Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[N:10]1.Cl.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH:33]1[CH2:38][C:39]([OH:41])=[O:40]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])[NH:12][C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH:33]2[CH2:38][C:39]([OH:41])=[O:40])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Yield: 42.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate (1.21 g, 2.2 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.4 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.58 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12]1.FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[S:11]1[CH:15]=[CH:14][C:13]([CH:16]2[O:17][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:12]1
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ccsc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(c3ccsc3)c3ccccc3N2c2ccccc21
Yield: 69 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 3-Thiophenecarboxaldehyde (0.084 g, 66 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in. THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(thiophen-3-yl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a yellow solid (0.109 g, 69% yield, dr determined by 1H NMR analysis of crude reaction mixture is 1:1).
Reaction SMILES: CO[CH2:3][CH2:4][O:5][CH2:6][CH2:7]OC.C(Cl)C.C[O-].[Na+].OC1C=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CO>[CH2:4]([O:5][C:6]1[CH:7]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH3:3]
Reactant: COCCOCCOC
Reactant: Nc1ccc(O)cc1
Agent: CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(N)cc1
Reaction time: 6 h
Yield: 72.1 %

Procedure:
In accordance with the process of Example 2, 150 ml of diethyleneglycol dimethyl ether, 19.3 g (0.3 mole) of ethyl chloride, 42.2 g (0.22 mole) of sodium methylate in 28% methanol solution and 21.8 g (0.2 mole) of p-hydroxyaniline were charged in the autoclave and the reaction was carried out at 80° C. for 6 hours with stirring to obtain 19.7 g of p-ethoxyaniline having a boiling point of 135° to 136° C./24 mmHg. (yield: 72.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[C:16]([CH3:19])([CH3:18])[CH3:17].[N:21]#[C:22][NH2:23].O1CCCC1.C(N(CC)CC)C>O>[NH2:23][C:22]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:21]=1
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 1 h
Yield: 75 %

Procedure:
7.0 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.7 g (0.04 mol) of cyanamide were added to 100 ml of tetrahydrofuran. Then, 4.0 g (0.04 mol) of triethylamine was dropwise added under reflux and stirring. After completion of the dropwise addition, the stirring was continued at the same temperature for further 1 hour. After cooling, the reaction solution was poured into water, and the precipitate was extracted with toluene. The organic layer was washed with water and dried. Then, the solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 5.3 g (yield: 74.6%) of the desired compound as white prismatic crystals. The melting point: 208°-212° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer A) and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])/[C:5](/[F:25])=[C:6](\[C:8]1[CH:9]=[C:10]([CH:22]([CH3:24])[CH3:23])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])/[CH3:7])[CH3:2].[H-].[CH2:28]([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])/[C:5](/[F:25])=[C:6](\[C:8]1[CH:9]=[C:10]([CH:22]([CH3:24])[CH3:23])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][CH2:19][CH3:28])[CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])/[CH3:7])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C(=O)OCC)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-enoic acid ethyl ester (Intermediate 15, 199 mg, 0.55 mmol) in 10 ml of anhydrous THF under argon at 0° C. was added a 1.0 M solution of diisobutylaluminum hydride (2.20 ml, 2.20 mmol) in hexanes. The resulting mixture was stirred at 0° C. to 25° C. for 1 h. The reaction was cooled to 0 ° C. and quenched slowly with saturated NH4Cl (0.5 ml), Celite (200 mg), and diluted with diethyl ether (10 ml). The resulting mixture was stirred at 25 ° C. for 1 hour. The product was filtered through a pad of Celite. The solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography using ethyl acetate: hexane (1:4) to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH3:25])=[N:15][N:16]2[CH3:24])=[O:11])([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[N+](=[CH2:28])=[N-]>CN(C)C=O>[C:1]([C:4]([NH:9][C:10]([C:12]1[C:20]([C:21]([O:23][CH3:28])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH3:25])=[N:15][N:16]2[CH3:24])=[O:11])([CH3:8])[CH:5]([CH3:6])[CH3:7])(=[O:3])[NH2:2]
Reactant: Cc1nn(C)c2ccc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)c12
Reactant: C=[N+]=[N-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c(C)nn2C)c1C(=O)NC(C)(C(N)=O)C(C)C

