Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[N:2]1.[CH3:9][O:10][C:11](=[O:26])[C@H:12]([CH3:25])[NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH3:24].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:9][O:10][C:11](=[O:26])[C@H:12]([CH3:25])[N:13]([C:6]([C:4]1[N:3]=[N:2][S:1][CH:5]=1)=[O:7])[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH3:24]
Reactant: O=C(Cl)c1csnn1
Reactant: COC(=O)[C@H](C)Nc1c(C)ccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C)N(C(=O)c1csnn1)c1c(C)ccc2ccccc12
Yield: 95.3 %

Procedure:
14 g (0.095 mole) of 1,2,3-thiadiazole-4-carbonyl chloride in 30 ml of toluene were added dropwise to a solution of 22.9 g (0.0945 mole) of N-(2-methyl-1-naphthyl)-alanine methyl ester in 100 ml of dry toluene at from +15° C. to +30° C. The mixture was stirred at 80° C. for 8 hours, during which the hydrogen chloride formed was continuously expelled in a weak stream of nitrogen. The mixture was cooled and stirred with a solution of 5 g of sodium bicarbonate in 100 ml of water. The organic phase was separated off, dried over sodium sulfate, decolorized with charcoal and evaporated under reduced pressure. The oily residue which remained was dried at 50° C. and under 0.1 mbar for 3 hours to give 32 g (95.2% of theory) of N-(1,2,3-thiadiazol-4-yl-carbonyl)-N-(2-methyl-1-naphthyl)-alanine methyl ester as a light-brown resin.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[N:5]=[CH:4][N:3]=1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[C:7]4[O:8][CH2:9][CH2:10][NH:11][C:6]=4[N:5]=[CH:4][N:3]=3)[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1.[C:14]([OH:16])([C:13]([F:18])([F:17])[F:12])=[O:15]
Reactant: Clc1ncnc2c1OCCN2
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc5c4OCCN5)CC3)n2)cc1C(F)(F)F
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (30.0 mg; 0.17 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (109.2 mg; 0.17 mmol; 1.0 eq.) and cesium carbonate (227.8 mg; 0.7 mmol; 4.0 eq.) in 1 ml of DMSO was stirred at 120° C. for 48 hrs. The reaction mixture was purified by pre-HPLC to afford the title compound as TFA salt (48.6 mg, 43% yield); LC-MS (M+H=532, obsd.=532);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([N:13]([CH2:22][CH2:23][CH3:24])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>CCOCC>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([N:10]2[CH2:11][CH:12]([N:13]([CH2:22][CH2:23][CH3:24])[C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:21])[Cl:20])=[O:15])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[O:35])=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCCN(C(=O)OCC(Cl)(Cl)Cl)C1CNN=C1c1ccc(Cl)cc1
Solvent: CCOCC
Product: CCCN(C(=O)OCC(Cl)(Cl)Cl)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To half of the ether solution of 3-(4-chlorophenyl)-4-(N-propyl-N-(2,2,2-trichloroethoxycarbonyl)-amino)-4,5-dihydro-1H-pyrazole (Example 349c) (≤149 mmole) was added 18.7 g (100 mmole) of 4-trifluoromethylphenyl isocyanate. After stirring for 30 minutes, the mixture was concentrated in vacuo and dissolved in 200 ml of 50/50 diethyl ether/hexanes and cooled to -20° C. Crystals of the desired compound formed and were filtered yielding 30 g of the desired compound, mp 172°-173° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]1([NH:6][C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)nc(NC2CCCC2)n1
Product: Clc1cc(N2CCCC2)nc(NC2CCCC2)n1
Yield: 72.4 %

Procedure:
2-Cyclopentylamino-4,6-dichloropyrimidine is reacted with pyrrolidine as described in Example 12 to give the title compound as an oily product in a yield of 72.4%.
Reaction SMILES: COCCOC[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.Cl.C[OH:28]>>[OH:28][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1
Reactant: CO
Reactant: COCCOCc1ccc(-c2cc3ccccc3n2S(C)(=O)=O)cc1
Agent: Cl
Product: CS(=O)(=O)n1c(-c2ccc(O)cc2)cc2ccccc21
Reaction time: 2 h

