Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]([C:18](=[O:21])[CH2:19]Cl)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:19][C:18]1=[O:21]
Reactant: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)cc2Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 100 g (0.3 mol) of N-(2′-chloro-4′,6′-difluorophenyl)-N-chloroacetyl-4-methylaniline and 103 g (0.78 mol) of aluminum chloride is added 400 ml of 1,2-dichlorobenzene. The reaction is heated to 140° for 2 hours. The reaction is cooled to room temperature and added to a mixture of 100 ml of concentrated HCl and 700 ml water (cooled to 0-5° in a dry ice/acetone bath). The mixture is extracted twice with 400 ml of methylene chloride. The combined organic layers are washed with 600 ml of 3N HCl. The organic layer is stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO G-60). The solids are filtered off and the solvents are evaporated under reduced pressure to give a tan solid which is recrystallized from ethanol to give N-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole, mp 137-14°.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:12].C(N(CC)CC)C.[CH3:20][C:21]1[N:25]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[S:36][CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=3)[CH2:31][CH2:30]2)=[O:28])[N:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=1>ClCCl>[CH3:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[N:2]([CH3:1])[C:40]([C:38]1[N:39]=[C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:43]([F:44])([F:45])[F:46])=[N:24]3)[CH2:34][CH2:33]2)[S:36][CH:37]=1)=[O:41]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CNC1c2ccccc2CC1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CC3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.4 %

Procedure:
To a solution of 2,3-dihydro-N,2-dimethyl-1H-inden-1-amine (177 mg, 1.1 mmol) and triethylamine (0.22 mL, 1.6 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (421 mg, 1 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 215 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:18]I.O>O1CCCC1>[CH3:1][S:2][CH:3]([CH3:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: CI
Reactant: CSCC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 40.8 %

Procedure:
To 5.00 g of 2-methylthio-4'-(trifluoromethyl)acetophenone dissolved in 50 ml of tetrahydrofuran was added under ice-cooling 0.855 g of a 60% aqueous solution of sodium hydride, and the mixture was reacted at room temperature with stirring until no bubbles were produced. After an addition of 3.34 g of methyl iodide, the mixture was stirred at room temperature for a further 2 hours. The resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography- using n-hexane to obtain 2.16 g of an oily product of 2-methylthio-4'-(trifluoromethyl)propiophenone (yield: 40.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21](O)[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20].CN(C)C=O.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([Cl:31])[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20]
Reactant: Cc1c(Cl)cc(C(C)O)c2c1CN(C(=O)OC(C)(C)C)CCO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(C)Cl)c2c1CN(C(=O)OC(C)(C)C)CCO2
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 7-chloro-9-(1-hydroxyethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (280 mg, 0.82 mmol) and N,N-dimethylformamide (30 μL) in methylene chloride (6 mL) was stirred and thionyl chloride (120 μL, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 20 minutes. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired product (295 mg, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:4]=1.[CH2:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:19]([N:18]([CH2:21][CH3:22])[CH2:17][CH2:16][O:15][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:35]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=1)[CH3:20].[CH2:19]([N:18]([CH2:21][CH3:22])[CH2:17][CH2:16][O:15][C:5]1[CH:4]=[C:3]([CH2:2][N:1]([CH2:2][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:6]=[C:5]([O:15][CH2:24][CH2:23][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:4]=2)[S:35]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=1)[CH3:20]
Reactant: CCN(CC)CC
Reactant: CCN(CC)CCOc1cc(CN)nc(-c2ccccn2)c1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc(CN(Cc2cc(OCCN(CC)CC)cc(-c3ccccn3)n2)S(=O)(=O)c2cccs2)nc(-c2ccccn2)c1
Product: CCN(CC)CCOc1cc(CNS(=O)(=O)c2cccs2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %
Yield: 53 %

