Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([C:19](Cl)=[O:20])[C:14]=1[CH3:22]>ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([C:19]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:20])[C:14]=1[CH3:22]
Reactant: Cc1c(Cl)ncnc1C(=O)Cl
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. a solution of 5.8 mL pyridine and 15 mL tert.-butanol in 10 mL dichloromethane was added dropwise to 6.0 g 6-chloro-5-methyl-pyrimidine-4-carboxylic acid chloride in 10 mL dichloromethane. The reaction mixture was heated to RT and stirred for 30 min. The reaction mixture was diluted with dichloromethane and washed successively with a 2M sodium hydroxide solution, twice with a 10% aqueous citric acid solution and a sodium chloride solution. The organic phase was dried and evaporated down. The residue was taken up in dichloromethane and purified by flash chromatography. The product-containing fractions were evaporated down and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)CN2CCOCC2)cc1

Procedure:
A suspension of 17.6 (0.07 mole) of Compound II and 1.76 g. of 10% palladium on carbon in 175 ml of ethanol was reduced using a Parr Hydrogenator until hydrogen uptake ceased. The catalyst was removed by filtration and the ethanol solution evaporated. The solid thus obtained was recrystallized twice from water and once from toluene whereby 5.1 g. of yellow needles of the Compound I were obtained, m.p. 107°-110° C., U.V.λmax (Am): 318(21,000), 232(6,800).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[C:5]1[O:6][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:3]([C:15]([NH2:17])=[O:16])[N:4]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1Br
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccccc1
Temperature: 150 °C
Yield: 10 %

Procedure:
A mixture of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.060 g, 0.2 mmol), phenyl boronic acid (0.048 g, 0.4 mmol), Pd(dppf)2Cl2 (0.008 g, 0.01 mmol) and 1M sodium carbonate solution (0.395 mL, 0.4 mmol) in acetonitrile (4 mL) was heated in the microwave at 150° C. for 15 minutes. The reaction mixture was partitioned between 1M sodium hydroxide solution and EtOAc and the aqueous phase washed with EtOAc. The organic phase was passed through a MP-SH resin cartridge. (0.5 g) and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-phenyloxazole-4-carboxamide (0.0047 g, 0.02 mmol, 8%) as a white solid. 1H NMR (DMSO) δ 7.40 (2H, t,), 7.54 (3H, m), 7.75 (3H, m), 8.24 (2H, m). LCMS (2) Rt: 2.89 min; m/z (ES+) 301.
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH:39]=3)=[CH:34][CH:33]=2)[C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.Cl.O1CCOCC1.Cl>O>[C:44]([C@@H:41]1[CH2:42][CH2:43][C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH:14]([C:15](=[O:31])[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[CH3:30])=[CH:21][CH:22]=3)[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:48])=[O:5])=[CH:8][CH:9]=3)=[CH:37][CH:36]=2)=[CH:39][CH2:40]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)C(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(C3=CC[C@H](C(C)(C)C)CC3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)C(Cc2ccc(C(=O)O)cc2)c2ccc(C3=CC[C@H](C(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{2-[4-(4-(R)-tert-Butylcyclohex-1-enyl)-phenyl]-2-(4′-chloro-2′-methylbiphenyl-4-ylcarbamoyl)-ethyl]-benzoic acid tert-butyl ester (727 mg, 1.1 mmol) was added 4N HCl/dioxane (30 mL), water (5 mL) and conc. HCl (1 mL). The resulting solution was stirred at rt overnight. The excess solvent was removed under vacuum and the residue co-evaporated with toluene to afford the desired crude product as a gummy oil. The crude material was used the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-])=O>CO.CCOC(C)=O.CCO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[C:7]2[C:6]([CH2:5][CH2:4][C:3](=[O:2])[NH:14]2)=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(c1)NC(=O)CC2
Reaction time: 12 h
Yield: 43.4 %

Procedure:
A solution of 3-(4-methoxy-2-nitro-phenyl)-acrylic acid methyl ester (4.00 g, 16.9 mmol) in MeOH (100 mL) and EtOAc (20 mL) is added a slurry of Pd/C (200 mg) in EtOH (20 mL). The suspension is hydrogenated under a pressure of 60 psi for 12 hours. The mixture is then filter through a pad of celite and the filtrate is concentrated and purified on silica gel chromatography column with 30-40-50% EtOAc/Hexanes to obtain the title product (1.30 g, 43%) and an uncyclized by-product (0.60 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:29])[CH:4]=1.[CH3:30][NH:31][CH3:32]>CN(C)C(=O)C>[CH3:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:29])[CH:4]=1)[CH3:32]