Procedure:
A solution of 4-[(1-Carbamoyl-1,2-dimethylpropyl)carbamoyl]1,3-dimethyl-1H-indazole-5-carboxylic acid (0.720 g, 2.07 mmol) in dry dimethylformamide is treated with sufficient ethereal diazomethane to give a permanent yellow color. The excess diazomethane is quenched with acetic acid, and the reaction mixture is concentrated in vacuo. The resultant residue is chased 2 times with xylene recrystallized from 50% aqueous methanol to give the title product as a white solid, mp 221°-222° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[N-]=[N+]=[N-].[Na+].[OH2:21]>Cl.CO.CCOC(C)=O>[OH:21][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C
Yield: 40 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (280 mg, 1.25 mmol, 1 equiv) in a mixture of 2N aqueous HCl solution (2.5 ml) and MeOH (5 ml) at 0° C. was added NaN3 (190 mg, 2.75 mmol, 2.2 equiv) portionwise over 20 min. H2O (5 ml) was added and the resulting mixture was heated at 90° C. for 1 h then cooled to room temperature and diluted with AcOEt. The two layers were separated and the aqueous phase was extracted twice with AcOEt (20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to give a crude product which was triturated with Et2O/MeOH to give 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D36) (110 mg, 40%) as a light tan solid.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10]Br.C[N:18]([CH:20]=O)C>>[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10][O:4][C:1]1[CH:13]=[CH:12][C:9]([CH2:10][C:20]#[N:18])=[CH:8][CH:15]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(F)c1CBr
Agent: [K+]
Product: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-Hydroxybenzyl cyamide (5 g, 37.5 mmol) and K2CO3 (6.74 g, 48.8 mmol) in dry DMF (20 ml) was added 2,6-Difluorobenzyl bromide (7.77 g, 37.5 mmol). The reaction mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The crude residue was taken in EtOAc and washed with water and brine. The aqueous layer washed one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide the title compound as a white solid.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C([N:25](CC)CC)C.[C:30]([NH:35]N)(=O)[CH2:31][CH2:32][CH3:33]>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:25][C:30]([CH2:31][CH2:32][CH3:33])=[N:35][N:6]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CCCC(=O)NN
Reactant: CCN(CC)CC
Agent: Cl
Product: CCCc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Yield: 8 %

Procedure:
The procedure described in example 123 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylamine (0.25 mL, 1.86 mmol) and butyric acid hydrazide (127.7 mg, 1.25 mmol) was used to prepare the title compound (16 mg, 8% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.6 (s, 1H), 8.0–8.1 (m, 3H), 7.68–7.7 (d, 1H), 7.42 (t, 2H), 2.7 (t, 2H), 1.75 (m, 2H), 0.95 (t, 3H), ES-MS (m/z) 322 [M+1]+.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#N.[Cl-].[NH4+].C([O:25]CC)C>>[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: CCCCCCCCCCBr
Reactant: N#Cc1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CCCCCCCCCCC(=O)c1cccnc1
Yield: 32.9 %

Procedure:
To anhydrous ether was added 3.60 g of magnesium for Grignard reaction, and 36.5 g of 1-bromodecane was dropwise added while stirring. After the magnesium was completely dissolved, a diethyl ether solution of 15.6 g (0.15 mol) of 3-cyanopyridine was dropwise added and the mixture was refluxed for 4 hours. After cooling, saturated ammonium chloride solution was added, the diethyl ether layer was separated, and the aqueous layer was further extracted with diethyl ether. The ether layers was combined, washed with water, and then dried over anhydrous sodium sulfate. After concentration under a reduced pressure, the product was purified by separation by silica gel chromatography (ethyl acetate:hexane=1:4) to obtain 12.2 g of the desired product (yield 32.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](O)=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.C1C=C[C:31]2[N:36]([OH:37])N=NC=2C=1.[CH2:38](Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:36]([O:37][CH3:38])[CH3:31])=[O:15])=[C:10]([C:17]3[CH:18]=[CH:19][C:20]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:21][CH:22]=3)[C:9]=2[CH3:27])=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Reactant: ClCCCl
Reactant: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 76.7 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (compound 49ε, 0.800 g, 1.98 mmol) in DMF (15 ml) was added HOBT (0.333 g, 2.17 mmol) at room temperature followed by the addition of N, O-dimethylhydroxylamine hydrochloride (0.386 g, 3.96 mmol). The reaction mixture was then cooled to 0° C., and to the cooled reaction mixture was added EDC (0.570 g, 2.97 mmol) and triethylamine (0.80 g, 1.10 ml, 7.92 mmol). The reaction mixture was then stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was taken in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.680 g, 76.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([O:10][C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: COc1cccc(F)c1O
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: COc1cccc(F)c1Oc1nc(Cl)ncc1Cl

