Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]=[C:24]1[CH3:49]>C(OCC)(=O)C>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]=[C:24]1[CH3:49]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2cc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogen carbonate (1.38 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[1-(1-benzothien-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.55 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.31 g, 51%).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:36][CH2:37][CH2:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C1COCC1>[OH:11][N:12]([C@H:13]([CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:33])([F:34])[F:35])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[CH2:36][CH2:37][CH2:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH:1]=[O:2]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)[C@@H](CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To formic acid (114 mL, 3.03 mol) at 0° C. was added acetic anhydride (28.6 mL, 0.303 mol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and added to a solution of 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine (30.6 g, 60.5 mmol) and formic acid (114 mL, 3.03 mol) in THF (600 mL). The reaction was brought to room temperature and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×300 mL). The residue was then dissolved in methanol (300 mL) and heated to 40° C. for one hour. The solution was then cooled to room temperature and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the racemic compound as a pale orange foam (22.94 g, 43 mmol, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.31 min; Mass spectrum (ESI+): m/z=463 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: NCCOc1ccccc1
Reactant: COc1cccc(CN)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COc1cccc(CNc2ccc3nc(NCCOc4ccccc4)ccc3c2)c1

Procedure:
The title compound, MS: m/e=400.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 3-methoxybenzylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.CS(C)=[O:16].[O-]Cl=O.[Na+]>O.CC(C)=O>[CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([C:12]([OH:16])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2c(C=O)csc12
Reactant: CS(C)=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: CSc1ncnc2c(C(=O)O)csc12
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (513 mg, 3.29 mmol) was dissolved in water (2 mL) and then 4-(methylthio)thieno[3,2-d]pyrimidine-7-carbaldehyde (300 mg, 1.68 mmol) dissolved in acetone (3 mL) and DMSO (3 mL) was added thereto at 0° C. NaClO2 (194 mg, 2.15 mmol) dissolved in water (2 mL) was added at the same temperature to the reaction mixture, which was stirred for 2 hours. After the reaction was completed water (10 mL) was further added to the reaction mixture, which was stirred for 2 hours and filtered to obtain a solid. The solid was washed with water several times and dried with N2 gas to obtain the title compound as a white solid.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[C:15]([C@@H:17](N)[CH2:18][C:19]3[N:23]([CH:24]4[CH2:26][CH2:25]4)[C:22]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[N:21][N:20]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH:34](O)=O.C=O>CO>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[C:15]([C@@H:17]([N:2]([CH3:1])[CH3:34])[CH2:18][C:19]3[N:23]([CH:24]4[CH2:26][CH2:25]4)[C:22]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[N:21][N:20]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: [BH3-]C#N
Reactant: N[C@@H](Cc1nnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)[C@@H](Cc1nnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1