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(CN(C)C)cc3C)c(=O)c2)nc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9d, 120 mg, 0.26 mmol) in N,N-dimethylacetamide (2 mL) is added dimethylamine (0.76 mmol, 2 M solution in THF). The reaction mixture is stirred for 4 h at 40° C. The mixture is purified via reverse phase HPLC chromatography (Waters XBridge 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:3]=1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33].[OH-].[Na+]>O1CCCC1.O.C(O)(=O)C>[Cl:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[N:4]1[C:5](=[O:7])[CH2:6][C:2]([NH:1][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])=[N:3]1
Reactant: NC1=NN(c2cc(Cl)ccc2Cl)C(=O)C1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: C=C(C)C(=O)NC1=NN(c2cc(Cl)ccc2Cl)C(=O)C1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
30 g (0.12 mol) of 3-amino-1-(2,5-dichlorophenyl)-2-pyrazolin-5-one was dissolved in 250 ml of tetrahydrofuran to which were added 21 ml (0.27 mol) of pyridine and 2.5 ml of nitrobenzene. To the mixture there was further added dropwise 28.2 g (0.27 mol) of methacryloyl chloride while cooling with ice and the mixture was stirred for about 30 minutes. After adding 250 ml of water, the mixture was extracted with ethyl acetate and the extract was dried with anhydrous sodium sulfate. After distilling off the solvent at from 20° C. to 30° C. under a reduced pressure, the residual oily product was dissolved in a mixture of 360 ml of water and 200 ml of ethanol, to which was then added dropwise an aqueous solution containing 14.8 g (0.37 mol) of sodium hydroxide dissolved in 50 ml of water at room temperature. After stirring for 30 minutes, acetic acid was added to the mixture for neutralization and the crystals thus deposited were collected by filtration. By recrystallization from acetonitrile, 19.5 g (52% yield) of Coupler Monomer (8) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.7 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-isopentyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-isopentyl-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[N:11][N:10]([CH:18]([CH3:20])[CH3:19])[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][C:38]=1[F:44].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>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:21])[N:10]([CH:18]([CH3:20])[CH3:19])[N:11]=2)=[O:17])=[CH:39][C:38]=1[F:44]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4nn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (500 mg, 2 mmol), 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (535 mg, 1.70 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (639 mg, 1.68 mmol) and N,N-diisopropylethylamine (279 uL, 1.60 mmol) in N,N-dimethylformamide (8 mL) was stirred at rt for 3 h. The solvent was removed and the residue dissolved in EtOAc and washed with saturated NaHCO3 solution water and brine. After drying over magnesium sulfate, solvent was evaporated and the product was purified by ISCO silica gel chromatography (hexane: EtOAc 1:4) to give 835 mg (83%), which triturated with ether and dried. mp=225-226° C.; LCMS m/z=590 (M+1); 1H NMR DMSO) δ: 10.87 (s, 1H), 8.49 (d, 1H, J=5.2 Hz), 7.97 (dd, 1H, J=12.6, 2.2 Hz), 7.59-7.36 (m, 8H), 6.50 (d, 1H, J=4.9 Hz), 4.90 (m, 1H), 3.95 (s, 6H), 3.32 (s, 3H), 1.38 (d, 6H, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(C)Nn1c(CO)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nn1c(CO)nc2c(N)nc3c(c21)CCCC3
Reaction time: 18 h

Procedure:
A mixture of [4-amino-1-(isopropylamino)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (0.120 g, 0.442 mmol) and platinum (IV) oxide (0.100 g, 0.422 mmol) in trifloroacetic acid (10 mL) was hydrogenated on a Parr apparatus at 50 psi (3.4×105 Pa) at room temperature for 18 hours. The mixture was diluted with chloroform (20 mL) and filtered through a pad of CELITE filter agent. The filter agent was rinsed with a 4:1 chloroform/methanol solution. The filtrate was concentrated under reduced pressure to yield an oil that was suspended in water (10 mL) and treated with 10% aqueous sodium hydroxide until pH 7 was reached. A white precipitate was isolated by filtration, rinsed with water, and dried overnight under vacuum to provide [4-amino-1-(isopropylamino)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methanol.