Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH2:1]([O:8][C@@H:9]1[C:13]([CH2:14][O:15][S:16]([CH3:19])(=[O:17])=[O:18])([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1[O:35][S:43]([CH3:42])(=[O:45])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
Nucleoside 27 (20 g, 37 mmol) was dissolved in anhyd dichloromethane (100 mL) and anhyd pyridine (100 mL) was added. The solution was cooled to 0° C. and methanesulfonyl chloride (4.4 mL, 56 mmol) was added dropwise. After 2 h the reaction was quenched with sat. aq NaHCO3 (200 mL), and the phases were separated. The aq phase was extracted with dichloromethane (2×150 mL), and the combined organic phases were washed with aq HCl (1 M, 2×200 mL), sat. aq NaHCO3 (2×250 mL) and brine (250 mL). The organic phase was dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude product was co-evaporated with toluene affording 28 (22 g, 96%) as a white foam. Rf=0.41 (100% EtOAc); ESI-MS m/z found 635.0 ([MNa]+, calcd 635.1). All analytical data were identical to those previously reported. (Håkansson, A. E.; Koshkin, A.; Sørensen, M. D.; Wengel, J. J. Org. Chem. 2000, 65, 5161-5166)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccccc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and benzoic acid as starting materials, MS (LC/MS): 407.2 (M+H).
Reaction SMILES: F[C:2]1[N:24]=[C:23]([F:25])[C:22]([I:26])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C@@H:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][OH:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:25][C:23]1[N:24]=[C:2]2[C:3]([C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[C@@H:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][OH:16])=[CH:21][C:22]=1[I:26]
Reactant: CCOC(=O)C(=CN[C@H](CO)C(C)(C)C)C(=O)c1cc(I)c(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H](CO)C(C)(C)C)c2nc(F)c(I)cc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(1-hydroxy-3,3-dimethylbutan-2-ylamino)acrylate Intermediate 80 (4.47 g, 9.27 mmol, 1 equiv.) in DMF (46 mL) was added potassium carbonate (1.92 g, 13.9 mmol, 1.5 equiv.) was added, and the reaction was stirred at 70° C. for 30 min. The reaction was cooled to 0° C. and quenched with saturated ammonium chloride (5 mL). The reaction was partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (2×30 mL), and the organics were concentrated. The compound was purified via silica gel chromatography and concentrated to afford (S)-ethyl 7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate Intermediate 78 as a solid (3.37 g, 79%). Calcd for C17H26FIN2O4. H1NMR (d6-DMSO) δ 8.69 (s, 1H), 4.24 (m, 3H), 3.98 (m, 2H), 1.28 (t, 3H), 0.95 (s, 9H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC(=O)CCC1C(=O)N(N)C(=O)NC=1.[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37][N:36]=2)[CH:32]=[CH:33][CH:34]=1.C1(N2CCN([NH-])CC2)CCCC1>>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([NH:12][C:41]([C:38]3[CH:39]=[N:40][C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[N:36][CH:37]=3)=[O:42])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: NN1CCN(C2CCCC2)CC1
Agent: COC(=O)CCc1c[nH]c(=O)n(N)c1=O
Agent: [NH-]N1CCN(C2CCCC2)CC1
Product: O=C(NN1CCN(C2CCCC2)CC1)c1cnc(-c2cccc(F)c2)nc1

Procedure:
Following procedures similar to those of Example 64 but using substituting 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting 4-cyclopentyl-piperazin-1-ylamine for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid methyl ester, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (4-cyclopentyl-piperazin-1-yl-amide (64%) as a solid. MS: 370 (M+H).
