Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([OH:23])[CH:20](O)[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+]>CC1C=CC=CC=1.C(O)CCC>[CH3:21][CH:20]1[CH2:19][O:23][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9]1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: CC1COC(c2ccccc2)(c2ccc(N)c([N+](=O)[O-])c2)O1

Procedure:
A solution of 31.5 parts of (4-amino-3-nitrophenyl)phenylmethanone, 15.2 parts of 1,2-propanediol and 5 parts of 4-methylbenzenesulfonic acid in 40 parts of butanol and 450 parts of methylbenzene is stirred and refluxed for 17 hours. The reaction mixture is cooled and 90 parts of ammonium hydroxide are added (to remove the 4-methylbenzenesulfonic acid). The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off (the filtrate is set aside), yielding a first fraction of 13.8 parts of 4-(4-methyl-2-phenyl-1,3-dioxolan-2-yl)-2-nitrobenzenamine; mp. 155.2° C. The filtrate, which was set aside, is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, methanol and hexane (88:2:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding a second fraction of 3.6 parts of 4-(4-methyl-2-phenyl-1,3-dioxolan-2-yl)-2-nitrobenzenamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 7) and 4-fluorobenzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 3.67 (br s, 4H), 4.24 (br s, 2H), 4.43 (br s, 2H), 5.64 (s, 2H), 7.25 (t, J=8.9 Hz, 2H), 7.60 (m, 3H), 7.83 (s, 1H), 7.95 (s, 1H); LC retention time 3.21 min; MS: m/z (ESI) 494 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+]>[C:8]1([S:14]([NH:1][CH:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(CO)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CO)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
DL-serine (1.051 g) was dissolved in a 1 M aqueous NaOH solution (20 ml). Benzenesulfonyl chloride (1.77 g) was added at 0° C. After 30 min the ice bath was removed and the mixture was stirred for 18 h at room temperature. The mixture was again placed in an ice bath. The mixture was acidified to pH 1 using 25% aqueous HCl. The colorless precipitate was collected by filtration, washed with 1 M HCl and dried to give (RS)-2-benzenesulfonylamino-3-hydroxy-propionic acid (1.23 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1)=[NH:18])([O-:17])=[O:16]
Reactant: NCCCSc1ncco1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCCSc1ncco1)N[N+](=O)[O-]

Procedure:
Reacting 2-(3-aminopropylthio)oxazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N' -[3-(2-oxazolyl)thiopropyl] guanidine. Similarly, reaction of the same starting material with N,S-dimethyl-N' -nitroisothiourea by the procedure of Example 2(iii) gives N-methyl-N' -nitro-N" -[3-(2-oxazolyl)thiopropyl]guanidine.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][C:12]([F:16])([F:15])[CH2:13][OH:14])[N:10]=1)([O-:5])=[O:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)C>C1COCC1>[N+:3]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][C:12]([F:16])([F:15])[CH2:13][O:14][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1nc(CC(F)(F)CO)c[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COCC(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Temperature: -50 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a suspension of sodium hydride (500 mg, 20.8 mmol) in dry THF (20 ml) which was cooled at -50° C., a solution of 3-(2'-nitroimidazolyl)-2,2-difluoropropanol (2.0 g, 9.6 mmol) in dry THF (10 ml) and then a solution of ethyl bromoacetate (2.4 g, 14.4 mmol) in dry THF were dropwise added. Then, the reaction mixture was gradually warmed to a room temperature and stirred for 4 hours at the temperature. After the reaction, the mixture was cooled by ice. Ethanol (2 ml) was added to the mixture, concentrated and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain ethyl 2-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropoxy]acetate (2.4 g)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([CH:36]=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.CC(=CC)C.[O-:44]Cl=O.[Na+]>C(O)(C)(C)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([C:36]([OH:44])=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: [O-][Cl+][O-]
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C(=O)O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
5-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate F4, 19 mg, 0.036 mmol) was dissolved in 2-methyl-2-butene (300 μl, 2.83 mmol) and t-Butanol (0.5 ml), then a solution of NaClO2 (32.6 mg, 0.360 mmol) and K2H2PO4 (49.0 mg, 0.360 mmol) in 0.5 mL of water added and the mixture stirred at rt for 2 hrs. The reaction was quenched by the addition of 2M HClaqueous (1 ml) and the crude purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (8 mg, 40.9%) as white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=2)=[CH:2]1.N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]\[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:19]=2)=[CH:2]1
Reactant: N[C@H](COc1cncc(C#Cc2ccncc2)c1)Cc1c[nH]c2ccccc12
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: N[C@H](COc1cncc(/C=C\c2ccncc2)c1)Cc1c[nH]c2ccccc12
Yield: 73.6 %