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[S:34][CH:33]=[CH:32][C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]3)=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccsc23)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccsc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (68.8 mg, 0.515 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step 2, 45.4 mg, 0.188 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (58.8 mg, 0.169 mmol) in DCM (2.0 mL) was then added, followed by pyridine (123.7 mg, 1.564 mmol) and the mixture was stirred at room temperature for a further 2 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow oil (92.2 mg, 96%). LCMS calc. for C27H28F2N5O3S2 (M+H)+: m/z=572.2. found 572.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:12][C:11]1[CH:13]=[CH:14][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:15])=[CH:7][C:8]=1[O:9][CH3:10])[CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1ccc(/C=C/C(=O)OC)cc1OC
Yield: 91.7 %

Procedure:
4.16 g (20.0 mmol) ferulic acid methyl ester was dissolved in 115 ml 2-butanone. 2.09 ml (22.0 mmol) n-butyl bromide and 11.06 g (80 mmol) potassium carbonate were added. The reaction suspension was then heated at reflux temperature for 20 hours. The reaction mixture was filtered. The filtrate was concentrated by evaporation. The crude product was recrystallised from 42 ml isopropyl alcohol and yielded 4.85 g (92%) methyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][C:11]([CH3:18])=[CH:12][C:13](OCC)=[O:14].S(=O)(=O)(O)O.CCOCC>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:18])[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[CH3:8])[O:9][C:13](=[O:14])[CH2:12]1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CCOC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3,5-Dimethylphenol (IIa) (3.2 g, 26.2 mmol), ethyl 3,3-dimethylacrylate (5 mL, 36 mmol, 1.4 eq.) and concentrated sulfuric acid (1.5 mL) were dissolved in anhydrous benzene (30 mL), and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and washed successively with water (2×40 mL), 5% aqueous NaHCO3 solution (2×20 mL), brine (2×20 mL) and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under vacuum to obtain a dark brown gummy material. To this gummy material was added anhydrous ether (5 mL) and boiled for 2 min on a steam bath. The title compound, IIIa, (3.34 g, 16.4 mmol, Y: 62.4%) was crystallized out from the mixture upon cooling in an ice bath; mp, 95.8-96.3° C.; 1H-NMR (300 MHz, acetone-d6) δ ppm: 1.41 (6H, s, 4,4-Me2), 2.24 (3H, s, 5-Me), 2.46 (3H, s, 7-Me), 2.61 (2H, s, 3-H2), 6.68 (1H, s, Ar-H), 6.76 (1H, s, Ar-H); MS (Isobutane-DCI) m/e: 205 (M+H)+ ; IR (KBr) ν max: 1770, 1250, 1190, 870 cm-1.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1[C:12]([Cl:13])=[N:11][C:9](Cl)=[N:8][C:6]=1[Cl:7].Cl>C(OCC)C.C1(C)C=CC=CC=1>[Cl:7][C:6]1[N:5]=[C:12]([Cl:13])[N:11]=[C:9]([CH2:1][CH3:2])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1nc(Cl)nc(Cl)n1
Reaction time: 1 h
Yield: 63 %

Procedure:
1.5 equivalent of ethylmagnesium bromide dissolved in diethyl ether (prepared by reacting magnesium with ethyl bromide) are added dropwise to a suspension of one equivalent of cyanuric chloride in toluene, while keeping the temperature of the reaction mixture between 10° and 15° C. After the addition, this mixture is kept at room temperature for one hour. An aqueous solution containing 1.5 equivalent of hydrochloric acid is then added. The two phases are separated, the organic phase is dried over sodium sulfate, then the solvent is removed under reduced pressure. 2,4-dichloro-6-ethyl-1,3,5-triazine is purified by distillation under reduced pressure. Yield: 63%. B.P.: 83° C./17 mbars.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[NH:11][N:10]([CH2:20][CH2:21][CH2:22][OH:23])[N:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[NH:11][N:10]([CH2:20][CH2:21][CH2:22][O:23][C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)[N:9]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1cccc(C=NNC2=NN(CCCO)NC(N3CCOCC3)=C2)c1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: COc1cccc(NC(=O)OCCCN2N=C(NN=Cc3cccc(C)c3)C=C(N3CCOCC3)N2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-triazin-2-yl}-propan-1-ol (1 mmol) is dissolved in acetonitrile (4 mL). To the mixture is added m-methoxyphenylisocyanate (149 mg., 1 mmol) and a catalytic amount of dimethylaminopyridine. The reaction is stirred at 60° C. for 16 hours. The reaction is then cooled to 4° C., and the precipitate is filtered, washed with acetonitrile (1 mL) and dried to give Compound 103, (3-methoxy-phenyl)-carbamic acid 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-triazin-2-yl}-propyl ester.
