Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[NH:6]2.[C:17](Cl)([Cl:19])=[O:18]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:6]1[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[C:11]2=[C:2]([CH3:1])[S:3][CH:4]=[C:5]12)=[O:18]
Reactant: Cc1scc2c1C(=O)Nc1ccccc1N2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1scc2c1C(=O)Nc1ccccc1N2C(=O)Cl

Procedure:
From 4,9-dihydro-1-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and phosgene in a mixture of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro-1-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained, m.p. 235°-236° C. (chloroform);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=O)C(Cl)=O>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 60 °C
Yield: 88.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (4 g, 18 mmol) in methanol (10 mL) was added dropwise oxalyl dichloride (4.6 g, 36 mmol). The reaction was heated to 60° C. overnight and added slowly into ice water, and extracted with DCM (50 mL×2). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give the desired product (3.7 g, 88%) as brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:13]([CH:14]=O)=[CH:12][C:5]2[B:6]([OH:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:13]([CH:14]=[N:16][OH:17])=[CH:12][C:5]2[B:6]([OH:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1
Reactant: NO
Reactant: CC1(C)OB(O)c2cc(C=O)c(Cl)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2cc(C=NO)c(Cl)cc21
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (200 mg, 0.89 mmol) and NH2OH.HCl (74 mg, 1.07 mmol) in THF (12 mL) and H2O (3 mL) at rt was added NaOAc (110 mg, 1.34 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to give crude compound 5-chloro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH2:11](I)[CH3:12].O1CCOCC1>C(OCC)C>[CH2:11]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:12]
Reactant: CCI
Reactant: Nc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCSc1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of 25 grams (0.193 mole; M.W. 125.19) of 3-aminothiophenol in 200 ml. of 5N sodium hydroxide was added, dropwise, over a period of 1 hour, a solution of 29.9 grams (0.193 mole) of ethyl iodide in 50 ml. of 1,4-dioxane. The resulting suspension was allowed to stir at room temperature for 1 hour, 200 ml. of ethyl ether were then added, and stirring was continued for an additional 30 minutes. The ether layer was separated, washed with a saturated aqueous solution of sodium bisulfite, dried over Na2SO4, and evaporated in vacuo to yield 28.10 grams of m-ethylthioaniline.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.Cl>C(OCCO)C>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: O
Solvent: CCOCCO
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
5.0 g (32 mmol) of 2-chloro-3-nitropyridine was dissolved in 2-ethoxyethanol (150 mL), and water (150 mL) was added thereto. To the mixed solution, 3.9 g (32 mmol) of 4-methoxyaniline and 6 N hydrochloric acid (1 mL) were added, and the mixture was heated to reflux for 12 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure, to obtain 6.6 g (yield: 85%) of N-(4-methoxyphenyl)-3-nitropyridin-2-amine as orange-colored crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]=[CH:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH:3]=[O:4].[CH:12]([Mg]Cl)=[CH2:13].O>O1CCCC1>[CH3:1][CH:2]([CH2:5][CH:6]=[CH:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH:3]([OH:4])[CH:12]=[CH2:13]
Reactant: C=C[Mg]Cl
Reactant: CCC(C)C=CCC(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)C(C)CC=CC(C)CC
Yield: 94 %

Procedure:
54 g (0.35 mole) of 2,6-dimethyl-oct-4-en-1-al are added in the course of 15 minutes to a solution of 0.4 mole of vinyl-magnesium chloride in 2 liters of tetrahydrofuran, whilst cooling with ice. After a reaction time of 30 minutes, the mixture is hydrolyzed with 40 ml of water, the organic phase is isolated and the solvent is distilled off. The reaction product is fractionated, giving 60 g of the above allyl alcohol (yield, 94% of theory). B.p. = 48°-52° C at 0.02 mm Hg; nD25 = 1.4591.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=2[N+:19]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=2[NH2:19])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c(N)c1