Procedure:
A mixture of Example 14D (40 mg, 0.11 mmol), 5% Pd/BaSO4 (8.1 mg) and quinoline (8.1 μL) in methanol (3 mL) was stirred under hydrogen (20 psi) at room temperature for 12 minutes and filtered. The filtrate was concentrated and the residual oil was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide the desired product (30 mg, 75%). MS (APCI) m/e 369 (M−H)−; 1H NMR (300 MHz, CD3OD) δ 8.57 (d, J=6.8 Hz, 2H), 8.29 (d, J=2.4 Hz, 1H), 8.04 (s, 1H), 7.69 (d, J=6.4 Hz, 2H), 7.57 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.33 (t, J=1.7 Hz, 1H), 7.21 (s, 1H), 7.14 (m, 2H), 7.02 (td, J=8.1, 1.0 Hz, 1H), 6.95 (d, J=12.2 Hz, 1H), 4.24 (dd, J=10.5, 3.0 Hz, 1H), 4.08 (dd, J=10.5, 5.6 Hz, 1H), 3.92 (m, 1H), 3.26 (m, 2H); Anal. Calcd for C23H22N4O. 3.6 TFA: C, 46.45; H, 3.30; N, 7.17. Found: C, 46.56; H, 3.35; N, 7.34.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH2:15]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:15][C:6]1[CH:5]=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][C:7]=1[C:2]#[N:3]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Yield: 47 %

Procedure:
Heat a mixture of copper (I) cyanide (2.24 g, 25.00 mmol) and 2-bromo-4-trifluoromethyl-phenylamine (5.0 g, 20.83 mmol from Avocado) in 1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute the reaction mixture with 100 ml of ethyl acetate and wash the dark solution twice with 28% aqueous ammonium hydroxide, twice with saturated aqueous sodium chloride (brine) and twice with water. Collect the organic layer, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue via flash chromatography eluting with a step gradient starting with hexanes and going to 70% hexanes with 30% ethyl acetate to obtain 1.821 g (9.78 mmol, 47% yield) the title compound as a green amorphous solid: Mass Spectrum (m/e): 187(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][C:12]3([CH2:15][O:14][CH2:13]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CCO.[Pd]>[CH2:13]1[C:12]2([CH2:11][N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:1])[CH2:16]2)[CH2:15][O:14]1
Reactant: O=[N+]([O-])c1cccc(N2CC3(COC3)C2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N2CC3(COC3)C2)c1
Yield: 89.1 %

Procedure:
To a solution of 6-(3-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (130 mg, 0.59 mmol) in 5 mL of EtOH was added 10% Pd/C (20 mg), the mixture was stirred for 15 hours at room temperature in a hydrogen atmosphere. Insoluble matters were removed and the filtrate was concentrated in vacuo to give 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)aniline (100 mg, 98%). LC-MS: 191 [M+H]+, tR=0.99 min.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: NO
Reactant: Cc1cnc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: Cc1cnc(NC(=O)[C@H](CC2CCC(=NO)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 244.4 %

Procedure:
A solution of hydroxylamine hydrochloride (17.0 mg, 0.24 mmol) in methanol (0.5 mL) and 2,6-lutidine (0.5 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 62, 34 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 hexanes/ethyl acetate to ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-(5-methyl-pyrazin-2-yl)-propionamide (75 mg, 100%) was a white foam: [α]23589=−30.0° (c=0.32 chloroform); EI-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1365.
Reaction SMILES: [OH-:1].[Na+].[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6]>>[CH2:13]([OH:14])[C@H:11]1[O:12][C@@H:4]([O:3][C@H:9]2[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@H:4]([OH:3])[O:1][C@@H:11]2[CH2:13][OH:14])[C@H:5]([OH:6])[C@@H:7]([OH:8])[C@@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [Na+]
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
A cellobiose (Sigma C7252) stock solution of 10 mM final concentration was prepared in 50 mM sodium acetate buffer pH=4.5. For the assay 2000 μl substrate-stock (10 mM)+100 μL diluted enzyme sample were mixed and incubated at 40° C. Reactions were stopped at t=0, 10, 20 and 30 minutes by mixing 100 μl incubate+100 μl 50 mM sodiumhydroxide. Samples were subjected to ultrafiltration and analyzed using High Performance Anion Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD), performed on a Dionex DX-500 equipped with an ED 40 pulsed amperometric detector. Activity is expressed in μmol glucose released/ml/min
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])=[O:5])[CH3:2].[C:12](OCC)(OCC)([O:14][CH2:15][CH3:16])[CH3:13].C(OC(=O)C)(=O)C>>[C:9]([C:8](=[C:12]([O:14][CH2:15][CH3:16])[CH3:13])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])#[N:10]
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)NC(=O)C(C#N)=C(C)OCC

