Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:24][CH2:23][CH3:25])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(C)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(F)c21
Yield: 85 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 2-iodopropane (0.20 mL, 2.00 mmol) to give the title compound (0.279 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Cl:14]Cl>ClC(Cl)(Cl)Cl>[Cl:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: ClCl
Reactant: COC(=O)C(=O)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CCl
Yield: 35 %

Procedure:
100 g (0.56 mole) of methyl 2-methylphenylglyoxylate in 600 ml of tetrachloromethane are initially taken. The mixture is then refluxed while being exposed to a 300 W Hg vapor lamp, and 28 g (0.39 mole) of chlorine gas are passed in during this procedure. After a conversion of about 50% (determined by thin-layer chromatography), the reaction is terminated and the mixture is evaporated down. The residue is then subjected to fractional distillation. 29 g of product were obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[Cl:37][C:38]1[CH:39]=[C:40]([OH:47])[CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]([O:47][C:40]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:38]([Cl:37])[CH:39]=1)=[O:9]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Oc4ccc(C(=O)Cl)c(Cl)c4)cc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Oc4ccc(C(=O)Oc5ccc([N+](=O)[O-])c(Cl)c5)c(Cl)c4)cc3)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid 3-chloro-4-(chlorocarbonyl)phenyl ester obtained was dissolved in 150 ml of benzene and then added dropwise to a solution of 1.2 g of 3-chloro-4-nitrophenol in 110 ml of dry pyridine. The mixture was stirred at 65° C. overnight, then poured into a mixture of 500 ml of ice-water and 100 ml of concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed three times with 100 ml of 3N hydrochloric acid each time and three times with 200 ml of water each time, then dried and evaporated. The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-nitrophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/acetone (volume ratio 19:1). The fractions which were almost pure according to thin-layer chromatography (2.8 g) were recrystallized twice from ethyl acetate; m.p. (C-N) 132° C., cl.p. >250° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].N1C=CC=CC=1.[Cl-:26].[Cl-].IC1C=CC=CC=1>O1CCCC1>[NH2:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[CH:6][C:7]=1[Cl:26]
Reactant: CC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Reactant: [Cl-]
Solvent: c1ccncc1
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(N)c(Oc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenoxy)acetophenone (1.7 g), pyridine (0.52 g), and iodobenzene dichloride (1.8 g) in tetrahydrofuran (20 ml) was stirred overnight at 5° C. The mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water, an aqueous solution of sodium bisulfite, and water. The organic layer was evaporated to give a powder of 4'-amino-3'-chloro-5'-(2,4-difluorophenoxy)acetophenone (1.5 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]>CN(C=O)C>[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:1])[C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1ccc(O)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCCn1ccc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-Chlorosuccinimide (1.6 g, 11.96 mmol) was added to a solution of intermediate D5 (2.0 g, 11.96 mmol) in DMF (30 ml). The reaction was stirred at room temperature overnight and then it was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 0-5% methanol/DCM as eluent) to yield intermediate D8 (2.0 g, 83%).
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].CI>C(OCC)(=O)C>[CH3:2][O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 94 %

Procedure:
To a 20 ml tetrahydrofuran solution of 1.87 g (7.95 mmol) of benzyl 4-hydroxy-1-piperidinecarboxylate, 413 mg (60% in oil, 10.33 mmol) of sodium hydride and 792 μl (12.72 mmol) of methyl iodide were added at 0° C., and the mixture was stirred at room temperature for 16.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and washed with water. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.08 g (94%) of the captioned compound.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].Cl>[OH-].[Na+]>[C:14]([S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([SH:1])([CH3:13])[CH3:12])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)SC[C@H](NC(=O)C(C)(C)S)C(=O)O
Temperature: 0 °C
Yield: 74.8 %

Procedure:
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine (11.2 g, 0.05 mol) is dissolved in N sodium hydroxide (50 ml) and then pivaloyl chloride (6.6 g, 0.055 mol) and N sodium hydroxide (60 ml) are added dropwise while stirring under a nitrogen atmosphere at 0° C. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6 N hydrochloric acid. The produced oil is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness to yield 11.5 g (75.0%) S-pivaloyl-N-(2-mercapto-2-methylpropanoyl)-L-cysteine.
Reaction SMILES: [C:1]([Cl:7])(=[O:6])[CH2:2][CH:3]=[CH:4][CH3:5].C=CC=C.Cl>O>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:1]([Cl:7])(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CC=CCC(=O)Cl
Agent: C=CC=C
Agent: Cl
Solvent: O
Product: CCC=CC(=O)Cl