Procedure:
2,5-Dichloro-4-(2-fluoro-6-methoxy-phenoxy)-pyrimidine was prepared from 2-Fluoro-6-methoxy-phenol and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. (1.95 g, 96%) LCMS 290 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 7.38-7.34 (m, 1H), 7.10-7.03 (m, 2H), 3.80 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:14])([CH3:13])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(CN2CCN3C(=O)C([NH:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)=CC=C3C2=O)=CC=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:13][C:9]1([CH3:14])[N:6]2[C:7](=[O:8])[C:2]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)=[CH:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10]1
Reactant: COc1ccc(CN2CCn3c(ccc(Nc4ccncn4)c3=O)C2=O)cc1
Reactant: CC1(C)NC(=O)c2ccc(Cl)c(=O)n21
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2ccc(Nc3ccncn3)c(=O)n21
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a solution of 6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (4, 0.25 g, 1.18 mmol) in 1,4-dioxane (8 mL), pyrimidin-4-amine (5, 0.14 g, 1.41 mmol), Brettphos (0.19 g, 0.23 mmol) and cesium carbonate (0.76 g, 2.36 mmol) were added and the reaction mixture was degassed with argon for 5 min. Tris dibenzylideneacetone dipalladium (0) (0.11 g, 0.12 mmol) was added. The reaction was degassed with argon for another 5 min and then stirred at 100° C. for 10 h. The reaction mixture was cooled to room temperature, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 2) as a light yellow solid. Yield: 0.036 g, 11%; MS (ESI) m/z 272[M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.42 (s, 1H), 8.81-8.73 (m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.87 (d, J=7.7 Hz, 1H), 1.82 (s, 6H).
Reaction SMILES: [CH2:1]([OH:3])C.[CH2:4]=[O:5].[NH2:6][CH2:7][C:8]([OH:10])=[O:9]>C(N(CC)CC)C>[OH:5][CH2:4][N:6]([CH2:1][OH:3])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCO
Reactant: NCC(=O)O
Reactant: C=O
Solvent: CCN(CC)CC
Product: O=C(O)CN(CO)CO

Procedure:
To 500 ml. of anhydrous ethanol, 48.0 g. of triethylamine, 30.6 g. of paraformaldehyde are added. The mixture is stirred at boiling temperature and 37.5 g. of glycine are added. N,N-bis-hydroxymethyl-glycine formed in the reaction mixture is reacted without isolation with 69.0 g. of diethyl phosphite and the reaction mixture is stirred for 20 minutes at 80° C. The reaction mixture is further processed as disclosed in Example 1. 60-62 g. of crystalline N-phosphonomethyl-glycine are obtained. Purity: above 98%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][OH:30].CN(C)[CH:33]=[O:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:29]([O:34][CH3:33])=[O:30])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CO
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h
Yield: 65 %