Procedure:
Sodium cyanoborohydride (0.1 mL, 1M in THF) was added to a solution of (S)-1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine (30 mg) in methanol (0.8 mL) containing 96% formic acid (0.1 mL) and 37% formalin solution (0.1 mL). The residue was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated. Purification was performed by flash column silica gel chromatography with 3% (2 M ammnonia methanol) in dichloromethane to give 22 mg of the title compound. 1H NMR (CDCl3): d ppm 8.76 (d, 2H), 8.06 (s, 1H), 7.97 (d, 1H), 7.73 (d, 2H), 7.47 (d, 1H), 7.45 (t, 1H), 5.00 (dd, 1H), 3.76 (dd, 1H), 3.51 (dd, 1H), 3.42 (m, 1H), 2.45 (br s, 6H), 1.26 (m, 2H), 0.88 (m, 1H), 0.79 (m, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[C:21]([CH3:32])[NH:20][N:19]=1.C([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#N>>[CH3:32][C:21]1[C:22]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]5[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]45)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)=[C:18]([CH3:17])[NH:19][N:20]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1n[nH]c(C)c1-c1ccc(-c2ccc(N3CC[C@@H]4CN(C)C[C@@H]43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 7D, substituting the product of Example 41A for the product of Example 7C and substituting 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 4-cyanophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 7.59 (d, J=8.14 Hz, 2H) 7.52 (d, J=8.82 Hz, 2H) 7.30 (d, J=8.14 Hz, 2H) 6.66 (d, J=8.82 Hz, 2H) 4.11-4.23 (m, 1H) 3.51-3.62 (m, 1H) 3.24-3.36 (m, 1H) 2.88-3.04 (m, 1H) 2.70-2.79 (m, 1H) 2.49-2.66 (m, 3H) 2.33 (s, 9H) 2.10-2.25 (m, 1H) 1.90-2.03 (m, 1H). MS: (M+H)+=373.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([O:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(NC(=O)OC(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To a solution of 5-tert-butoxycarbonylamino-2-hydroxybenzoic acid (1.02 g, 4.02 mmole) in DMF (20.0 ml) was added with acetyl chloride (39 mg, 4.83 mmole) and potassium carbonate (555 mg, 4.02 mmole). The reaction mixture was stirred for 4 hr at room temperature. After the reaction mixture was concentrated, the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/hexane to give 0.62 g (52% yield) of 2-ethanoyloxy-5-tert-butoxycarbonylaminobenzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:7]=1[Cl:8]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cnnc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
3,4,5-Trichloropyridazine (3 g, 16.36 mmol) was dissolved in dry NMP (18 mL) and cooled in an ice-bath. DIPEA (2.326 g, 3.135 mL, 18 mmol) was added, followed, dropwise, by 1-methylpiperazine (1.721 g, 1.906 mL, 17.18 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure to give an brown solid which was partitioned between 10% MeOH in DCM and saturated NaHCO3. The aqueous layer was extracted with further 10% MeOH in DCM (5×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (7.5% MeOH in DCM, ˜300 mL silica, loaded in DCM) to provide 3,4-dichloro-5-(4-methylpiperazin-1-yl)pyridazine as a light yellow solid (2.36 g, 58% Yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)COc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
To a stirred solution of 2-bromo-4-chlorophenol (3.38 g, 16.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (25 ml) under an atmosphere of nitrogen, was added cesium carbonate (8.0 g, 24.4 mmol). The mixture was cooled to 0° C. before addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.78 g, 16.3 mmol) drop-wise over 2 minutes. The reaction was allowed to warm to room temperature and stirred for 14 hours. To encourage complete reaction the reaction mixture was warmed to 120° C. for 3 hours. The reaction mixture was cooled to room temperature then water (50 ml) was added. The layers were separated and the aqueous was extracted with heptane (3×50 ml). All organic extracts were combined then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (4.20 g, 89%). Material was taken on without further purification.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:5][C:6]1[CH:13]=[C:12]([CH:11]=[CH:10][C:7]=1/[CH:8]=[CH:25]/[N+:22]([O-:24])=[O:23])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccn2)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To an acetic acid (15.0 mL) solution of 2-fluoro-4-(pyridin-2-ylmethoxy)-benzaldehyde (1.07 g, 4.63 mmol) described in Manufacturing Example 95-1-1 were added nitromethane (1.41 g, 23.2 mmol) and ammonium acetate (714 mg, 9.26 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.20 g) as a crude product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[CH:3]=[N:2]1.[CH2:9]([NH2:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([NH:11][C:6]([C:4]1[CH:3]=[N:2][NH:1][CH:5]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1cn[nH]c1
Reactant: CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cn[nH]c1
Yield: 97 %

Procedure:
Following the same procedure in Example 28 (Step C of Method B), using 1H-pyrazole-4-carbonyl chloride (0.47 g, 3.6 mmol), ethylamine (3.0 mL, 2.0 M in THF, 6.0 mmol) and triethylamine (1.01 g, 1.39 mL, 10 mmol) in CH2Cl2 (15 mL), provided the title compound as a white solid. Yield: 0.49 g (97% yield). 1H NMR (400 MHz, METHANOL-D4) δ 1.18 (t, J=7.23 Hz, 3 H) 3.34 (q, J=7.23 Hz, 2 H) 7.92 (s, 1 H) 8.09 (s, 1 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.N>O>[Cl:18][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]([CH3:15])[N:11]=1
Reactant: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1

Procedure:
To 21 g of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine was added 63 ml of phosphorus oxychloride and the mixture was refluxed for 1 hour. This reaction mixture was cooled, poured into iced water, and neutralized with 28% aqueous ammonia and the crystals that separated out were collected by filtration. The crystals were washed with water and dried to provide 21 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[O-:25]Cl=O.[Na+]>C(O)(C)(C)C.O.CC(OC)(C)C>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([C:13]([OH:25])=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (132 g, 0.519 mol) and 2-methyl-2-butene (364 g, 5.19 mol) in tert-butanol (1500 mL), a solution of NaH2PO4 dihydrate (249 g, 2.08 mol) in water (1500 mL) is added. To this mixture, NaClO2 (187.8 g, 2.08 mol) is added in portions. The temperature of the reaction mixture is kept below 30° C., and evolution of gas is observed. Upon completion of the addition, the orange bi-phasic mixture is stirred well for 3 h before it is diluted with TBME (1500 mL). The org. layer is separated and washed with 20% aq. NaHS solution (1500 mL) and water (500 mL). The org. phase is then extracted 3 times with 0.5 N aq. NaOH (1000 mL), the aq. phase is acidified with 25% aq. HCl (500 mL) and extracted twice with TBME (1000 mL). These org. extracts are combined and evaporated to dryness to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid. 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 2.31 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 4.86 (s, 2H), 7.34-7.53 (m, 5H), 7.68 (s, 2H), 12.70 (s, 1H).
Reaction SMILES: [NH:1]([S:8]([C:11]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].[NH:20]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:21]([C:23]([NH:25][C@H:26]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34]O)=[O:29])[CH3:27])=[O:24])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.CO>[NH:20]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[C@H:21]([C:23]([NH:25][C@H:26]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:1]([S:8]([C:11]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:10])[C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3])=[O:29])[CH3:27])=[O:24])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCCO
Reactant: COC(=O)[C@H](C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](C)N(CCCCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 10 h

