Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13])([O:3][CH2:4][CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:22]([C:6]1([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13])[CH:21]=[CH2:20]
Reactant: CCOC(=O)C1CCCCCC1=O
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1(C(=O)OCC)CCCCCC1=O
Temperature: 57.5 °C
Reaction time: 17 h

Procedure:
2-carboethoxycycloheptanone (1 mmol), finely powdered potassium carbonate (2 mmol), allyl bromide (1.5 mmol), and tetrabutyl ammonium iodide (10 mg/mmol) are combined in dry DMF (1.25 mL/mmol) and stirred under N2 at 55 to 60° C. for 16 to 18 hours. The room temperature reaction mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allyl-2-carboethoxycycloheptanone. This material is combined with lithium chloride (5 mmol), water (1.05 mmol) and dimethyl sulfoxide (5 mL/mmol) and the mixture refluxed for approximately 4 hrs. The mixture is poured into water and extracted with Et2O and EtOAc. The combined organics are washed with brine, dried, and stripped of all solvent under reduced pressure to provide 2-allylcycloheptanone. A sample of the 2-allylcycloheptanone is converted to the title compound by the method of EXAMPLE 24 using hydroxylamine hydrochloride and NaOAc in a mixture of EtOH and water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:30][CH:31]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[N:11]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH:31]([CH3:32])[CH3:30])=[CH:35][CH:36]=2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a suspension (20 mL) of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), [4-(1-methylethoxy)phenyl]boronic acid (0.46 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.47 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.59 g, 100%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[N:3]=1.B(O)(O)[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1.P(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.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.O>[CH3:12][NH:11][C:7]1[N:6]=[C:5]2[N:4]([CH2:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]3)[N:3]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[C:10]2=[CH:9][N:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CNc1ncc2c(Br)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ncc2c(-c3ccc(C)cc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
A 30 mL microwave tube was charged with tert-butyl 4-((3-bromo-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.070 g, 0.16 mmol), p-tolylboronic acid (0.065 g, 0.48 mmol), potassium phosphonate (0.10 g, 0.48 mmol), tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), dioxane (2 mL) and water (0.5 mL). After stirring for 5 min, the reaction was heat at 150° C. for 10 min in microwave. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated, and purified by Isco to provide tert-butyl 4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.064 g, 89%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[O:10][CH:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1>CO.C(Cl)Cl>[Br:25][C:5]1[CH:4]=[C:3]([F:2])[C:11]2[O:10][CH:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc2c1OC(C1CCNCC1)C2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Fc1cc(Br)cc2c1OC(C1CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidine hydrochloride (1.18 g, 4.58 mmol) in MeOH (36.6 mL) at 0° C. was added NBS (0.815 g, 4.58 mmol) in one portion. Upon completion of addition, the reaction mixture was immediately warmed to room temperature, where it stirred for 3 hours. At the conclusion of this period, the reaction mixture was quenched with aqueous Na2H2S2O5 (5%, 5 mL). The solvent was removed under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 (5 mL), washed with NaHCO3 (aq, sat, 3 mL) and brine (3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to afford Compound 3E as a colorless oil (1.3 g, 95% yield). LC/MS (m/z)=301 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[C:12]([O:14][CH3:15])=[O:13].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[CH3:15][O:14][C:12]([C:7]1[C:8]2[C:3](=[C:2]([NH:1][C:24]([NH:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=3)=[O:25])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1)=[O:13]
Reactant: COC(=O)c1nccc2c(N)cccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12

Procedure:
Prepared from methyl 5-aminoisoquinoline-1-carboxylate (Description 106) and [4-(trifluoromethyl)benzyl]isocyanate (description 58) according to the procedure of description 61. m/z (ES+) 404 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:32][N:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]1=[O:48].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:31][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:36]=[CH:35][C:34](=[O:48])[N:33]([CH3:32])[CH:38]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6ccc(=O)n(C)c6)ccn45)cccc32)n1
Temperature: 90 °C
Yield: 51.3 %