Reaction SMILES: N[C:2]1[C:11]2[C:10](=[O:12])[C:9]([CH3:13])=[N:8][N:7]([CH3:14])[C:6]=2[N:5]=[C:4]([NH2:15])[N:3]=1.[OH-:16].[Na+]>>[NH2:15][C:4]1[NH:3][C:2](=[O:16])[C:11]2[C:10](=[O:12])[C:9]([CH3:13])=[N:8][N:7]([CH3:14])[C:6]=2[N:5]=1
Reactant: Cc1nn(C)c2nc(N)nc(N)c2c1=O
Reactant: [OH-]
Agent: [Na+]
Product: Cc1nn(C)c2nc(N)[nH]c(=O)c2c1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 5,7-diamino-1,3-dimethylpyrimido-(4,5-c)pyridazin-4(1H)-one (0.50 g) and 1.5 N aqueous sodium hydroxide (35 ml) was stirred at reflux for 24 hours after which time a small amount of solid was removed by filtration of the hot mixture. On cooling, the yellow filtrate deposited white needles which were collected by filtration and dissolved in warm water (20 ml). Adjustment of this aqueous solution to pH 5 by dropwise addition of 6 N hydrochloric acid and subsequent cooling to room temperature provided a very finely divided white precipitate which was collected, washed with water and dried under vacuum at 70° C. to give 7-amino-1,3-dimethylpyrimido-(4,5-c)pyridazine-4,5(1H, 6H)-dione (0.38 g; 76% of theoretical yield). The u.v., i.r., and n.m.r. spectra of this compound were identical to those of the sample made according to the procedure of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Product: COc1cccc(C2(O)CCCN(C(=O)c3c(F)cccc3F)C2)c1

Procedure:
The compound of Example 23 was prepared according to the general preparation protocol A from 2,6-diflourobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:43]([N:45]([CH2:48][CH2:49]O)[CH2:46][CH3:47])[CH3:44]>O1CCCC1>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([O:28][CH2:44][CH2:43][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)CCO
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)OCCN(CC)CC)CC2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 829 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide in 25 ml. of tetrahydrofuran was added 357 mg. of carbonyldiimidazole. The mixture was heated under reflux for 10 minutes, and then 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was again heated under reflux for 10 minutes, and then an additional 258 mg. of 2-(N,N-diethylamino)-ethanol was added. The mixture was heated under reflux for 15 minutes and then it was cooled to room temperature. The solvent was removed by evaporation in vacuo, and the residue was dissolved in 75 ml. of ethyl acetate. The ethyl acetate solution was washed successively with water, 1 N sodium hydroxide, water and saturated sodium chloride solution. The ethyl acetate solution was then dried using sodium sulfate, and the ethyl acetate was removed by evaporation in vacuo. The residue (960 mg.) was recrystallized from isopropyl ether giving 570 mg. of the title compound, m.p. 78°-80° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:55][C:56]1[S:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1>C(Cl)Cl>[S:57]1[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=[C:56]1[NH:55][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1
Yield: 65.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (119 mg, 0.27 mmol), triethylamine (70 μL, 0.51 mmol), and 2-aminobenzthiazole (41 mg, 0.27 mmol) in methylene chloride (5 mL) was stirred at 25° C. under nitrogen for 2.33 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (48 mg, 66%) as a white solid: mp 206-209° C.; EI-HRMS m/e calcd for C22H24N2O3S2 (M+) 428.1228, found 428.1233.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[N:12]1([CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([O:20][CH2:19][CH2:18][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: N#Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1

Procedure:
Compound is prepared from 4-cyanobenzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 213-214° C.; 1H NMR (300 MHz, CDCl3) δ 2.70 (m, 4H), 3.00 (t, 2H), 3.78 (t, 4H), 4.35 (t, 2H), 6.80 (d, 1H), 7.50-7.70 (m, 5H), 7.80 (d, 1H), 7.95 (d, 2H), 8.31 (s, 2H); MS 402 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[OH:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc3ccccc3c2)cc1)c1ccccc1Cl