Procedure:
To a cold (−15° C.) vigorously stirring solution of Ns-Ala-OMe (50 mg, 0.17 mmol), Boc-Ala-Ala-NH—(CH2)4—OH (57 mg, 0.17 mmol) and PPh3 (68 mg, 0.26 mmol) in dry THF (1.5 mL) was added DIAD (53 mg, 0.26 mmol) slowly dropwise. After 7 h another portion of PPh3 (68 mg, 0.26 mmol) and DIAD (52 mg, 0.26 mmol) was added and stirred for further 10 h, when TLC (MeOH:DCM) indicated complete consumption of the starting material. The mixture was concentrated under vacuum and the resulting residue was diluted with EtOAc (15 mL), washed with water (2 mL), dried over Na2SO4 and concentrated under vacuum to give a crude residue which was purified by silica gel flash column chromatography (EtOAc:Hexanes—3:1) to give the desired product as a viscous oil in good yields (71 mg, 76%). TLC (MeOH:DCM—1:9—Rf=0.5).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([OH:16])[CH:15]=1)[CH2:11][OH:12].[CH2:17](Cl)[C:18]#[CH:19].[CH3:21][C:22]([CH3:24])=O>>[CH2:17]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH2:24][C:22]#[CH:21])[CH:15]=1)[CH2:11][OH:12])[C:18]#[CH:19]
Reactant: OCc1cc(O)cc(O)c1
Reactant: C#CCCl
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1cc(CO)cc(OCC#C)c1
Yield: 97 %

Procedure:
Finely powdered K2CO3 (14 g, 0.10 mol), and KI (17 g, 0.10 mol) were stirred in acetone (200 mL) under a nitrogen atmosphere. 3,5-Dihydroxybenzyl alcohol (4.2 g, 0.030 mol), and propargyl chloride (5.3 g, 0.071 mol) were added and mixture was allowed to reflux overnight. After the solution was filtered, and evaporated down to dryness, the residue was diluted with DCM, worked up and the solvents were removed in vacuo leaving a yellow oil, which solidified upon standing to give 6.3 g in 97% yield.
Reaction SMILES: P([O-])([O-])([O-])=O.[NH2:6][C@H:7]([C:12]([O-:14])=[O:13])[CH2:8][C:9]([O-])=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:59]([O-:64])(=[O:63])C(C)O.[C:65]([O-:73])(=[O:72])[CH:66]([CH2:68][C:69]([O-:71])=[O:70])[OH:67]>>[C:69]([OH:71])(=[O:70])[CH2:68][C:66]([C:65]([OH:73])=[O:72])=[O:67].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][C:59]([OH:64])=[O:63]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Reactant: O=C([O-])CC(O)C(=O)[O-]
Reactant: CC(O)C(=O)[O-]
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Product: N[C@@H](CCC(=O)O)C(=O)O
Product: O=C(O)CC(=O)C(=O)O

Procedure:
0.5 ml of a turbid serum specimen is mixed with 3.1 ml of a reagent solution of the following composition: Phosphate buffer, pH 7.4; aspartate, NADH, lactate dehydrogenase (LDH), malate dehydrogenase (MDH), 2.85 vol.-% of the agent of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][Cl:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Cl-:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(/C=C/CCl)cc1Oc1ccccc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(C=CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Product: [Cl-]

Procedure:
A mixture of E-3-(4-fluoro-3-phenoxyphenyl)-1-chloroprop-2-ene (42 g), triphenylphosphine (42 g) and xylene (300 cm3) was heated at the reflux temperature for 16 hours. After cooling, crystals of 3-(4-fluoro-3-phenoxyphenyl)prop-2-en-1-yl triphenyl phosphonium chloride (68 g) were filtered from the reaction mixture, washed with dry diethyl ether, dried by suction and stored in a desiccator under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cccc(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1cccc(Br)c1)S(C)(=O)=O
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of N-(3-bromophenyl)methanesulfonamide (5.15 g, 20.6 mmol, Combi-Blocks) in dry dimethylformamide (100 ml) was treated with potassium carbonate (4.3 g, 31.2 mmol) at room temperature with stirring under argon. After stirring for 10 minutes methyl iodide (2.9 g, 20.6 mmol) was added dropwise over 5 minutes and stirring continued at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a brown oil (4.90 g, 90%); 1H-NMR (400 MHz, CDCl3): 2.86 (3H, s), 3.32 (3H, s), 7.26 (1H, m), 7.35 (1H, m), 7.43 (1H, m), 7.53 (1H, m).