Procedure:
A solution of 23 g of crude N-acetyl-4-(2-nitro-4-acetylphenyl)-piperidine in 250 ml of ethanol is hydrogenated with 4.5 g of palladium (5%) on barium carbonate (decomposed) until 3 equivalents of hydrogen have been absorbed. The catalyst is then filtered off, and the filtrate is concentrated in vacuo to dryness. The crude N-acetyl-4-(2-amino-4-acetyl-phenyl)-piperidine thus obtained is purified by way of the hydrochloride, m.p. 220°-222° (from ethanol).
Reaction SMILES: C(OC(=O)CC1C=CC([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22](C4CC4)[CH:23]=2)[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]3([CH3:30])[CH3:29])=CC=1F)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:13]([C:14]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3([CH2:27][CH2:28]3)[CH2:18][C:17]([CH3:29])([CH3:30])[C:16]=2[CH:15]=1)#[CH:12]
Reactant: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CC1(CC1)O2

Procedure:
Following general procedure E and using 3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 37, 0.4 g, 1.42 mmol), potassium carbonate (0.98 g, 7.1 mmol) and methanol, the title compound was obtained as a yellow oil (0.3 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-4-yl]-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-4-yl]-propionic acid as off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([NH:32][C@@H:30]([C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=3)[CH3:31])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (45 mg, 0.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C)C=O.O>[C:17]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1)#[N:18]
Reactant: N#C[Cu]C#N
Reactant: CCc1cc(Br)cc(C)c1CC(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C#N)cc(C)c1CC(=O)OC
Temperature: 130 °C

Procedure:
7.5 g of methyl 4-bromo-2-ethyl-6-methylphenylacetate were dissolved in 140 ml of dimethylformamide, 5.5 g of copper cyanide were added, and the mixture was heated for 18 hours at 130° C., until the reaction was complete. The mixture was then cooled to room temperature and diluted with water, and the product was extracted repeatedly using tert-butyl methyl ether. The combined organic phases were dried over magnesium sulphate, concentrated and distilled. This gave 3.4 g (52% of theory) of methyl 4-cyano-2-ethyl-6-methylphenylacetate of a boiling point of 123-130° C. and a melting point of 65-72° C.
Reaction SMILES: [C:1]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([Br:28])=[C:23]([O:29][CH2:30][C:31]#[N:32])[CH:22]=[CH:21]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:28][C:24]1[C:23]([O:29][CH2:30][C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:22][CH:21]=[C:20]2[C:25]=1[CH:26]=[CH:27][C:18]([C:10]1[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])=[CH:19]2
Reactant: N#CCOc1ccc2cc(-c3oc4ccccc4c3C(=O)c3ccccc3)ccc2c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a stirred solution of {[6-(3-benzoyl-1-benzofuran-2-yl)-1-bromo-2-naphthyl]oxy} acetonitrile (0.174 g, 0.361 mmol) in DMF (10 mL) at room temperature was added NaN3 (0.117 g, 1.81 mmol) followed by NH4Cl (0.097 g, 1.81 mmol). The reaction was heated to 100° C. for 2 h. After this time, it was concentrated and diluted with 2 N HCl (˜5 mL). This mixture was stirred at room temperature for 1 h. The solid was filtered and washed with excess water and hexane then dried under high vacuum to afford the product (0.190 g, 99%) as a light. brown solid, mp>183° C. (dec.). Mass spectrum (+APCl, [M+NH4]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): δ14.75-17.75 (br s, 1H), 8.28 (d, 1H, J=2.0 Hz), 8.03 (d, 1H, J=9.0 Hz), 8.00 (d, 1H, J=8.8 Hz), 7.78-7.83 (m, 3H), 7.76 (dd, 1H, J=1.7, 8.8 Hz), 7.67 (d, 1H, J=9.0 Hz), 755 (d, J=7.6 Hz, 1H), 7.32-7.38 (m, 3H), 7.45-7.52 (m, 2H), and 5.71 ppm (s, 2H). Elemental analysis for C27H17BrN4O3.1.0H2O: Calculated: C, 59.68; H, 3.52; N, 10.31. Found: C, 59.72; H, 3.23; N, 10.51.
Reaction SMILES: [C:1]123C(=O)[O:10][C:8](=[O:9])[CH:2]1[CH2:3][CH:4]([CH2:7]2)[CH2:5][CH2:6]3.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][CH:3]1[CH:4]2[CH2:7][CH:1]([CH2:6][CH2:5]2)[CH:2]1[C:8]([OH:10])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C1OC(=O)C23CCC(CC12)C3
Solvent: ClC(Cl)Cl
Product: O=C(O)C1C2CCC(C2)C1OCc1ccccc1