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-hydroxy naphthalene, the title compound was isolated as a yellow solid in 72% yield (99% purity by HPLC).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[N:5](S(C2C=CC=CC=2)(=O)=O)[CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6]([NH:7][CH:8]=[N:9][C:10]=2[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCC(NC(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-{1-[5-ethyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D7 (174 mg) and cesium carbonate (347 mg, 1.066 mmol) in MeOH (1.5 mL) and THF (3 mL) was stirred at room temperature for 3 hours. LCMS showed loss of starting material so the mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was isolated (phase separator) and then concentrated. The crude material was purified by MDAP to give E18 (6 mg), 1H NMR (d6-DMSO) δ 11.59 (1H, brs), 8.38 (1H, d), 8.24 (1H, s), 8.78 (2H, d), 7.52 (1H, t), 7.46 (2H, t), 7.09 (1H, s), 4.06 (1H, m), 3.95 (2H, d), 3.02 (2H, t), 2.77 (2H, q), 1.94 (2H, d), 1.76 (2H, ddd), 1.26 (3H, t), MS(ES+) 350 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][C:7]2[C:11]3[C:16](=[CH:15][N:14]=[CH:13][CH:12]=3)[C:17](=[O:18])[N:19]([CH3:20])[C:6]=2[CH:5]=1
Reactant: CNC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cnccc2c2cc(F)c(Cl)cc21
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (56.6 mg, 1.42 mmol) in THF (5 mL) at 0° C. was slowly added 4-(4-chloro-2,5-difluorophenyl)-N-methylnicotinamide (100 mg, 0.354 mmol) in THF (5 mL). The resultant mixture was stirred at room temperature for 1 h. The reaction was then quenched by addition of cold water (1 mL) and extracted with ethyl acetate (2×2 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (1:1 ethyl acetate in petroleum ether) to afford 8-chloro-9-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (82 mg, 0.297 mmol, 84% yield) as white solid. LC/MS (ESI) m/e 262.5 [(M+H)+, calcd for C13H9ClFN2O 263.0]; LC/MS retention time (method D): tR=1.79 min; HPLC retention time (method A): tR=7.35 min; HPLC retention time (method B): tR=7.07 min.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=O)/[CH:14]=[CH:15]/[O:16]C>>[CH:1]1([CH2:7][CH2:8][CH:9]2[O:10][C:15](=[O:16])[CH:14]=[C:13]2[O:12][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCC1CCCCC1
Reactant: CO/C=C/C(=O)OC
Product: COC1=CC(=O)OC1CCC1CCCCC1

Procedure:
Using general procedure A, cyclohexanepropanal (Stratakis, Manolis et al., Journal of Organic Chemistry (2002), 67(25), 8758-8763) was reacted with 3(E)-methoxy-acrylic acid methyl ester to give rac-5-(2-cyclohexyl-ethyl)-4-methoxy-5H-furan-2-one as a colorless solid. MS: 225.2 ([M+H]+).
Reaction SMILES: [H-].[Na+].N1C2C(=CC=CC=2)C=[CH:4]1.ClC1N=C(Cl)C(C)=CN=1.[OH:21][CH:22]([CH2:47][N:48]([CH3:50])[CH3:49])[CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([NH:29][C:30]2[N:35]=[C:34]([N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][CH2:37]3)[CH:33]=[CH:32][N:31]=2)=[CH:27][CH:26]=1>CN1C(=O)CCC1>[OH:21][CH:22]([CH2:47][N:48]([CH3:50])[CH3:49])[CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([NH:29][C:30]2[N:35]=[C:34]([N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37]3)[C:33]([CH3:4])=[CH:32][N:31]=2)=[CH:27][CH:26]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Agent: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1-n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 116 mg, 2.9 mmol) was added to a solution of indole (340 mg, 2.9 mmol) in NMP (2 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then added dropwise to a cold (0° C.) solution of 2,4-dichloro-5-methylpyrimidine (489 mg, 3.0 mmol) in NMP (3 ml). The mixture was stirred at 0° C. for 3 hours and then 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Method 1, 500 mg, 1.76 mmol) was added. The mixture was heated at 100° C. overnight and then silica (2 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% 2.0M methanolic ammonia solution in DCM, to give the product as a white solid (166 mg, 13%). NMR: 2.1 (m, 9H), 2.3 (m, 2H), 3.9 (m, 3H), 4.8 (d, 1H), 6.85 (d, 1H), 6.9 (d, 2H), 7.2 (m, 2H), 7.6 (m, 5H), 8.5 (s, 1H), 9.5 (s, 1H); MS (MH+): 418.
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:16](O)[CH2:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])C=Cc1cc(F)cc(F)c1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Add acetic anhydride (160 mL) to a solution of 1-(3,5-difluorophenyl)-2-nitroethanol (330 g) and 4-dimethylaminopyridine (18 g) in dichloromethane (1000 mL), over 30 minutes and stir the reaction mixture overnight. Dilute with dichloromethane (600 mL) and wash with 2% aqueous hydrochloric acid, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, dry (magnesium sulfate) and concentrate. Wash the crude with hexanes to give the desired compound (220 g).