Procedure:
combining 3-pentenoylchloride with water, butadiene, and hydrochloric acid to form a mixture where the ratio of butadiene to pentenoylchloride is 1:1 to 6:1 and the molar ratio of water to 3-pentenoylchloride is 1:1 to 15:1, and reacting this mixture at a temperature in the range of about 0 degrees C. to 100 degrees C., preferably 30 to 50 degrees C., and at a pressure of about 50 to 600 psig to form a mixture comprising an organic phase containing 3-pentenoic acid, chlorovaleric acid, 3-chloro-1-butene and 1-chloro-2-butene, and an aqueous phase,
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1>CN1CCCC1=O>[CH3:13][C:14]1[N:18]=[CH:17][N:16]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[N:15]=1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: Cc1nc[nH]n1
Solvent: CN1CCCC1=O
Product: Cc1ncn(-c2nccc3[nH]c(=O)ccc23)n1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A stirred mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 20 g of 3-methyl-1H-1,2,4-triazole and 75 ml of N-methylpyrrolidinone was heated in an oil bath at 170°-180° C. for 18 hours and then cooled to room temperature whereupon a tan solid crystallized out. The mixture was diluted by adding 125 ml of water and the separated solid was collected, washed with water, air-dried and combined with another 1.2 g sample of the same material obtained in another run starting with 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were recrystallized from dimethylformamide and dried in an oven at 95°-100° C. for three days to yield 6.1 g of 5-(3-methyl-1H-1,2,4-triazole-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[CH:5]2.C(O)(=O)C.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[F:22]
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 35.7 mmol; Intermediate 1), acetic acid (4 mL), Selectfluor (25.3 g, 71.4 mmol), and acetonitrile (100 mL) was refluxed under N2 for 2 h. The reaction was allowed to cool to rt, diluted with ethyl acetate (420 mL), and then washed with water (270 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as yellow solids (6.0 g, yield 78.1%). 1H NMR (DMSO-d6, 400 MHz): δ 12.77 (s, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].CC#N.CCOC(C)=O>O>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)Cn1c(=O)ccc2ccccc21
Reactant: CCCCC1CCNCC1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCC1CCN(C[C@@H](C)Cn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 43.7 %

Procedure:
A 4 mL vial was charged with crude (S)-1-(3-iodo-2-methyl-propyl)-1H-quinolin-2-one (0.66 g), 4-butylpiperidine (0.43 g, 3.0 mmol) and dry CH3CN (1 mL). The mixture was shaken at 50° C. for 72 h and then poured onto The compound EtOAc (50 mL) and water (25 mL). The water phase was extracted (2×25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 1:4) and then cation-exchange CC producing the title compound (0.300 g, 44%). 1H NMR (CD3OD) δ 7.88 (d, J=9.2 Hz, 1H), 7.73-7.66 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 4.42-4.26 (m, 2H), 2.90 (brd, J=11.4 Hz, 1H), 2.74 (brd, J=11.4 Hz, 1H), 2.40-2.16 (m, 3H), 1.94-1.78 (m, 2H), 1.64-1.54 (m, 2H), 1.35-1.00 (m, 9H), 0.96-0.85 (m, 6H); 13C NMR (CD3OD) δ 163.7, 140.2, 139.5, 130.8, 129.1, 122.5, 121.4, 120.4, 115.3, 64.0, 55.1, 54.2, 46.8, 36.3, 35.8, 32.4, 32.3, 29.8, 28.9, 22.8, 16.1, 13.2.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]([CH3:4])[CH3:3].[F:7][C:8]([F:19])([F:18])[CH2:9][CH2:10][Si:11](OC)([O:14][CH3:15])[O:12][CH3:13].[SiH4].CCCCCC>C(OCC)C.CCCCCC>[F:19][C:8]([F:7])([F:18])[CH2:9][CH2:10][Si:11]([CH2:1][CH:2]([CH3:4])[CH3:3])([O:12][CH3:13])[O:14][CH3:15]
Reactant: CC(C)C[Mg]Cl
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Agent: [SiH4]
Solvent: CCOCC
Solvent: CCCCCC
Product: CO[Si](CCC(F)(F)F)(CC(C)C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen, a 500 ml Schlenk flask was cooled to room temperature and charged with 150 ml of diethyl ether and isobutylmagnesium chloride (0.06 mol, 30.24 ml). This was stirred and heated slightly to 30° C. A second Schlenk flask (100 ml) was purged with nitrogen to room temperature and charged with 75 ml hexane and 3,3,3-trifluoropropyltrimethoxy silane (0.0504 mol, 10 ml) and stirred. The silane/hexane solution was added dropwise via cannula to the Grignard/diethyl ether mixture producing a white precipitate midway through the addition. After addition (1.25 hrs.), the reaction mixture was stirred at room temperature for one hour. The flask was fitted with a reflux condenser and the reaction mixture was refluxed for two hours, then allowed to cool to room temperature. The reaction mixture was filtered through a medium porosity frit, using Celite diatomaceous earth and glass wool as a filtering aid. The solids collected weighed 7.55 g (theoretical=4.56 grams of magnesium salts). The slightly cloudy filtrate was kept under nitrogen overnight.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:32]5[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3)nc21
Reactant: OC1CCNCC1
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCC(O)CC4)cc3)nc21
Yield: 62 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 181 was used in place of the compound obtained in Example 48, and 4-hydroxypiperidine was used in place of N-methylpiperazine. In this manner, 72 mg (62%) of the captioned compound was obtained.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[Al](C)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:21]=[C:22]([C:33](OCC)=[O:34])[N:23]([CH3:32])[C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(Cl)Cl>C1(C)C=CC=CC=1.CCCCCC>[N:2]1([NH:1][C:33]([C:22]2[N:23]([CH3:32])[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[Cl:12])[N:21]=2)=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.33 mL (3.05 mmol) of 1-aminopiperidine in 2 mL of dry toluene under N2, 1.5 mL (3.05 mmol) of 2M trimethylaluminum in hexane was added with cooling in ice bath. The cold bath was removed, reaction was stirred for 1 h and 0.5 g (1.22 mmol) of ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate in 3 mL of toluene, and 1.5 mL of CH2Cl2 was added. The mixture was heated in a 60° C. bath for 2 h, cooled, quenched with water and the pH was adjusted to 5 with 1.2 N HCl. The solution was extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography using 30% EtOAc/hexane as an eluant to isolate the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:36][CH2:35][CH2:33][OH:34])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Product: CS(=O)(=O)CCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.33 (t, J=4.9 Hz, 1 H), 8.56 (s, 1 H), 7.67 (s, 1 H), 7.22 (dd, J=8.4, 5.4 Hz, 2 H), 7.01 (t, J=8.6 Hz, 2 H), 4.37 (t, J=7.8 Hz, 2 H), 4.12 (s, 2 H), 3.86 (t, J=5.2 Hz, 2 H), 3.63 (m, 2 H), 3.14 (t, J=6.8 Hz, 2 H), 2.95 (s, 3 H), 2.18 (m, 2 H); HRMS C22H24FN3O6S (M+H)+ calcd 478.1370, found 478.1440.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CC(N(C)C)=O.C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:14]2[N:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:16][N:15]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)Nc3ccc(Cl)cc3)c(C(F)(F)F)n2)CC1

