution with water, the product was extracted with CH2Cl2 and dried. Chromatography on alumina, eluting with EtOAc, gave 450 mg (90% yield) of benzyl 4-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-piperidinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.33 (m, exchangeable with D2O, 1H), 3.16 (m, 2H), 3.04 (tt, J=11.9, 3.7 Hz, 1H), 2.81 (br t, J=11.9 Hz, 1H), 2.43 (m, 2H), 2.22 (s, 6H), 2.12 (br d, J=12.8 Hz, 2H), 1.74 (ddd, J=25.0, 12.6, 4.5 Hz, 2H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([C:21]1[CH:26]=[CH:25][C:24](OC2C=CC=CC=2)=[CH:23][CH:22]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)=[O:7].F[C:37](F)(F)[C:38]([OH:40])=O>>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]2[CH:3]=[CH:4][N:5]([C:21]3[CH:26]=[CH:25][C:24]([O:40][C:38]4[CH:37]=[CH:11][CH:10]=[CH:9][CH:14]=4)=[CH:23][CH:22]=3)[C:6]2=[O:7])=[CH:14][CH:13]=1
Reactant: COC(CN(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(Oc2ccccc2)cc1)OC
Reactant: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(2,2-Dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-phenoxy-phenyl)urea (0.33 g) was shaken with trifluoroacetic acid (5 ml) for 16 hours. Volatiles were removed and the residue was taken up in dichloromethane (10 ml) and washed with sodium hydroxide solution (0.1N; 1 ml). The aqueous phase was extracted with dichloromethane (10 ml), and the combined organic phases were concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 98:2 with 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 415.50 (C25H25N3O3); MS (ESI): 416 ([M+H]+), was obtained in this way.
Reaction SMILES: [Br-:1].C1(C(O)(C2C=CC=CC=2)C(O[CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:18](=[O:20])[NH2:19])=O)CCCCC1.[C:35]([OH:51])(=[O:50])[C:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[Br-:1].[OH:37][C:36]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]([O:51][C@@H:16]1[CH2:15][CH2:14][N+:13]([CH3:27])([CH:17]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:18](=[O:20])[NH2:19])[CH2:12]1)=[O:50]
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C[N+]1(C(C(N)=O)c2cnccn2)CC[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with benzilic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26]CC=C)=[CH:21][CH:20]=2)=[O:16])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.[Cl-].[Na+].O.[Pd]>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([OH:26])=[CH:21][CH:20]=2)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOc1ccc2[nH]c(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2[nH]1

Procedure:
To a solution of 3370 mg (8.27 mmol) {2-[(5-Allyloxy-1H-indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (36) in 100 ml methanol was added 5 ml water, 750 mg Pd (10% on C) and 300 mg p-toluenesulfonic acid. After heating at reflux for 6 h the reaction mixture was added to a 1:1 mixture of brine and saturated NaHCO3 solution. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over Na2SO4 and filtrated over celite. The solvent was removed and the residue was subjected to silica gel chromatography (petrolether/ethyl acetate 2:1). {2-[(5-Hydroxy-1H-indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (37) was recrystallized from diethyl ether/petrol ether to yield 1265 mg (3.44 mmol) crystalls, mp. 197° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([O:37]C)[C:34]([Cl:39])=[C:33]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CN(C=O)C>[Cl:39][C:34]1[C:33]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=2)=[CH:32][C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:50][O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[O:11]2)=[CH:36][C:35]=1[OH:37]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(OC)c2Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(O)c2Cl)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of compound 76 (3.0 g, 3.82 mmol) in DMF (38 mL) was added NaSEt (1.1 g, 13.35 mmol) at 90° C. The mixture was stirred at 90° C. for 6 hours. To a mixture was added 1N HCl (50 mL) and extracted EtOAc (200 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 77 (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7]1
Reactant: COc1ccc([N+](=O)[O-])cc1OC1CCN(C)C1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1OC1CCN(C)C1

Procedure:
A solution of 3-(2-methoxy-5-nitro-phenoxy)-1-methyl-pyrrolidine (3.0 g, 0.12 mmol) in ethanol (50 ml) was hydrogenated over 10% palladium on charcoal catalyst for 2 hrs to afford the title compound (D25). Found MH+ 223.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40][NH2:41]>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:41][CH2:40][C:39]4[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=4[CH3:37])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1CN
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1CNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3C)c(C)c1)C2