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1>CO>[Br:7][C:8]1[C:9]([NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CO
Product: CC(C)(C)CNc1nc(Cl)ncc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
Neopentylamine (30 ml, 0.255 mol) is added dropwise at 0° C. over 20 min to a soln. of 5-bromo-2,4-dichloropyrimidine (29.17 g, 0.128 mol) in MeOH (230 ml). After stirring for 20 min at 0° C., the mixture is warmed to room temperature, stirred for 3 h, and evaporated. The residue is suspended in 300 ml of EtOAc, washed with sat. aq. NaHCO3 soln. (80 ml) and brine (80 ml), dried (MgSO4), and evaporated. The residue is chromagraphed on silica gel column (800 g of silica gel; hexane/EtOAc 5:1) to give the product (A) (32.64 g, 92%). White crystals. 1H-NMR (400 MHz, CDCl3) δ 1.00 (s), 3.36 (d, J=8.0), 5.52-5.61 (br. s), 8.12 (s). Rf 0.48 (hexane/EtOAc 5:1).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([Pb+3])[CH:19]=1.[CH:22]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:30])[CH2:24][C:23]2=[O:31].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([CH:24]2[C:25](=[O:30])[CH:26]3[CH2:29][CH:22]([CH2:28][CH2:27]3)[C:23]2=[O:31])[CH:19]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: Cc1ccc(Cl)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
To a solution of 5-chloro-2-methylphenyllead triacetate (0.41 g, 0.80 mmol) in chloroform (4 ml) is added bicyclo[3.2.1]octane-2,4-dione (0.10 g, 0.72 mmol) and 4-dimethylaminopyridine (0.46 g, 3.62 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (1 ml) is added, and the mixture is stirred at 80° C. for 1 hour (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 1M hydrochloric acid, and the organic phase separated. The aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a crude oil. Purification by preparative reverse-phase HPLC furnishes 3-(5-chloro-2-methylphenyl)bicyclo[3.2.1]octane-2,4-dione (0.063 g, 33%) as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:18])=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:25]1([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37](=[O:40])[CH2:38]Br)=[O:31])[CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:38][C:37]([N:33]2[CH2:34][CH2:35][CH2:36][C@H:32]2[C:30](=[O:31])[NH:29][CH:25]2[CH2:28][CH2:27][CH2:26]2)=[O:40])[C:13]2[C:8](=[CH:9][C:10]([CH3:18])=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2cc(Cl)c(C)cc2n1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2cc(Cl)c(C)cc2n1

Procedure:
To a solution of 1.1 g 6-Chloro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 25 ml DMF were added 2.7 g of cesium carbonate followed by dropwise addition of a solution of 1.8 g (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclobutylamide in 25 ml DMF over a period of 3 h. After this time another portion of cesium carbonate (700 mg) and (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclobutylamide (700 mg) were added over 1.5 h. The mixture was evaporated, diluted with DCM and washed with aqueous LiCl (4%). The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation. Yield: 3.3 g.
Reaction SMILES: C([NH:4][C:5]([CH2:25][OH:26])([CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)[OH:10])[CH2:6][OH:7])(=O)C.[Li+].[OH-]>CO.O>[NH2:4][C:5]([CH2:8][CH:9]([OH:10])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)([CH2:6][OH:7])[CH2:25][OH:26]
Reactant: CCCCCCCCc1ccc(C(O)CC(CO)(CO)NC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCc1ccc(C(O)CC(N)(CO)CO)cc1

Procedure:
2-Acetamido-4-(4-octylphenyl)-2-hydroxymethylbutane-1,4-diol (21′) (0.73 g) is dissolved in methanol (10 ml). Thereto is added a solution of LiOH (0.86 g) in water (10 ml), and the mixture is refluxed under heating for 2 hr. The reaction mixture is cooled and extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The solvent is distilled away and the mixture is purified by silica gel column chromatography to give the title compound (22) as a colorless and amorphous powder. The resulting Compound (22) has the same physico-chemical characteristics as indicated in Example 2.