Procedure:
A solution of the product of Step D (1.5 g, 4.0 mmol) in methanol (10 mL) was treated with HCl (10 mL, 4 N in dioxane). The reaction was allowed to stir for 2 hr, concentrated, and purified by silica gel chromatography (methanol:dichloromethane), to afford the title compound (0.93 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][CH:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: CC(=O)Oc1ccc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To an ice-cooled solution of product obtained in Step 4 of Example 8 (5.3 g) in dimethylformamide (18 ml) was added (2-aminothiazol-4-yl)glyoxylic acid (2.03 g), and the mixture was stirred overnight at room temperature. The resulting solution was poured into ice water (100 ml), and the mixture was acidified (pH 2) with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether, giving 6.30 g of the objective compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[NH:11][C:10](=[O:17])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1.Br[CH:34]([CH3:36])[CH3:35].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([O:17][CH:34]([CH3:36])[CH3:35])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: CC(C)Br
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OC(C)C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Oily sodium hydride (60%, 0.1 g) was added to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (0.5 g) in N,N-dimethylformamide (20 ml) under ice-cooling. After stirring at room temperature for 30 minutes, 2-bromopropane (0.5 ml) was added. The mixture was stirred at 60° C. for 5 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-isopropoxyquinoline-3-carboxylate (0.388 g, 70%) which was then recrystallized from ethyl ether. mp. 142°-143° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[C@H:10]([F:26])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C@H:10]1[C@H:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2C(F)(F)F)[C@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: F[C@@H]1CNCC[C@H]1NCc1ccccc1C(F)(F)F
Yield: 96.9 %

Procedure:
Using a similar procedure to that described in Example 1, step 4, trans-1-tert-butoxycarbonyl-3-fluoro-4-[2-(trifluoromethyl)benzylamino]piperidine (0.4615 g, 1.23 mmol) was reacted with trifluoroacetic acid (1.5 mL) in dichloromethane (3 mL) to give 0.3292 g (97%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.35 (1H, m), 2.02 (1H, m), 2.55-2.69 (2H, m), 2.82 (1H, m), 2.99 (1H, m), 3.31 (1H, m), 4.02 (2H, m), 4.34 (1H, two m), 7.35 (1H, t, J=7.6 Hz), 7.53 (1H, t, J=7.6 Hz), 7.63-7.67 (2H, m). m/e (ES+) 277 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(O)(=O)C>O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:7]1[CH:14]=[CH:18][CH:17]=[CH:16]1)([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: NCc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1Cn1cccc1

Procedure:
The starting material is prepared as follows: The mixture of 3,078 g of o-nitrobenzylamine and 2,670 g of 2,5-dimethoxytetrahydrofuran is added rapidly to 10,000 ml of glacial acetic acid at 86° while stirring under nitrogen. The mixture is stirred at 95° for 1.25 hours, cooled to 25° and combined with 30,000 ml of water. It is extracted with ethyl acetate, the extract is washed with 10% aqueous sodium hydroxide and 10% aqueous sodium chloride, filtered and evaporated to yield the 1-(o-nitrobenzyl)-pyrrole.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25]>>[CH2:1]([S:8][C:9]1[C:10]([O:17][CH3:18])=[C:11]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Br)cc(F)cc1SCc1ccccc1
Reactant: O=C1CCCCN1
Product: COc1c(SCc2ccccc2)cc(F)cc1N1CCCCC1=O

Procedure:
Intermediate 13 (4.22 g, 12.9 mmol) was treated with piperidin-2-one (1.41 g, 14.2 mmol) according to the procedure described in 1.5). Yield after triturating (with n-heptane-ethyl acetate, 4:1) and filtration: 2.67 g (60%), crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[N:22])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)([O-:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])[CH:3]=1)#[N:22]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: N#Cc1ccccc1-c1cc(Br)cn(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cc(-c2ccccc2[N+](=O)[O-])cn(-c2ccccc2)c1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
5-Bromo-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one (100 mg), 60 mg of 2-nitrophenylboronic acid and 130 mg of cesium carbonate were suspended in 10 ml of dimethylformamide, then 20 mg of tetrakistriphenylphosphine palladium were added and the mixture was stirred at 120° C. in a nitrogen atmosphere for 4 hours. After allowing to cool, the reaction solution was poured into water, the mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate system) to give 35 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:30][CH:32]2[CH2:33][O:34]2)=[C:9]([CH:22]=1)[C:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCC2CO2)c(C(=O)Nc2cccc3[nH]ccc23)c1

Procedure:
A mixture of 3.5 g of the product of Step C, 150 ml of acetone, 1.5 g of potassium carbonate and 9 ml of epibromohydrin was refluxed for 2 hours and after the addition of another 9 ml of epibromohydrin, the mixture was refluxed for 20 hours and was filtered. The filtrate was washed with acetone and evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ether and was filtered. The product was dried at 80° C. to obtain 3.4 g of 5-acetylamino-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide melting at 230° C.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.Br[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:2]2)[CH2:6]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(OCCCN2CC3CNCC(C2)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
4-[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propoxy]benzonitrile (6.5 g, 0.0226 mol; see WO 01/28992) and tert-butyl 2-bromoethylcarbamate (6 g, 0.0271 mol; see WO 01/28992) were dissolved in 80 mL of dry acetonitrile. Anhydrous potassium carbonate (4.68 g, 0.034 mol) was added and the mixture was stirred at 60° C. overnight. A further portion of tert-butyl 2-bromoethylcarbamate (2.53 g, 0.0113 mol) was added and the reaction heated at 65° C. overnight. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The product was purified by column chromatography using methanol-chloroform as eluent to give the sub-title compound (4.5 g) as a yellow solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[Br:12]N1C(=O)CCC1=O>ClCCl>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][C:4]2=[O:11]
Reactant: O=C1CCNc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=C1CCNc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
To a solution of 2,3-dihydroquinolin-4(1H)-one (2.94 g) in dichloromethane (25 mL) was added N-bromosuccinimide (3.63 g). The mixture was stirred at room temperature for 1.5 h and was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on silica gel using a 35% ethyl acetate in heptane solvent solution and gave 4.14 g of the title compound. MS (ESI−) for C9H8BrNO m/z 225.77 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([O:6]/[N:7]=[C:8](/[C:14](=[O:16])[CH3:15])\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:17].S(Cl)([Cl:21])(=O)=O>C(Cl)Cl>[NH:1]1[CH2:5][CH2:4][C@H:3]([O:6]/[N:7]=[C:8](/[C:14](=[O:16])[CH2:15][Cl:21])\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)C(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)C(=O)CCl
Reaction time: 20 h