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 2-methylbenzylamine, m.p. 128-130° C. MS [(+)ESI, m/z]: 538 [M+H]+
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])C1C=CC=CC=1.CCN([CH:40]([CH3:42])[CH3:41])C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[O:19]1[C:17]2[CH:16]=[CH:12][CH:42]=[CH:40][C:41]=2[CH:21]=[C:20]1[C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10]
Reactant: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)OCc2ccccc2)c1C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)c2cc3ccccc3o2)c1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 288.9 %

Procedure:
Under an atmosphere of argon, acid chloride 12 (10.8 mg, 60 μmol) was added in portions to a stirred solution of 11 (24 mg, 50 μmol), Hünig's base (26 μL, 19 mg, 15 μmol), and DMAP (0.6 mg, 5.0 μmol) in dichloromethane (250 μL) at room temperature. The reaction was stirred for 10 minutes then heated to 30° C. for 20 minutes. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 13 (21.3 mg, 87%) as a solid: LRESIMS m/z 492 [M+H]+, calcd. for C23H20F3N3O4S1 492.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:27][CH:26]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(4-Methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-methoxybenzylamine using method H. NMR; δH [2H6]—DMSO 9.07,(1H, t), 7.98,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.55-7.50,(3H, m), 7.26,(2H, d), 6.89,(2H, d), 4.43,(2H, d), 3.72,(3H, s), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.24 min, MH+ 414.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ncccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCc1ccc(Oc2ncccn2)cc1

Procedure:
A stirred solution of 4.0 grams (0.02 mole) of (4-pyrimidin-2-yloxyphenyl)methanol (known compound) and seven drops of pyridine in 35 mL of methylene chloride was cooled in an ice-water bath and a solution of 2.0 mL (0.027 mole) of thionyl chloride was added dropwise. Upon completion of addition the reaction mixture was stirred at about 10° C. to 20° C. during a three-hour period. After this time, the reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The mixture was then stirred for 30 minutes and the organic layer was separated. The aqueous layer was extracted with one 50 mL portion of methylene chloride. The extract was combined with the organic layer, and the combination was passed through silicone-coated filter paper to remove traces of water. The filtrate was concentrated under reduced pressure, yielding grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC(C)([O-])C.[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][C:47](Br)=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:40])([F:39])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[CH:48]=[C:47]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: C1COCCN1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N3CCOCC3)ccc21

Procedure:
Combine tris(dibenzylideneacetone)dipalladium (0) (0.015 g, 0.017 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphyl (0.031 g, 0.050 mmol) and sodium t-butoxide (0.023 g, 0.235 mmol) in toluene (3 mL) in a 10 mL microwave vessel and purge this suspension with nitrogen at room temperature for 5 min. Add morpholine (0.016 mL, 0.185 mmol) followed by isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.100 g, 0.168 mmol) and irradiate this mixture at 110° C. for 15 min. Dilute the cooled mixture with dichloromethane and filter through Celite. Remove the filtrate solvent under reduced pressure and purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound a yellow solid (0.041 g, 40%): ESI MS 602 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(O)C>[C:12]1([C:10]2[N:1]=[C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ncccn1
Solvent: CCO
Product: c1ccc(-c2cn3cccnc3n2)cc1
Yield: 102.4 %