Procedure:
A mixture of [2-(6-Aminomethyl-[2,2′]bipyridinyl-4-yloxy)-ethyl]-diethylamine (107 mg, 0.357 mmol), triethylamine (136.5 μL, 1.07 mmol), Thiophene-2-sulfonyl chloride (195.4 mg, 1.07 mmol) and dichloromethane (5 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to afford thiophene-2-sulfonic acid [4-(2-diethylamino-ethoxy)-[2,2′]bipyridinyl-6-ylmethyl]-amide as a yellow oil (85.0 mg, 53%) and thiophene-2-sulfonic acid bis-[4-(2-diethylamino-ethoxy)-[2,2′]bipyridinyl-6-ylmethyl]-amide as a brown oil (58.7 mg, 22%).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:25][C:26]([NH:28]/[N:29]=[C:9]2\[C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16]3[C:11]\2=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NNC(=O)CC1CCCCC1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC2CCCCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-cyclohexylacetohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.01-1.07 (m, 2H), 1.18 to 1.39 (m, 7H), 1.60-1.72 (m, 5H), 1.81 (d, 2 H), 1.92-1.94 (m, 1H), 2.27 (d, 1H), 2.69 (d, 1H), 3.70 (t, 2H), 3.87 (s, 3H), 6.42 (s, 1H), 6.62 (d, 1H), 7.52 and 7.74 (d for isomers, 1H), 12.39 and 13.99 (br s for isomers, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(C)C=CC=CC=1.[CH3:24][OH:25]>C(OC)(OC)OC>[CH3:24][O:25][CH:12]([O:13][CH3:17])[C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Oc1cccc(C=O)c1
Reactant: Cc1ccccc1
Reactant: CO
Solvent: COC(OC)OC
Product: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two g (9 mmol) of 3-tert.-butoxycarbonyloxy-benzaldehyde were dissolved at room temperature in 10 ml of methanol and 1.2 ml of trimethyl orthoformate. To obtain complete solution, 1.5 ml of toluene were added. This was followed by the addition of 3.75 mg of RhCl3 [CH3C(CH2PPh2)3 ] as catalyst. The mixture was then stirred overnight at room temperature. The solvents were separated off by steam distillation, and the oily residue was taken up in a little toluene. The rhodium catalyst was filtered off over a G-4 frit. After the toluene had been stripped off under reduced pressure, the product was dried in an oil pump vacuum.
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]=[C:12]2[N:16]([CH3:17])[C:15]([CH3:18])=[C:14]([C:19]([O:21]CC)=[O:20])[S:13]2)=[O:10])=[CH:7][CH:6]=1)#[N:4].C(Cl)Cl>CO>[C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]=[C:12]2[N:16]([CH3:17])[C:15]([CH3:18])=[C:14]([C:19]([O-:21])=[O:20])[S:13]2)=[O:10])=[CH:7][CH:6]=1)#[N:4].[Na+:2]
Reactant: CCOC(=O)c1sc(=NC(=O)c2ccc(C#N)cc2)n(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)[O-])sc(=NC(=O)c2ccc(C#N)cc2)n1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
10% Aqueous sodium hydroxide solution (48 ml) was added to a mixture of ethyl 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (9.88 g), methylene chloride (250 ml) and methanol (250 ml), followed by stirring at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give sodium 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (10.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][C:27]([F:26])([F:37])[F:38])=[N:9]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1cccc2nc(NCc3ccccc3OC(F)(F)F)ccc12)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=491.8 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonylchloride and 2-(trifluoromethoxy)benzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1([CH3:39])[OH:38].CCN(C(C)C)C(C)C.[Na+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]4([CH3:39])[OH:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(O)CCCCC1N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCC4(C)O)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.97 g, 2.09 mmol) and 2-amino-1-methylcyclohexanol, 30b, (0.40 g, 3.13 mmol) in DMF (10 mL) was added iPr2NEt (0.73 mL, 4.17 mmol). The reaction mixture was heated at 90 C for 17 hours. The reaction mixture was cooled to room temperature and diluted into aqueous saturated NaCl solution. The aqueous phase was extracted twice with EtOAc. The organic phases were washed with twice with aqueous saturated NaCl solution, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-50% EtOAc/hexanes-loaded with CH2Cl2) to afford the desired product, 30c, as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[OH2:20]>C(Cl)(=O)CCCCCCCCCCCCCCC>[C:19]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][CH3:3]
Reactant: O
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Temperature: 0 °C

Procedure:
α-Hydroxypalmiticacid (3.2 g) was dissolved in pridine (15 ml), and palmitoyl chloride (3.3 g) was added thereto under stirring at 0° C. The resulting mixture was allowed to stand over night at room temperature. The reaction mixtue was poured into water and the aqueous solution was stirred at room temperature for 1 hour, followed by acidification with 1 N hydrochloric acid solution, and extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give a residue which was recrystallized from petroleum ether to afford crystals of 2-hexadecanoyloxyhexadecanoic acid (5.4 g). M.p. 55° to 56° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=O)[CH3:14].C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[N:22][OH:23])[CH3:14]
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)c1nc(-c2cccnc2)[nH]c1C
Temperature: 25 °C

