Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1[CH:19]=[C:18]2[N:12]([CH:13]=[N:14][NH:15][C:16]2=O)[CH:11]=1.P(Cl)(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:18]1[CH:19]=[C:10]2[C:11]([Cl:22])=[N:12][CH:13]=[N:14][N:15]2[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncn2cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ncnn2cccc12
Temperature: 100 °C
Yield: 81 %

Procedure:
Diisopropylethylamine (3.5 mL, 20.3 mmol) was added to a solution of pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (2.5 g, 18.5 mmol) dissolved in toluene (37.5 mL) under nitrogen atmosphere. Subsequently, after adding phosphorus oxychloride (5.1 mL, 55.7 mmol), the mixture was heated for 20 hours at 100° C. The resulting reaction mixture was cooled to 0° C. and, after slowly adding sodium bicarbonate aqueous solution, stirred at room temperature for 30 minutes. The resulting aqueous layer was extracted with ethyl acetate, dried with magnesium sulfate, and then filtered. The filtrate was concentrated in vacuum. The resulting yellow solid product was subjected to the next step without purification (2.31 g, 15.0 mmol, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CC(C)O
Solvent: CCCCO
Product: CCOC(=O)c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reaction time: 30 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 100 mg of ethyl 4-aminobenzoate in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for 30 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 202 mg of expected product is thus obtained in the form of white-cream crystals.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C>O1CCCC1.C(OCC)(=O)C.Cl>[NH2:8][C@H:12]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=3)[N:19]=2)=[CH:16][N:17]=1)[CH2:11][OH:10]
Reactant: Cc1ccnc(Nc2cccc(-c3cnc([C@@H]4COC(C)(C)N4C(=O)OC(C)(C)C)s3)n2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccnc(Nc2cccc(-c3cnc([C@@H](N)CO)s3)n2)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
To a solution of (S)-2,2-dimethyl-4-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}oxazolidine-3-carboxylic acid tert-butyl ester (1.90 g, 4.06 mmol) obtained in Example 12 in tetrahydrofuran (10 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added and stirred at 60° C. for 5 hours. After the reaction solution was concentrated, it was neutralized with a saturated aqeous sodium bicarbonate, and extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over magnesium sulfate, it was concentrated and the residue was purified by flash chromatography on silica gel (chloroform:methanol=20:1) and the title compound (588 mg, 44%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:13])[NH:5][C:6]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:24][CH:23]=1>CN(C=O)C>[CH:36]1([CH:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:5]3[C:4](=[O:13])[C:3]4[C:7](=[C:8]([F:11])[CH:9]=[CH:10][C:2]=4[F:1])[C:6]3=[O:12])=[CH:23][CH:24]=2)[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C1NC(=O)c2c(F)ccc(F)c21
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2=O)cc1)C1CCCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
500 mg (2.71 mmol) of 4,7-difluoro-1H-isoindole-1,3(2H)-dione and 889.7 mg (2.71 mmol) of cesium carbonate were added to a solution of 964.7 mg (2.71 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate in 2 ml of DMF. The mixture was stirred at 60° C. for 2 h, and the reaction mixture was then added to ice-water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 5:1). This gave 424 mg (34.1% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]([OH:30])[CH2:24][NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:14])[NH:4][CH:3]=1.Cl.C([OH:34])C.[OH-].[Na+]>O>[CH3:27][C:26]([NH:25][CH2:24][CH:23]([OH:30])[CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:14])[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:34])[NH:4]2)([CH3:29])[CH3:28]
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]cc(Cl)c12
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 6.37 g of the product of Step A, 192 ml of N hydrochloric acid and 192 ml of ethanol was stirred for 17 hours at room temperature and was then diluted with water. The mixture was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 2.32 g of 1,3-dihydro-4-[3-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-3-oxopropyl]-2H-indol-2-one.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:51])([CH3:52])[CH3:50])=[O:47])[NH:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC(C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.31 mL, 2.2 mmol) and 4-methylbenzenesulfonyl chloride (0.141 g, 0.74 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.239 g, 0.427 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-{[(4-methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.255 mg, 67%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak AD-H 5 μm 250×20 mm, hexane/2-propanol 9:1, 25 mL/min):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12](=O)[CH2:13][CH3:14].C(O)(C)C.Cl>C(OCC)(=O)C>[CH2:13]([CH:14]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1)[CH3:12]
Reactant: Nc1ccncc1S(N)(=O)=O
Reactant: CCC=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCC1Nc2ccncc2S(=O)(=O)N1