Procedure:
A mixture of 9.5 g of 2-aminopyrimidine (0.1 mole), 20 g of ω-bromoacetophenone (0.1 mole) and 200 ml of 95% ethanol is refluxed for three hours and then heated at 60° for an additional 12 hours with stirring. After cooling, the reaction product is condensed to a thick liquid by evaporating it in a rotary evaporator. The residue is mixed with 500 ml of methylene chloride and 100 ml of 3 N sodiumhydroxide solution. The mixture is stirred for 10 minutes and then separated in two layers in a separatory funnel. The lower layer (solvent) is collected, washed with 100 ml of water and then evaporated to dryness under reduced pressure. The residue is washed with 2-propanol on a glass filter and dried in vacuum to yield about 20 g of 2-phenylimidazo(1,2-a)pyrimidine, m.p. 200° to 202° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=O)[C:3]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:32][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][CH2:4][C:3]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1=C(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)COC(C)=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 4 ml of hexamethylphosphoramide was dissolved 0.33 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, to this solution was added 50 mg of sodium hydride (60% oily), and the mixture was stirred at room temperature for 30 minutes. Then, 0.2 ml of dimethyl sulfate was added, and the mixture was stirred at 65° C. for 1 hour, and at room temperature overnight. Thereafter, the reaction mixture was added to ice water, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-methoxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran [Compound No. (2a-17)] as a pale yellow crystal.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[C:11](=[CH:16]\[NH:17][NH:18][C:19]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][N:20]=1)/[C:12](OC)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].OS([O-])(=O)=O.[Na+]>C(O)C.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[N:17][N:18]([C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][N:20]=2)[C:12]=1[OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)/C(=C/NNc1cc(C#N)ccn1)CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To a mixture of methyl (2E)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(4-cyanopyridin-2-yl)hydrazinyl]methylidene]butanoate (3.3 g, 8.77 mmol) in ethanol (50 mL) at 0° C. was added t-BuOK (2.95 g, 26.33 mmol). The reaction mixture was stirred overnight at r.t. It was then cooled to 0° C., diluted with ethyl acetate, and acidified with NaHSO4 (5%) to pH=3. The organic phase was separated and concentrated to a residue which was washed with PE/EA to give 300 mg of the title compound (10%). 1H NMR (400 MHz, CD3OD): δ 0.00 (6H, s), 0.85 (9H, s), 2.49 (2H, d, J=6.4 Hz), 3.74 (2H, d, J=6.4 Hz), 7.48 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.60 (1H, s), 8.57 (1H, d, J=4.8 Hz), 8.61-8.63 (1H, m). [M+H] Calc'd for C17H24N4O2Si, 345. Found, 345.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[C:46]([CH3:52])=[CH:45][CH:44]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:41][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[N:48]5[CH:49]=[CH:50][N:51]=[C:47]5[C:46]([CH3:52])=[CH:45][CH:44]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Cc1ccc(Br)n2ccnc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)n2ccnc12
Temperature: 150 °C
Yield: 60.5 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (205 mg, 0.30 mmol), 5-bromo-8-methylimidazo[1,2-a]pyridine (75 mg, 0.35 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol) and copper(I) thiophene-2-carboxylate (11 mg, 0.06 mmol) in dioxane (3 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give a solid that was triturated in MeOH, filtered and dried at 60° C. under vacuum for 24 hours to give 201 as a white solid (97 mg, 62%). LCMS (Method G) RT 5.11 min; [M+H]+ 535. 1 H NMR (400 MHz, CHCl3-d): δ 9.29 (s, 1 H); 7.93 (d, J=7.3 Hz, 1 H); 7.75 (s, 1 H); 7.37 (s, 1 H); 7.15 (d, J=7.3 Hz, 1 H); 7.13-6.96 (m, 1 H); 5.21 (s, 1 H); 4.06 (t, J=4.7 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.86 (s, 2 H); 2.73 (s, 3 H); 2.62 (s, 8 H); 1.25 (s, 6 H)
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[OH:35][C:6]1[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:10](=[O:28])[N:11]2[CH2:21][CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Temperature: 25 °C
Yield: 19.4 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.076 mmol), β-alanine (545 mg, 6.1 mmol) and NaOMe solution (9 mL, 4.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 7.8 mg of the title compound as a pale brown solid. MS: (+) m/z 529.41 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[NH:26][CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:30][C:31]1[N:32]=[N:33][C:34](Cl)=[CH:35][CH:36]=1>CS(C)=O>[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[N:26]([C:34]4[N:33]=[N:32][C:31]([Cl:30])=[CH:36][CH:35]=4)[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(-c2ccc(Cl)nn2)cc1C1c2ccccc2C=Cc2ccccc21
Temperature: 80 °C

Procedure:
Cesium carbonate (2.15 g) was added to a stirred solution of the product of example 1 step (iv) (2 g) in dimethylsulphoxide (20 ml). After 5 minutes 3,6-dichloropyridazine (1 g) was added and the mixture heated at 80° C. for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.8 g.