Procedure:
33.2 g (0.2 mol) bicyclo[2.2.1]heptane dicarboxylic anhydride and 27 g (0.25 mol) benzyl alcohol were charged to 500 ml chloroform in a 1 L round bottom flask. The system was refluxed for 16 hours with magnetic stirring. The solvent was then removed by rotary evaporator. The solid was then dried and grounded. The product was characterized using FTIR and GC-MS. The yield was quantitative.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: O=C(O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 75 a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=377.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12]C(=O)C)=[CH:5][C:4]=1[CH3:16].[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH2:12])=[CH:5][C:4]=1[CH3:16]
Reactant: COc1nc([N+](=O)[O-])c(NC(C)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc([N+](=O)[O-])c(N)cc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The crude product (1.93 g) of N-(6-methoxy-5-methyl-2-nitro-3-pyridinyl) acetamide was dissolved in methanol (36 ml), 5N sodium hydroxide solution (6 ml) was added, and the reaction mixture was stirred for 15 minutes at room temperature. After water was added to the reaction solution, it was extracted with ethyl acetate and dried over magnesium sulfate, and the solvent was evaporated, thereby yielding the title compound (1.06 g, 5.79 mmol) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH3:21])[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C>CCO>[CH3:35][O:34][C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[C:31]=1[O:32][CH3:33])[CH2:27][N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:15]1[CH3:21]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: COc1cc2c(cc1OCc1ccccc1)CCNC2C
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cc(OC)c(OC)c(OC)c1)C2C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
A solution of 250 (170 mg, 0.6 mmol), 3,4,5-trimethoxybenzyl chloride (156 mg, 0.72 mmol) and triethyl amine (0.17 ml, 1.2 mmol) in EtOH (3 ml) was heated in the microwave at 130° C. for 1.5 h, then at 170° C. for 30 min. The reaction mixture was concentrated in vacuo. Purification (flashmaster: 20 g, gradient elution 100% hex to 50% hex:50% EtOAc over 25 min) afforded The title compound (58 mg, 21%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.36 (3H, d, J=6.7 Hz, CH3CH), 2.47-2.55 (1H, m, one of CH2), 2.67-2.84 (2H, m, 2×CH, CH2), 2.98-3.07 (1H, m, one of CH2), 3.59-3.73 (2H, m, CH2), 3.83 (9H, s, 3×OCH3), 3.88 (3H, s, OCH3), 5.09 (2H, s, CH2), 6.56-6.62 (4H, m, 4×CH), 7.27-7.44 (5H, m, 5×CH, phenyl). LC/MS (ES+) tr=1.26 min, m/z 464.34 (M++H).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[CH2:21]([O:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])=[CH:13][CH:14]=1)=[O:19])[CH3:22]
Reactant: COP(OC)OC
Reactant: CCOC(=O)c1ccc(OC(=O)Cl)cc1
Product: CCOC(=O)c1ccc(OC(=O)P(=O)(OC)OC)cc1

Procedure:
From 16.1 g (0.13 mole) of trimethylphosphite and 22.8 g (0.10 mole) of 4-ethoxycarbonylphenyl chloroformate. (100° C., 3 hours). Yield 26.7 g (88%). Bp0.05 205°-7° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([NH:7][C:8]2[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(NC3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(cyclohexylamino)-2-phenylquinoxaline-6-carboxylate (80 mg, 0.22 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (44.32 mg, 1.11 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 20 mL of water. The pH value of the solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (76%) of 3-(cyclohexylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[NH:10][N:9]=[CH:8][CH2:7]2)=[CH:2]1.[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12]>C(O)C>[CH2:11]([NH:13][C:14]([N:10]1[CH:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:7][CH:8]=[N:9]1)=[S:15])[CH3:12]
Reactant: C1=NNC(c2ccsc2)C1
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)N1N=CCC1c1ccsc1
Yield: 0.3 %