Procedure:
0.5 g of 4-aminopyridine-3-sulfonamide (Preparation 2) and 0.34 g (2 equivalents) of propionaldehyde are introduced into 5 cm3 of isopropanol to which 10 drops of a saturated solution of hydrochloric acid in ethyl acetate have been added. After refluxing for 2 h, the solution obtained is concentrated to dryness and the residue is recrystallized from a 1/3 isopropanol/petroleum ether (40°-60° C.) mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18]>CN(C=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[CH2:16][NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: CN(C)C=O
Product: COc1cc(NCC(=O)Nc2ccc(F)cc2)ccc1-c1cnco1

Procedure:
A solution of 1D, (101 mg, 0.53 mmol) and 2-chloro-4′-fluoroacetanilide (50 mg, 0.27 mmol) in DMF (0.15 mL) was heated at 100° C. for 15 h. After the reaction had cooled, the solvent was removed under reduced pressure, and the residue was subjected to preparative HPLC to give 1 as a tan solid. LC/MS: ret. timeA=3.527 min., MS (M+H)+=342.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (0.81 g) in chloroform (5 ml) was added dropwise to a stirred solution of 4'-acetyl2'-(2,4-difluorophenylthio)methanesulfonanilide (1.8 g) and benzoyl peroxide (8 mg) in chloroform (20 ml). After stirring for 1 hour at room temperature, the mixture was washed with water and an aqueous solution of sodium bisulfite successively. The organic layer was dried and concentrated to give 4'-bromoacetyl-2'(2,4-difluorophenylthio)methanesulfonanilide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.Cl>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]1[CH:18]=[C:13]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:5]=2)[N:14]=[N:15][CH:16]=1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: COc1cnnc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Reaction time: 22.5 h
Yield: 95 %