Procedure:
7-Bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.05 g, 0.12 mmol) was dissolved in dimethoxyethane:dimethylformamide (1:1, 0.8 mL) in a 2 dram vial, and 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.04 g, 0.17 mmol), PdCl2(dppf)*dcm (0.005 g, 0.006 mmol), and 2 M sodium carbonate (0.17 mL, 0.34 mmol) were added. Nitrogen was bubbled through the reaction mixture for 5 minutes before capping the vial and heating in a sand bath at 90° C. overnight. The reaction mixture was diluted with ethyl acetate and water. A greenish precipitate formed and was collected. The crude material was purified by preparatory thin layer chromatography (silica, 20×20 cm, 0.5 mm) developed in a chamber with 10% MeOH/DCM. The UV active band with Rf=0.1 was isolated and the silica washed with 10% MeOH/DCM. The filtrate was concentrated to give N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide as a beige solid (31 mg).
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[NH:11]1[C:20](=[O:21])[C:19]2NC=N[C:15]=2N=C1N.[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])CCCNC(=N)N.N[C@H](C(O)=O)C>>[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:15][CH2:19][C:20](=[O:21])[NH2:11]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[C@H](N)C(=O)O
Agent: Nc1ncnc2nc[nH]c12
Product: NC(=O)CC[C@H](N)C(=O)O
Reaction time: 12 h

Procedure:
Site-specific mutagenesis was carried out according to standard techniques described by Kunkel (Kunkel T A. Rapid and efficient site-specific mutagenesis without phenotypic selection; Proc Natl Acad Sci USA 1985, 82: 488-492) by inserting an adenine in place of guanine in position 34099 (the mutagenesis was also repeated by inserting an adenine in place of guanine in position 34099, and a guanine in place of adenine in position 34100). Sequencing of the cDNA was carried out for assurance that the mutation was correct and that any new mutations had not been introduced. Expression of the recombinant FIX was obtained using “human embryonic kidney cell line 293” and the methods already reported in the literature (Chang J L, Jin J P, Lollar P, et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J. Biol. Chem. 1998; 273:12089-12094). The recombinant FIX was isolated from the supernatant (culture medium) by means of an immunoaffinity column, as aforedescribed. Briefly, the supernatant of the cell culture was collected every 24 hours for 10 days and conserved at −20° C. For the purification the supernatant was thawed out and benzamidine and EDTA were added to a final concentration of 5 milliMoles and 4 milliMoles respectively. After filtration through a Millipore filter, the supernatant was incubated with fast-flow Sepharose Q resin for 12 hours at 4° C. The resin was then re-equilibrated in Tris, NaCl and benzamidine buffer and loaded onto the column. Elution was undertaken with a 0-60 nM calcium gradient. The eluate was then dialyzed in a Tris-NaCl buffer. The preparation was then applied to the immunoaffinity column following the method described in example 2 (in the “in vitro” expression of the recombinant protein). Starting from the culture medium, the procedure was the same as for the plasma, except for the precipitation procedure using BaCl. The culture medium was centrifuged at 4000 g for 20 minutes then subjected to dialysis in Tris-NaCl and loaded onto the immunoaffinity column at a rate of 0.5 ml/min. The remaining steps were the same as those taken for the plasma.
Reaction SMILES: [N+:1]([C:4]1[C:5](NN)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]>CO.O.C([O-])(=O)C.[Ag+]>[N+:10]([C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([O-:12])=[O:11]
Reactant: NNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Yield: 21.4 %