Procedure:
To a 20.0 g (0.0995 mole) amount of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone (prepared as described in Example 1) dissolved in 500 ml of boiling water were added 15.0 g (0.183 mole) of sodium acetate and 10.0 g (0.144 mole) of hydroxylamine hydrochloride. The mixture was stirred and heated for 4 hours, then cooled to room temperature. The resulting precipitate was collected by filtration and when dried at 140°-160° C. for 24 hours gave 20.3 g of the desired product as a white solid, mp 215°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:30]([CH3:54])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:30]([CH3:54])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.4 %

Procedure:
p-Methoxyaniline (0.045 g, 0.368 mmol), triethylamine (0.037 g, 0.368 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.062 g, 0.368 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.075 g, 0.184 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.040 g, 0.0780 mmol, 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.C(N(CC)CC)C>ClCCl.[Cu]>[N+:8]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([O:12][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:5][C:6]=1[CH3:11])([O-:10])=[O:9]
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (1.67 g), 3-trifluoromethylbenzene boronic acid (3.8 g), copper (1 acetate (1.82 g) and triethylamine (2.02 g) in dichloromethane (50 ml) was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and purified by silica gel chromatography eluting with light petroleum (b.p. 60-80° C.)/ethyl acetate (19:1) to give the title product as an oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH:28]([C:36]1[CH:37]=[CH:38][C:39]([CH:42]=[O:43])=[N:40][CH:41]=1)[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:42]([C:39]3[CH:38]=[CH:37][C:36]([CH:28]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH2:27][O:26][CH3:25])=[CH:41][N:40]=3)=[O:43])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: COCC(OC1CCCCO1)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(OC1CCCCO1)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 79.5 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridine-2-carbaldehyde (0.42 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (38 mg), triethylamine (0.1 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.70 g, yield 79%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 614 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.O.[Cl-].[Na+]>CCC(=O)CC>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]#[C:10][CH3:11])[CH2:12][C:13]([OH:21])=[O:14])=[CH:6][CH:7]=1
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(=O)CC
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
To a suspension of 5-[1-(4-hydroxyphenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxan e-4,6-dione (54.8 g) obtained in Substep 2 in 3-pentanone (200 mL) was added water (100 mL), followed by stirring the reaction mixture at 100° C. for 2 days. After cooling down to room temperature, the aqueous layer of the reaction mixture was saturated with sodium chloride, followed by extraction with 3-pentanone. The organic layer was dried and concentrated, followed by recrystallizing the residue from an ethyl acetate-hexane mixed solvent to give 3-(4-hydroxyphenyl)-hex-4-ynoic acid (34.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][N:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:19][C:14]1[CH:13]=[C:12]([N:7]2[CH2:8][C:9]3[CH:10]=[N:11][C:2]([Cl:1])=[CH:3][C:4]=3[N:5]([CH3:23])[C:6]2=[O:22])[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21

Procedure:
By analogy to Example A24, 6-chloro-4-(methylamino)nicotinaldehyde (from Example A24), 4-fluoro-3-nitroaniline and sodium triacetoxy borohydride are combined in glacial acetic acid to give crude 2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)-N-methylpyridin-4-amine, which is reacted with diphosgene by the procedure of Example A75 to give 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. Zn Dust is reacted with a suspension of 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one and NH4Cl in MeOH/THF (1:1) to provide 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. By analogy to Example A25, 4-methoxybenzylamine and 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one are combined and heated to 180° C. to provide 7-(4-methoxybenzylamino)-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, which is further reacted with trifluoroacetic acid to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: [Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([OH:14])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Br:34][CH2:35][C:36](Br)=[O:37].O>C(Cl)Cl>[Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([O:14][C:36](=[O:37])[CH2:35][Br:34])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1OC(=O)CBr
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy-3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (81 mg, 0.18 mmol) in CH2Cl2 (2 ml) at 0° C. were added collidine (47 μl, 0.36 mmol), and bromoacetylbromide (24 μl, 0.27 mmol). After 1 hour, the reaction mixture was worked up with CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the titled compound (76 mg, 74%).