Procedure:
1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (4.0 g, 0.024 mole), 3-chloro-5-methoxypyridazine (3.5 g, 0.024 mole), and 2,6-1-lutidine (3.0 g, 0.028 mole) were heated to reflux in toluene (75 mL) under N2 and held there for 22.5 h. The mixture was poured into diluted HCl (1%) aqueous solution and extracted 2×100 mL with ethyl acetate. The organic layer was extracted with brine followed by dilute NaOH (1%, 2×100 mL). The organic layer was dried (MgSO4), filtered through silica gel with ethyl acetate and evaporated in vacuo to give 5-methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-pyridazine (6.25 g, 95% yield) as a light brown solid. This solid was recrystallized from ethyl acetate/cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[N:17]([CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:18](=[O:22])[N:19]([CH3:21])[N:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH:24]1([CH2:23][N:17]2[C:18](=[O:22])[N:19]([CH3:21])[N:20]=[C:16]2[CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:7]=[CH:6][CH:5]=3)[CH2:13][CH2:12]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1nc(CCN2CCN(c3cccc(N)c3)CC2)n(CC2CCCCC2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(N2CCN(CCc3nn(C)c(=O)n3CC3CCCCC3)CC2)c1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 5-{2-[4-(3-aminophenyl)piperazino]ethyl}-4-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (D16; 450 mg, 1.129 mmol) in dry pyridine (5 mL), acetic anhydride (0.112 mL, 1.185 mmol) was added at room temperature. The reaction mixture was stirred for 1 h, toluene (30 mL) was added and the solvents were removed in vacuo to afford a light-brown solid. Purification by preparative LC-MS afforded 133 mg (27%) of the title compound as a light brown powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:21](Br)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH:21]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of 1-piperazineethanol (11.4 g), potassium carbonate powder (24.3 g) and N,N-dimethylformamide (100 ml) was added dropwise benzhydryl bromide (21.7 g). The mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aquus sodium chloride and dried over sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [eluent: hexane-ethyl acetate (2:1)] to give 21.9 g (84.2%) of 4-benzhydryl-1-piperazineethanol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH2:19]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:18][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 92 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]piperazine (0.4 g, 1.74 mmol) in 10 mL of dioxane was added, methyl vinyl sulfone (0.46 g, 4.34 mmol). The mixture was heated to 120° C. for 1 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (0.55 g, 1.6 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J=9.34 Hz, 1H), 6.41 (dd, J=9.34, 2.56 Hz, 1H), 6.31 (d, J=2.38 Hz, 1H), 3.93 (s, 3H), 3.36-3.43 (m, 4H), 3.19 (t, J=6.41 Hz, 2H), 3.03 (s, 3H), 2.92-2.99 (m, 2H), 2.60-2.68 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=2)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=3)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: Fc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.6) (1.79 g, 5.19 mmol) and commercially available 3-bromo-benzene-boronic acid (1.15 g, 5.73 mmol) according to the general procedure IVb. Obtained as a white solid (0.94 g, 39%). MS (EI) 464.0, 466.0 [(M)+]; mp 111° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[OH:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]3[NH:2][O:1][C:27](=[O:28])[N:21]=3)=[CH:9][CH:8]=1)[CH:19]=[CH:18]2
Reactant: N=C(NO)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1nc(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2)[nH]o1
Temperature: 65 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
N-hydroxy-4-(6-hydroxyquinolin-2-yl)benzimidamide (800 mg, 2.86 mmol) was dissolved in 25 mL of THF and CDI (557 mg, 3.44 mmol) and TEA (0.2 mL) was added. The mixture was stirred at 65° C. for 2 hours, followed by concentration in vacuo. The crude material was dissolved in 10 mL 1N NaOH and filtered through Celite. The mixture was then acidified with 1N HCl to a pH of 4.5 and the solids were filtered and dried. The solids were slurried in 10 mL of EtOAc overnight at 50° C. followed by filtration to yield Compound IV-12 (315 mg, 36% yield). 1H NMR (DMSO-d6, 400 MHz): δ 10.19 (s, 1H), 8.42 (d, 2H), 8.28 (d, 1H), 8.14-8.11 (d, 1H), 8.00-7.94 (m, 3H), 7.39-7.35 (dd, 1H), 7.21 (s, 1H). MS (ESI): m/z 306.44 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[CH2:6][CH:7]=[CH2:8])[CH3:2].[O:22]=[O+:23][O-:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[O:22]1[CH2:8][CH:7]([CH2:6][CH:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:21])[O:24][O:23]1
Reactant: O=[O+][O-]
Reactant: C=CCC(CCc1cccc(C(F)(F)F)c1)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CCc1cccc(C(F)(F)F)c1)CC1COOO1
Temperature: -78 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
2-[2-(3-Trifluoromethylphenyl)ethyl]pent-4-enoic acid ethyl ester (529 mg, 1.76 mmol) was dissolved in CH2Cl2 and cooled to −78° C. The resulting solution was treated with ozone until a light blue color was observed. The solution was degassed with N2, then polymer-supported Ph3P (3 mmol/g, 882 mg, 2.64 mmol) was added and the mixture was stirred for 3 h at room temperature. The solid was removed by filtration and rinsed with CH2Cl2. Evaporation of the filtrate provided an oil, which was purified by flash column chromatography (hexanes/ether) to give ethyl 2-((1,2,3-trioxolan-4-yl)methyl)-4-(3-(trifluoromethyl)phenyl)butanoate as a colorless oil (151 mg, 25%) and the desired ethyl 2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate as a colorless oil (83 mg, 16%). A solution of ethyl 2-((1,2,3-trioxolan-4-yl)methyl)-4-(3-(trifluoromethyl)phenyl)butanoate (150 mg, 431 μmol) in CH2Cl2 (20 mL) was cooled to −78° C., then Me2S (0.3 mL, 4.1 mmol) was added and the mixture was stirred for 2 d. The reaction mixture was diluted with CH2Cl2 (300 mL), washed with water (2×100 mL), and brine (100 mL), dried over Na2SO4, filtered, and evaporated to provide additional ethyl 2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate (123 mg): 1H NMR (300 MHz CDCl3) δ 7.50–7.30 (m, 4H), 5.26–5.20 (m, 1H), 5.14 (d, J=1.6 Hz, 1H), 5.04 (d, J=6.3 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 2.73–2.57 (m, 3H), 2.35–1.77 (m, 4H), 1.29 (t, J=7.1 Hz, 3H); 19F NMR (282 MHz, CDCl3) δ −63.0.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[O:35][N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: Cc1cc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (750 mg; compound B50) is reacted with 3-(chloromethyl)-5-methylisoxazole (231 mg; compound D6) in the presence of potassium carbonate (242 mg) in DMF (7 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=O)[CH3:10])=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO>[C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=[N:14][OH:15])[CH3:10])=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)C=Cc1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccc(C)cc1)=NO
Yield: 60.9 %

Procedure:
In a 250 ml single neck flask was charged 4.8 g (30.0 mmoles, 1.0 eq.) of 4-(p-tolyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.2 g of 4-(p-tolyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 60.9% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:33](=[O:34])[CH2:32][N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:24])[CH3:25])[CH2:27][CH2:28]4)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: CC(C)N1CCN(CC(=O)O)CC1
Product: CC(C)N1CCN(CC(=O)Nc2ccc3nc(NC4CCc5cc(F)ccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-isopropyl-piperazin-1-yl)-acetic acid (CAS no: 95470-68-1); MS: m/e=462.5 (M+H+).