Procedure:
Silver acetate (2.0 g) was added to a solution of the crude 3,5-dinitro-pyridinyl-hydrazine (2.2 g) in a mixture of methanol:H2O (1:1, 6 ml), and the mixture was stirred at reflux overnight. Solvent was evaporated, then water and conc. NH4OH were added. The mixture was extracted with ethyl ether, the combined extracts were dried over MgSO4, concentrated and purified by column chromatography (5:1 hexane: ethyl acetate) to give the title compound (400 mg) in 21.8% yield. MS (DCI/NH3) m/e: 124 (M-46+1). 1H NMR (CDCl3, 300 MHz) δ: 9.77 (m, 2H), 9.27 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH2:12][OH:13])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH:9]2[CH2:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[O:10]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc2c1OC(CO)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 50 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0° C. was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. Rf=0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103° C.; Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[C:4]([C:13]#[C:14][Si](C)(C)C)[CH:3]=1.C1COCC1.CO.O.[OH-].[Li+]>O>[C:13]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])=[O:10])#[CH:14]
Reactant: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1cc(F)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of ester 326 (3.30 g, 12.5 mmol) in 1:1 THF/methanol (100 mL) was added lithium hydroxide monohydrate (1.60 g, 38.1 mmol) in water (25 mL) and the mixture was stirred at r.t. for 30 min. It was then partially concentrated; the aqueous residue was washed with ether; then acidified with 3M HCl (aq), extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous MgSO4), filtered and concentrated to provide acid 327 (2.10 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.36 (dd, J=8.6, 5.9 Hz, 1H); 7.30 (dd, J=9.2, 2.7 Hz, 1H); 7.21 (dt, J=8.6, 2.7 Hz, 1H); 4.48 (s, 1H); 3.70 (s, 2H). LCMS: (M+Na) 201.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[N:12]=[C:11]([O:13][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:10]=[CH:9][N:8]=1
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(O)n3)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccnc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
30 mg of sodium hydride was added to a mixture of 0.3 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-pyrimidine, 127 mg of methyl bromoacetate and N,N-dimethylformamide at 0° C., then, the mixture was stirred at room temperature. The solution was poured into a mixture of ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.2 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-7].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[CH3:11][CH:12]([C:18](=O)[CH3:19])[C:13](OCC)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:13]([OH:14])[C:12]([CH3:11])=[C:18]([CH3:19])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1C
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 2-methyl-3-oxobutanoate (0.339 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature and the reaction mixture was stirred for 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10].C(OCC)(=O)C.O>CN(C)C=O>[CH:9]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:25][C:24]3[CH:26]=[C:27]([Br:1])[CH:28]=[CH:29][C:23]=3[O:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3ccccc3O2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
N-Bromo-succinimide (510 mg) is added to (4-(2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (830 mg) in N,N-dimethylformamide (20 mL). The mixture is heated to 50° C. and stirred at this temperature for 4 h. After cooling to room temperature over night, ethyl acetate and water are added and the mixture is extracted with ethyl acetate. The organic phase is washed with sodium thiosulfate solution and water and dried (Na2SO4). The solvent is evaporated and the residue is triturated with diisopropyl ether to afford the title compound as a white solid. Yield: 750 mg (71% of theory); LC (method 1): tR=1.43 min; Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:13][C:10]2[S:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[N:12][CH:11]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cnc(NC(=O)OC(C)(C)C)s2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
To a single necked round bottom flask (5-Formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1 g, 4.38 mmol) was dissolved in 20 ml methanol. To it piperidine-4-carboxylic acid ethyl ester (2.02 ml, 13.15 mmol) and 4-drops of glacial acetic acid was added and reaction mixture was stirred at room temperature for 2.5 hr. To it sodium cyanoborohydride (550 mg, 8.76 mmol) was added in portions and stirred for 12 hrs. Methanol was removed under reduced pressure using rotavapour. The residue was taken in water (15 ml) and ethyl acetate (25 ml), layers were separated, and aq. layer was re-extracted with ethyl acetate (25 ml). The combined organic layer was washed with brine (25 ml) and dried over anhydrous sodium sulfate. Solvent was evaporated on rotavapour, to get the yellow solid product. The crude material was purified by silica-gel column chromatography, eluting with 30-50% ethyl acetate in hexane. (0.98 g, 60% yield).
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][C:9]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([C:32]([CH:35]=[O:36])=[CH:33][N:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C@H:19]1[O:37][CH3:38])=[O:16]>O.CC(C)=O>[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][C:9]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([C:35]([OH:1])=[O:36])=[CH:33][N:34]=2)[CH2:20][C@H:19]1[O:37][CH3:38])=[O:16]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 133 mg (0.84 mmol) KMnO4 in 5 ml water was added to a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-formylisonicotinate (Example 154) in 20 ml acetone, and the mixture was stirred at room temperature for 4 h. After quenching with aqueous NaHSO3, the mixture was acidified to about pH=4 with 1N HCl and extracted twice with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to give a solid that was triturated with MeOH to give 175 mg of product. MS (ES) MH+: 499 for C21H24Cl2N4O6; NMR: 1.25 (t, 3H), 1.5-1.8, (m, 3H), 2.1 (s, 3H), 3.1 (m, 3H), 3.3 (s, 3H), 3.5 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 4.9 (m, 1H), 6.9 (s, 1H), 7.1 (d, 1H), 8.6 (s, 1H), 12.1 (s, 1H), 13.3 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:49])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[S:36][CH:37]=[C:38]([CH2:40][O:41]C3CCCCO3)[N:39]=2)[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[C:38]([CH2:40][OH:41])[N:39]=4)[CH:30]=3)[CH2:27][C:26](=[O:49])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.15 g) (Example J7) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.23 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.14 g).