Procedure:
2.4 g of ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)-oxyimino]-3-oxo-n-butyrate are dissolved in 15 ml of methylene chloride, and 1.6 g of sulfuryl chloride are added thereto. The mixture is stirred at 15° to 25° C. for 20 hours. Then, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in chloroform, and the solution is washed with water. The chloroform solution is dried and concentrated under reduced pressure to dryness. Ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]-3-oxo-4-chloro-n-butyrate is thereby obtained as crude product. The crude product thus obtained is dissolved in 20 ml of ethanol, and one g of thiourea and 1.2 g of N,N-dimethylaniline are added thereto. The mixture is stirred at 20° to 25° C. for 2 hours. Then, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in chloroform, and the solution is washed with water and an aqueous sodium bicarbonate solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with isopropanol, and the crystals are collected by filtration. 1.2 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[C:29](=[O:33])[C:30]([NH2:32])=[O:31])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:32][C:30](=[O:31])[C:29]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[CH2:27][CH3:28])=[O:33]
Reactant: CCc1c(C(=O)C(N)=O)c2cc(OCCCC(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C(=O)C(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 63.1 %

Procedure:
A solution of 450 mg (0.97 mmol) of 4-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid tert-butyl ester in 75 mL of methylene chloride and 1 mL of trifluoroacetic acid was stirred-at room temperature for 2.25 hours and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with EtOAc to give 250 mg (63% yield) of 4-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp 173°-175° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:33]=[CH:32][C:15]([O:16][CH2:17][CH:18]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:14][CH:13]=1>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:32][CH:33]=1
Reactant: COCCOCOC(CCCCCO)COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCOCOC(CCCCC=O)COc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Oxalyl chloride (2.9 ml, 33.6 mmol) is added to 25 ml of methylene chloride and cooled to −78° C. Dry dimethyl sulfoxide (4.7 ml, 67.2 mmol) is then added and the reaction is stirred at −78° C. After 45 minutes, (±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-ol 44 (3.7 g, 11.2 mmol) dissolved in CH2Cl2 is added and the reaction is stirred at −78° C. After 1 hour, the reaction is quenched with 15.7 ml of triethylamine and diluted with CH2Cl2. The reaction mixture is then washed with water, brine dried (Na2SO4) and concentrated. The crude product is purified on silica gel (ethyl acetate:hexane 1:9) to give (±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-al 45, 3.3 g, 89%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([CH:17]=[O:18])[CH:3]=1.[Cl:19]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([CH:17]=[O:18])[C:3]=1[Cl:19]
Reactant: Nc1cc(C=O)nc(Cc2ccc(F)cc2)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC#N
Product: Nc1c(F)c(Cc2ccc(F)cc2)nc(C=O)c1Cl
Yield: 136.7 %

Procedure:
Using the procedure for Example 15, 4-amino-5-fluoro-6-(4-fluorobenzyl)-picolinaldehyde (0.5 g, 2.014 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.218 g, 1.108 mmol) and CH3CN (20 mL) gave 4-amino-3-chloro-5-fluoro-6-(4-fluorobenzyl)picolinaldehyde (428 mg, 73.7%) as an orange solid: mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.28 (m, 3H), 6.97 (m, 2H), 4.84 (s, 2H), 4.14 (d, J=3.1 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −116.40, −139.04; 13C NMR (101 MHz, CDCl3) δ 190.27, 162.96, 160.53, 148.18, 145.80, 145.67, 145.61, 143.17, 139.85, 139.72, 133.24, 130.38, 130.31, 115.47, 115.26, 37.10, 37.08; EIMS m/z 282.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH2:19]Cl.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].[H-].[Na+]>CO>[CH3:26][O:25][C:23](=[O:24])[CH:22]([CH2:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])[C:21]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2CCl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cc1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C)C(=O)OC

Procedure:
The title compound was prepared by reacting 4-chloro-3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine with dimethyl malonate/NaH in methanol. The title compound was isolated as a colorless oil.
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]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([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:15])[C:16]4[O:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.