Procedure:
Following the method of Example 1, N-ethoxycarbonylcyanoacetamide is heated with triethyl orthoacetate and acetic anhydride to give α-cyano-β-ethoxy-β-methyl-N-ethoxycarbonylacrylamide, which in turn is reacted with 2,4,6-trichlorophenylhydrazine. The resulting compound α-cyano-β-methyl-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide (m.p.=183°-184°) is cyclized, yielding 5-cyano-6-methyl-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione, m.p.=>305°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCC(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of concentrated nitric acid (32 mL) and concentrated sulfuric acid (32 mL) were cooled in an ice salt bath. Solid 2-phenylbutyric acid (16.42 g, 100 mmol) was added in small portions maintaining the solution temperature below 10° C. The reaction was warmed to room temperature and allowed to stir for 1 hour. The product was isolated by pouring the reaction mixture onto 150 mL of crushed ice, filtering the white solid and recrystallizing from EtOH to give 14.5 g (69%) of the product as white crystals.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl-(2,4-difluoro-phenoxy)-dimethyl-silane (36, 5.90 g, 24.1 mmol) in tetrahydrofuran (100 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 10.6 mL, 26.5 mmol) slowly. The reaction was allowed to stir for 1 hour, then N,N-dimethylformamide (2.24 mL, 29.0 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The compound was isolated by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a colorless oil (37, 5.0 g, 76.0%). MS (ESI) [M+H+]+=272.2.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[O:3]1.I([O-])(=O)(=O)=O.[Na+].Cl>C1COCC1.O>[F:19][C:16]([S:15][C:12]1[CH:11]=[CH:10][C:9]([B:4]([OH:5])[OH:3])=[CH:14][CH:13]=1)([F:18])[F:17]
Reactant: CC1(C)OB(c2ccc(SC(F)(F)F)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a round-bottomed flask were added 4,4,5,5-tetramethyl-2-(4-trifluoromethylsulfanyl-phenyl)-[1,3,2]dioxaborolane (960 mg, 3.16 mmol) and sodium periodate (2.03 g, 9.48 mmol) in THF and water (4:1, 26 mL). The resulting suspension was stirred at rt for 30 min. HCl (1 N aq., 2.21 mL) was added to the suspension and the reaction mixture was stirred at rt for 18 h. The resulting precipitate was removed by filtration and washed with hexanes. The filtrate was diluted with water (25 mL) and extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (10 mL×2), and the combined organic layers dried (Na2SO4) and concentrated to yield the title compound (512 mg, 73%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 67.6 %

Procedure:
In 100 ml of pyridine were dissolved 13.0 g of 5-fluorouracil and 10.5 g of 2,3-dihydrofuran. To the solution were added 7.5 g of alumina and the mixture was reacted at 130° C. for 24 hours. After completion of the reaction, the reaction liquid was filtered to remove the catalyst and the solvent was distilled off. The residue was dissolved in chloroform to recover 3.04 g of insoluble unreacted 5-fluorouracil. The chloroform was distilled off from the chloroform layer and the residue was recrystallized from ethanol to give 13.52 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The yield of the end product was 88.9% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:18]1[C:22]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=2)=[CH:21][N:20]=[CH:19]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[N:24][CH:25]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)cn1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=0.96 min; Mass spectrum (ESI+): m/z=405 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[F:16].[OH-].[Na+].CCO.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[F:16]
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Nc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (4.18 g, 0.017 mol) to a solution of NaOH (1.361 g, 0.0340 mol) in mixture 50 ml EtOH and 50 ml water was added and the resulting mixture was stirred at RT for 6 h. The mixture was acidified with 2N HCl to pH 4-5 at 0° C. The precipitate was filtered, washed with water and dried on the air to afford 2-(4-chloro-3-fluorophenylamino)-2-oxoacetic acid (3′) (2 g, 55.2%) as a white solid. LC-MS (APCI+) m/z: calcd for C8H5ClFNO3: 216.99. found: 217 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13]N(C)[CH2:11][CH2:10]2)=[O:7])=[C:4]([F:19])[CH:3]=1.NC1CC[CH:24]([N:27]([CH3:29])[CH3:28])CC1>>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:10][CH2:11][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:13][CH2:14]2)=[O:7])=[C:4]([F:19])[CH:3]=1
Reactant: CN(C)C1CCC(N)CC1
Reactant: CN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Product: CN(C)C1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 173, on a 2.64 mol scale, utilising 1-amino-4-dimethylaminocyclohexane (ABChem. Inc.; 472 mg, 3.31 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (716 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](OCC)(OCC)OCC>COCCOCCOC>[Cl:9][CH2:10][C:11]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1ncccc1O
Reactant: CCOC(CCl)(OCC)OCC
Solvent: COCCOCCOC
Product: ClCc1nc2ncccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The commercially available 2-amino-3-hydroxypyridine (5.0 g) and diglyme (30 ml) were heated at 125° C. to obtain a solution. To this solution was added 2-chloro-1,1,1-triethoxyethane (9.9 g) and the mixture was held at 125° for 1 hour. The solution was cooled to room temperature and then decanted to remove a black byproduct residue. The filtrate was diluted with water (50 ml) and the resulting yellow precipitate was collected (1.5 g). A small sample was crystallized from isopropanol (m.p. 115°-118° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 75 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.043 mmol) and 1-amino-2-propanol (0.05 mL) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 75% yield) as a white solid. 1H NMR (CDCl3) δ 10.22 (br s, 1 H), 8.53 (s, 1 H), 7.31-7.25 (m, 2 H), 7.22-7.18 (m, 2 H), 7.03-6.92 (m, 4 H), 6.72 (s, 1 H), 4.03 (m, 1 H), 3.94 (s, 2 H), 3.56 (m, 1 H), 3.36 (m, 1 H), 1.24 (d, J=6.4 Hz, 3 H). MS m/z 466 (M+1).