Procedure:
1.82 g (1 mol equiv.) 5-Thiophen-3-yl-4,5-dihydro-1H-pyrazole (synthesized as described in WO 2008/034863) and 1.36 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 15 mL ethanol. The reaction mixture was refluxed for 5 hours, and subsequently concentrated on silica gel under reduced pressure. Purification by flash chromatography on silica gel (Et2O:PA=1:1) afforded 0.70 g (26%) 5-thiophen-3-yl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 2.86 (ddd, J=18.5, 3.3, 1.7 Hz, 1H), 3.39 (ddd, J=18.5, 11.4, 1.7 Hz, 1H), 3.56-3.77 (m, 2H), 6.01 (dd, J=11.4, 3.3 Hz, 1H), 6.93 (dd, J=5.0, 1.0 Hz, 1H), 7.02 (t, J=1.7 Hz, 1H), 7.13 (m, 1H), 7.26 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[CH3:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[BrH:19].BrBr>C(O)(=O)C>[Br:19][C:7]1[CH:6]=[C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[CH3:14])[CH:4]=[C:3]([C:15]([F:18])([F:17])[F:16])[C:2]=1[NH2:1]
Reactant: Cc1cn(-c2ccc(N)c(C(F)(F)F)c2)c(C)n1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(Br)c(N)c(C(F)(F)F)c2)c(C)n1

Procedure:
1-(4-Amino-3-trifluoromethylphenyl)-2,4-dimethylimidazole (10 g) was dissolved in glacial acetic acid (70 cm3). A solution of 45% w/w hyrdogen bromide in glacial acetic acid (7.4 cm3) was added. A solution of bromine (2.1 cm3)in glacial acetic acid (30 cm3) was then added dropwise. The mixture was heated at 70° for 3 hours, cooled, concentrated to a small volume by evaporation in vacuo, and basified to pH 8 by addition of aqueous sodium carbonate solution. The aqueous phase was extracted with chloroform (3×200 cm3) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with ethyl acetate. Combination and evaporation of appropriate fractions afforded 1-(3-bromo-4-amino-5-trifluoromethylphenyl)-2,4-dimethylimidazole (4.76 g), a small sample of which was recrystallised from ethyl acetate/hexane, m.p. 149°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[C:18]([CH:20]=O)[N:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:20][C:18]2[N:17]=[CH:16][NH:15][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(NCc3c[nH]cn3)CC2)cc1
Yield: 86.3 %

Procedure:
To a solution of 1-benzyl-4-piperidinamine (3.4 g), imidazole-4-carbaldehyde (1.4 g) and acetic acid (1.7 ml) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride (4.7 g), and mixed at room temperature for 15 hours. A 1 N aqueous sodium hydroxide solution was added to the reaction solution and pH of the aqueous layer was adjusted to about 12, and then extracted with chloroform (100 ml). The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a yellow oil (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]([CH3:15])=O.N1CCCCC1>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:13]([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 5-fluoro-1,3-dihydro-indol-2-one (2.84 g, 20 mmol), acetone (2.2 mL, 30 mmol) and piperidine (0.8 mL, 8 mmol) in methanol (100 mL) was heated to reflux for 16 hours. Then the reaction mixture was allowed to cool to room temperature. The solid was collected by filtration, washed with methanol (20 mL) and dried in vacuo to afford 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 68%) as powder.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19]>CN(C=O)C.O>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[S:19][C:2]=2[CH:9]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,4-difluorobenzaldehyde (50.17 g) and potassium carbonate (63.4 g) in DMF (500 ml) was added ethyl thioglycolate (38.7 ml) dropwise at 0° C. The mixture was stirred at room temperature for 18 hours, diluted with water, and extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid, water, and brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel using hexane-ethyl acetate (20:1) as an eluent to give the titled compound as colorless crystals (16.61 g).