Reaction SMILES: C1(=O)[N:5]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH:7]=[CH:8][CH2:9][N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11]1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/Cn1cnc2ncccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC=CCn1cnc2ncccc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
A solution of 1-[(E)-4-phthalimido-2-butenyl]-1H-imidazo[4,5-b]pyridine (2.19 g, 6.87 mmol) in ethanol (100 mL) at room temperature was treated with hydrazine monohydrate (3.33 mL, 68.7 mmol). After 10 min., the reaction mixture was warmed to 60° C. for 2 h, allowed to cool to 25° C., and recooled to 0° C. in an ice bath. The resulting slurry was filtered, and the filtrate was concentrated in vacuo. Purification by flash chromatography (6% NH4OH/ethanol) afforded 0.92 g of the title compound; mass (CI) m/z=211 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Product: COc1c(-c2ccc3c(c2)CC=C3CCS(N)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 63, Part A (26.5 mg, 0.051 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1 H) 7.86 (d, J=7.72 Hz, 2 H) 7.55-7.78 (m, 5 H) 7.50 (t, J=6.25 Hz, 1 H) 7.38 (d, J=2.57 Hz, 1 H) 7.16-7.21 (m, 1 H) 6.58 (s, 1 H) 5.69 (d, J=7.72 Hz, 1 H) 4.19 (d, J=4.78 Hz, 2 H) 3.48 (s, 2 H) 3.30 (s, 3 H) 2.96 (s, 3 H).
Reaction SMILES: C([Mg]Cl)(C)C.[NH2:6]/[C:7](=[N:9]\[O:10][C:11]([C:13]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=O)/[CH3:8]>C1COCC1>[F:23][C:22]1[C:13]([C:11]2[O:10][N:9]=[C:7]([CH3:8])[N:6]=2)=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cccc(F)c1C(=O)O/N=C(/C)N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1noc(-c2c(F)cccc2C(=O)O)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To THF (15 mL) was added 2 M i-PrMgCl in THF (2.2 mL, 4.47 mmol). This mixture was cooled to −78° C. and the product of Step B (1.09 g, 3.58 mmol) was added dropwise in THF (20 mL). The mixture was stirred for 30 min at −78° C. and then CO2 from a lecture bottle was bubbled into the solution for 3 h while allowing the temperature to slowly rise. When the temperature reached −20° C. the dry ice bath was replaced with an ice bath, bubbling of CO2 was ceased and the mixture was allowed to come to room temperature overnight. The mixture was quenched by the addition of H2O and a small amount of Et2O. The organic layer was washed 2× with 2N aq. NaOH and the combined aqueous layers were then washed 3× with Et2O. The aqueous layer was then acidified with concentrated HCl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product as a white solid (661 mg, 83%). MS (ESI) mass calculated for C10H7FN2O3, 222.04; m/z found, 223.0. 1H NMR (500 MHz, CDCl3): 7.96 (d, J=7.8, 1H), 7.72-7.64 (m, 1H), 7.50-7.44 (m, 1H), 2.56-2.48 (m, 3H).