Procedure:
To a stirred solution of 1-Boc-1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine (74.84 g, 226 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine (4.2 mL, 30.2 mmol), palladium acetate (0.100 g, 0.45 mmol), triphenylphosphine (0.235 g, 0.9 mmol), and methanol (24.5 mL) and the solution was placed under an atmosphere of carbon monoxide. After stirring for 48 h, the solvent was removed in vacuo. The residue was chromatographed over silica gel, eluting with 5–10% ethyl acetate in hexane. The product containing fractions were combined and concentrated in vacuo to give 2.35 g (65%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][Si:11](C#N)([CH3:13])[CH3:12].[C-:16]#[N:17].[K+].C1OCCOCCOCCOCCOCCOC1>ClCCl.C(OCC)C>[CH3:10][Si:11]([CH3:13])([CH3:12])[O:5][CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])[C:16]#[N:17]
Reactant: Cc1ccccc1C=O
Reactant: [C-]#N
Reactant: C[Si](C)(C)C#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccccc1C(C#N)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.00 g (8.33 mmol) of 2-methylbenzaldehyde dissolved in 20 mL of dichloromethane was added 1.33 mL (10.0 mmol) trimethylsilylcyanide, 1-2 mg of potassium cyanide, 1-2 mg of 18-crown-6, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted into diethyl ether, washed with 5% NaHCO3, brine, dried (MgSO4), filtered and evaporated. The residual oil was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.[CH2:13]([N:17]1[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=[C:18]1S(C)(=O)=O)[CH2:14][CH2:15][CH3:16].[Cl-:32].[NH4+]>CN(C=O)C.CCOCC.[H-].[Na+]>[CH2:13]([N:17]1[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=[C:18]1[NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Cl:32])[CH:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [Cl-]
Reactant: CCCCn1c(S(C)(=O)=O)nc(C(F)(F)F)cc1=O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCn1c(Nc2cc(Cl)cc(C(F)(F)F)c2)nc(C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
3-Amino-4-chlorobenzotrifluoride (2.9 g, 12.7 mmol) was dissolved in DMF (30 ml), sodium hydride (60% in oil, 540 mg, 13.5 mmol) was added, followed by stirring at room temperature for 30 minutes. Then, 3-butyl-2-methylsulfonyl-6-trifluoromethyl-4(3H)-pyrimidinone (3.0 g, 11.7 mmol) was added, followed by stirring for 4 hours. After completion of the reaction, the reaction solution was diluted with ether (20 ml), excess sodium hydride was neutralized with saturated ammonium chloride aqueous solution, and then the organic layer was separated and the resulting aqueous layer was extracted with ether (15 ml×2). The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=10:1), 3-butyl-2-(3-chloro-5-trifluoromethylphenyl)amino-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 22] was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:26]([CH3:27])[C:21]([O:20][CH3:19])=[C:22]([CH3:31])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1c(C)cc(B(O)O)cc1C
Product: CCCNC(=O)c1nnc2c(-c3cc(C)c(OC)c(C)c3)cccc2c1N
Yield: 83 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (125 mg, 0.40 mmol) and (4-methoxy-3,5-dimethylphenyl)boronic acid (144 mg, 0.80 mmol) were reacted to afford the title compound (121 mg, 82% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.57 (bs, 1H), 7.66-7.85 (m, 3H), 7.32 (s, 2 H), 3.78 (s, 3H), 3.46 (apparent q, J=6.6 Hz, 2H), 2.36 (s, 6H), 1.67 (apparent sextet, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=365 (M+H) HPLC 2.08 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C>[Pd].O1CCCC1>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1CC=C(c2cccnc2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: OC1CCC(c2cccnc2F)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a 150 mL round bottom flask was added 4-(2-fluoropyridin-3-yl)cyclohex-3-enol (324 mg, 1.677 mmol) followed by Ethanol (14.000 ml):Tetrahydrofuran (2.80 ml) and Palladium on carbon, 10% wt. (32.4 mg, 0.304 mmol). The system was evacuated and backfilled with nitrogen and hydrogen before leaving the reaction suspension exposed to the latter. It was stirred for 16 h at 1 atm. An additional 20% by weight of Pd/C was added before placing the vessel's interior under a hydrogen atmosphere using the same procedure used originally. The reaction was also heated to 40° C. After an additional 2 h, the reaction was complete. The black suspension was cooled to room temperature and filtered over Celite with two ethyl acetate rinses (2×30 mL). The clear filtrate was concentrated under reduced pressure and used without purification.