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (4-chloro-phenyl)-amide (0.8 g, 2.38 mmol, 1.0 equiv; commercially available from Maybridge, UK), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 3.57 mmol, 1.5 equiv; commercially available) and triethylamine (0.49 mL, 0.36 g, 3.57 mmol, 1.5 equiv) in anhydrous DMAc (2 mL) and acetonitrile (9 mL) was heated by microwave irradiation to 120° C. for 20 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.0 g (84%) of the title compound. MS (ISP): 500.3 [M+H]+.
Reaction SMILES: N#N.[C:3]1([CH:9]([OH:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH:10]([NH2:11])[CH:9]([OH:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H](C(=O)O)C(O)c1ccccc1
Reactant: CO
Agent: N#N
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-phenylserine (15.00 g, 82.79 mmol) in MeOH (78.0 mL) was treated at 0° C. with thionylchloride (6.23 mL, 91.06 mmol). The resulting mixture was then stirred at rt overnight. The volatiles were removed under reduced pressure and the residue was triturated in EA and filtered to give the title compound as a white solid. LC-MS-conditions 02: tR=0.40 min, [M+AcCN+H]+=237.46.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH:48]([OH:50])[CH3:49]>CN(C)C=O>[OH:50][CH:48]([CH3:49])[CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: CC(O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a)) was dissolved in dimethylformamide. Sodium iodide (7.5 mg, 0.5 mmol), triethylamine (76 mg, 0.75 mmol) and 3-chloro-2-propanol (48 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 4 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was washed with ether (5×2 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 75 mg (74%) The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([NH2:10])=[CH:7][CH:6]=1)=[O:4].[OH:11][C:12](=[C:17]1C(=O)OC(C)(C)[O:19][C:18]1=O)[CH2:13][C:14](=O)[CH3:15].CS(O)(=O)=O>O1CCOCC1.C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:13]=[C:14]([CH3:15])[N:10]([C:8]2[O:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)c1ccc(N)o1
Reactant: CC(=O)CC(O)=C1C(=O)OC(C)(C)OC1=O
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)o1
Temperature: 98 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
To a room temperature solution of methyl-2-amino-5-furoate (4.85 g, 34.4 mmol) in 1,4 dioxane (28.0 mL) was added 5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.16 g, 44.3 mmol). The reaction was stirred vigorously and heated quickly (within 8 minutes) to an internal temperature of 98° C. Upon reaching temperature, the reaction was maintained for 1.0 hour. At this time, the reaction was cooled to room temperature rapidly using an ice-bath and methane sulfonic acid (3.30 g, 34.4 mmol) was added. The reaction mixture was once again brought to an internal temperature of approximately 100° C. After 1.0 hour the reaction was diluted with 10 mL of toluene and allowed to cool to room temperature on its own accord. A solid formed after 3.0 hours that was collected and subsequently recrystallized from methanol/ethyl acetate (1:1). The developing crystals were allowed to form and stand for 12.0 hours prior to collection to furnish the desired product as a solid (3.78 g, 44%). 1H NMR (400 MHz, d7-DMF) δ 11.34 (s, 1H), 7.43 (app d, J=3.6 Hz, 1H), 6.79 (app d, J=3.6 Hz, 1H), 6.01 (s, 1H), 5.63 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 2.02 (s, 3H); LC/MS C-18 column, tr=1.47 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 250 (M+H). ES-HRMS m/z 250.0696 (M+H calcd for C12H12NO5 requires 250.0710). Step 2: Preparation of methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoate.