Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(SC)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].P(OCC)(OCC)OCC>CO>[C:1]([NH:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(NC(C)=O)(SC)c1ccccc1
Agent: CCOP(OCC)OCC
Solvent: CO
Product: COC(=O)C(NC(C)=O)c1ccccc1
Yield: 65.5 %

Procedure:
145 Milligrams of methyl α-acetylamino-α-methylthiophenylacetate was dissolved in 10 ml of methanol. To the solution 0.15 ml of triethyl phosphite was added, and the system was refluxed for 4.5 hours. Following a reduced pressure concentration, the residue was parted by a column chromatography (Florisil and methylene chloride) to provide 78 mg of methyl α-acetylaminophenylacetate. The yield was 65.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:4][C:3]=1[N+:22]([O-])=O>CCO>[NH2:22][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:2]=1[NH2:1])[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: Nc1ccc(OCCCN2C=Cc3ccccc3C2)cc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1ccc(OCCCN2CCc3ccccc3C2)cc1N
Yield: 97 %

Procedure:
From a mixture of N-[3-(4-amino-3-nitrophenoxy)propyl]isoquinoline (250 mg, 0.76 mmol) and stannous dihydrate (860 mg, 3.8 mmol) in EtOH (50 mL) was obtained 220 mg (97%) of N-[(3,4-diaminophenoxy)propyl]-1,2,3,4-tetrahydroisoquinoline as a yellow viscous oil. 1H NMR (CDCl3): 2.00-2.08 (m, 2H), 2.686 (t, 2H, J=7), 2.761 (t, 2H, J=5.5), 2.916 (t, 2H, J=5.5), 3.063 (s, 2H), 3.496 (s, 2H), 3.650 (s, 2H), 3.995 (t, 2H, J=7), 6.267 (dd, 1H, J=8.5; 2.5), 6.340 (d, 1H, J=2.5), 6.670 (d, 1H, J=8.5), 7.01-7.12 (m, 4H).
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=[NH:4].C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[O:14]=[C:11]1[NH:10][C:9]2[CH:15]=[C:5]([C:3]([NH2:4])=[NH:2])[CH:6]=[CH:7][C:8]=2[O:13][CH2:12]1
Reactant: N=C(NO)c1ccc2c(c1)NC(=O)CO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C

Procedure:
8.7 mmol of N-Hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine were dissolved in 25 ml acetic acid. 5 eq. of ammonium formiate and 0.05 eq. of Pd/C (10%) were added and the reaction mixture heated to reflux overnight. The reaction mixture was concentrated, cooled to 0° C. and the pH adjusted to 8 using aq. NaOH (28%). The resulting solid was filtered off and washed with water. MS(ISO): 192.2 (M−H+)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH3:13][O:14][CH2:15][CH2:16]Br>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:16][CH2:15][O:14][CH3:13])[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: COCCBr
Product: COCCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 80 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 2-bromoethyl methyl ether, the titled compound was obtained as a white solid. (Yield: 80%)
Reaction SMILES: [F:1][C:2]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[C:12]([O:24][CH3:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7](N)[CH:8]=[CH:9][CH:10]=1.N([O-])=O.[Na+].[ClH:30]>O.[Cu]Cl>[Cl:30][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[C:2]([F:1])=[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]=1[O:24][CH3:25]
Reactant: COc1ccc(Cc2ccc(F)cc2)c(F)c1Oc1cccc(N)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cc2ccc(F)cc2)c(F)c1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a 250 mL flask which contained the suspension of 3-[2-fluoro-3-(4-fluoro-benzyl)-6-methoxy-phenoxy]-phenylamine (P-02) (135 mg, 0.4 mmole) in aq HCl (12 N. 5 mL) was slowly added the solution of sodium nitrite (50 mg, 0.7 mmole) in water (3 mL) at 0° C. The mixture was allowed to stir at 0° C.-5° C. for 1 h, and then was cooled to 0° C. A solution of copper(I) chloride (55 mg, 0.4 mmol) in aq. HCl (12 N. 2 mL)) was added at 0° C. and the reaction mixture which resolved was allowed warm to rt and stir at rt for 1 h. The mixture was poured into 50 mL ice-water, extracted with ethyl acetate (3×30 mL), washed with water (2×30 mL), NaHCO3 (sat. 30 mL), brine (30 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by Prep TLC with ethyl acetate/Hexane as eluent to give 45 mg (33% yield) of product P-03.
Reaction SMILES: [C:1]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[N:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:32]1[N:33]=[C:34]([N:41]([C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][N:58]([CH:61]4[CH2:64][O:63][CH2:62]4)[CH2:57][CH2:56]3)=[CH:51][CH:50]=2)[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:35]2[N:36]([CH:38]=[CH:39][N:40]=2)[CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:24]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:9]1[N:10]=[C:11]([C:32]2[N:33]=[C:34]([N:41]([C:49]3[CH:54]=[CH:53][C:52]([N:55]4[CH2:56][CH2:57][N:58]([CH:61]5[CH2:62][O:63][CH2:64]5)[CH2:59][CH2:60]4)=[CH:51][CH:50]=3)[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:35]3[N:36]([CH:38]=[CH:39][N:40]=3)[CH:37]=2)[CH:12]=[N:13][CH:14]=1)=[O:25])([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)cc1)c1nc(Br)cn2ccnc12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Temperature: 110 °C
Yield: 90.8 %

Procedure:
The freshly formed N,N-BisBoc 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine XV (2.67 mmol based on 100% conversion, 2.0 equiv based on bromide) was dissolved in 20 Ml of 1,2-dimethoxyethane and to that solution was added tert-butyl (6-bromoimidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate IV (707 mg, 1.34 mmol, 1.0 equiv), Na2CO3 (283 mg, 2.67 mmol, 2.0 equiv), Pd(PPh3)4 (155 mg, 0.134 mmol, 0.1 equiv) and water (10 mL) and the solution was degassed for 5 min using N2 gas. The reaction was then placed under N2 atmosphere and heated at 110° C. for 90 min. LCMS showed complete consumption of the bromide starting material and the reaction was removed from heat and allowed to cool to RT. The reaction was diluted with 100 mL water and 100 mL 20% MeOH/DCM and the organic layer was recovered, extracted 1× sat. NaHCO3, 1× sat brine and then dried over Na2SO4. The solution was then filtered and concentrated down to an orange-red solid. The sample was then slurried in warm MeOH, sonicated then filtered, washing 2×20 mL with cold MeOH and then the cream-colored solid was dried on hi-vacuum overnight to yield 905 mg of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate XVI.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:30]2[C:35](=[O:36])[CH:34]3[CH2:37][C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([CH2:33]3)[C:31]2=[O:44])=CC=1.O>C(#N)C>[C:38]1([C:32]23[CH2:33][CH:34]([CH2:37]2)[C:35](=[O:36])[NH:30][C:31]3=[O:44])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(CN2C(=O)C3CC(c4ccccc4)(C3)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1NC(=O)C2(c3ccccc3)CC1C2
Reaction time: 1 h

Procedure:
A solution of 344 g of cerium(IV) ammonium nitrate in 1.1 1 of acetonitrile is added dropwise to a stirred solution of 53 g of 3-(4-methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 560 ml of acetonitrile at room temperature. After 1 hour, 515 ml of water are added and the mixture is stirred for 2 hours. It is concentrated to half the volume by distilling off the acetonitrile and is then diluted with 1 1 of water. The product which has precipitated is filtered off with suction, washed with water and dried in vacuo. The brown-yellowish crystalline substance is taken up in 800 ml of methylene chloride, 11 ml of n-propylamine are added and the mixture is left to stand overnight. The black solution is concentrated and 80 ml of methylene chloridediethyl ether (1:1) are added to the brown crystalline mass, and the crystals are filtered off with suction and dried under a high vacuum. The title compound is obtained as white crystals of m.p. 217-218° C.
Reaction SMILES: [F:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[CH3:4]>CO.[Pd]>[F:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(CF)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(CF)c1ccc(N)cc1

Procedure:
10.3 g (0.057 Mol) 4(1-fluoromethyl-ethyl)-nitrobenzene are dissolved in 250 ml absolute CH3OH and hydrogenated at room temperature and atmospheric pressure in the presence of 0.61 g 10% Pd/C.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>>[C:23](=[O:24])([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[C@@H:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C@H:7]1[CH3:14])[O:25][CH2:26][CH3:27]
Reactant: CC(O)CC(=O)C1C(C)C=CCC1(C)C
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)OC(C)CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 3-hydroxy-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (2.00 g, 84% pure, 8.0 mmol) in pyridine (1.85 g, 23.4 mmol) was treated at 0° C. with ethyl chloroformate (1.24 g, 23.4 mmol). The reaction solution was stirred at room temperature for 36 hours, treated with aqueous 5% HCl and extracted twice with ether, washed with water, saturated aqueous NaHCO3, then with saturated aqueous NaCl, dried over Na2SO4 and concentrated. The oil thus obtained was purified by flash-chromatography (cyclohexane/AcOEt=98:2), using SiO2 (100 g). Yield: 2.06 g (78%).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([O:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH2:29][N:20]1[CH2:19][CH:18]([O:30][S:2](=[O:4])(=[O:3])[OH:5])[CH2:17][O:16][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCOCC(O)CN1CCc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Product: CCCCCCCCCCOCC(CN1CCc2ccccc2C1)OS(=O)(=O)O

Procedure:
2-Decyloxymethyl-oxirane (1 equiv.), prepared according to Example 1 (except 1-decanol is substituted for 2-ethylhexanol), is dissolved in acetonitrile and warmed to 70° C. Stannic chloride (0.1 equiv.) is added to the reaction, which is maintained at 70° C. with stirring for 24-48 hours to give the oxazolidine. The reaction is cooled to from about 20° C. to about 25° C. and chlorosulfonic acid (1 equiv.) is added to the reaction at a temperature of from about 20° C. to about 25° C. to yield the product, through sulfation of the putative intermediate 1-Decyloxy-3-(3,4-dihydro-isoquinolin-2-yl)-propan-2-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=O)[CH:8]([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH2:9][CH3:10])=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:7]1[N:29]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:11][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(CC)OC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CC
Yield: 48.9 %

Procedure:
4-Trifluoromethyl-benzoic acid 3-ethoxycarbonyl-1-ethyl-2-oxo-propyl ester (25 mmol) is dissolved in acetic acid (100 mL) and dry ammonium acetate (10 g, 100 mmol) is added, then the reaction is heated under nitrogen to reflux. The reaction is monitored by TLC and HPLC but complete consumption of the starting material is never observed, and then allowed to cool. The cooled reaction is concentrated and diluted with 250 mL ethyl acetate. The residue is washed with 100 mL saturated sodium bicarbonate followed by water and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated and purified by column chromatrography. The fractions that contained pure product are concentrated to yield [5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (4.0 g, 12.22 mmol) or 50% yield.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O>[N:1]([N:11]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN(C1CCCCC1)C1CCCCC1
Temperature: 95 °C

Procedure:
A solution of 20.7 g of sodium nitrite in 60 ml of water is slowly added dropwise at RT to a mixture of 36.2 g of dicylohexylamine, 18 ml of conc. HCl and 300 ml of water. After this, the mixture is heated to 95° C. for 7 h. The nitro compound is extracted by shaking with ether. After drying over Na2SO4 and evaporating the ether, an oily residue remains which immediately crystallises.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]=1.N1C=CC=CC=1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]([NH:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:9]=1)=[O:5]
Reactant: COCC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with 2-methoxyacetyl chloride (6.6 mg, 0.061 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.056 mmol) in DCM (1 ml) and pyridine (0.045 ml, 0.557 mmol). The vial was capped and the contents stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (1 mL), MP-Trisamine (137 mg, 0.278 mmol) added, and the contents of the vial shaken at room temperature for 3 h. The resin was filtered, and washed through with DCM (1 mL). The volatiles were removed in vacuo to afford crude (R)-2-methoxy-N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide, which was taken forward without purification. MS ESI calc'd. For C37H35N6O3 [M+H]+ 611. found 611.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10](O)([CH3:12])[CH3:11]>C(OCC)(=O)C.C(O)(=O)C>[CH:10]([C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11]
Reactant: COc1cccc(C)c1C(C)(C)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(C)c1C(C)C
Yield: 98.9 %

Procedure:
A solution of 2-(2-methoxy-6-methylphenyl)-2-propanol (0.50 g, 2.77 mmol) in ethyl acetate-acetic acid (9:1, 10.0 mL) at room temperature was stirred under a H2 atmosphere for 16 h. The mixture was filtered through a Celite plug and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and washed with water. The organic layer was dried MgSO4, filtered and concentrated under reduced pressure to afford 2-iso-propyl-3-methylanisole (0.45 g, 100%) as colorless oil, which was used for the next step without further purification: 1H NMR (300 MHz, DMSO-d6): δ 7.01 (dd, J=12.0 Hz, 11.7 Hz, 1H), 6.78 (d, J=12.0 Hz, 1H), 6.70 (d, J=11.7 Hz, 1H), 3.74 (s, 3H), 3.28 (m, 1H), 2.26 (s, 3H), 1.24 (d, J=10.8 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:4]([CH:3]=1)[C:10]([OH:9])=[O:11]
Reactant: Oc1ccc(F)cc1
Reactant: O=C1OCc2ncc(Cl)cc21
Product: O=C(O)c1cc(Cl)cnc1COc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 3-chlorofuro[3,4-b]pyridin-5 (7H)-one (step 1 of Example 18) and 4-fluorophenol:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:9])=[CH:6][C:5]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:4][N:3]=1.O.[NH3:28]>C(O)(C)C>[NH2:28][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:9])=[CH:6][C:5]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:4][N:3]=1
Reactant: COc1cc(C(=O)c2cc(-c3nccs3)cnc2Cl)cc(OC)c1OC
Reactant: N
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)c2cc(-c3nccs3)cnc2N)cc(OC)c1OC
Yield: 38.84 %

Procedure:
(2-Chloro-5-(thiazol-2-yl)pyridin-3-yl)(3,4,5-trimethoxyphenyl)methanone (65 mg, 0.16 mmol) as a starting material was dissolved in isopropyl alcohol (3 ml), and ammonia water (10 ml) was added thereto. The mixture was heated for 3 hours in a Steel Bomb. After completion of the reaction, the reaction mixture was vacuum concentrated, and extracted with dichloromethane (30 ml) and water (10 ml). The organic layer was washed with brine, and dried over anhydrous MgSO4. The solid substance filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/1) to obtain a desired yellow solid compound (24.0 mg, 38.84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][NH:12][N:13]=1.[CH3:14][C:15](O)([CH3:17])[CH3:16].S(=O)(=O)(O)O.[OH-].[K+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:14][C:15]([N:13]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:10][NH:11][NH:12]1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)O
Reactant: COc1ccccc1-c1nn[nH]n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1=NNNN1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 5-(2-methoxyphenyl)-2H-tetrazole (0.83 g, 4.71 mmol), 2-methyl-2-propanol (0.7 g, 9.4 mmol), and sulfuric acid (0.24 g, 2.4 mmol) in 4.6 mL of TFA was stirred under nitrogen at room temperature for 16 hours. The reaction mixture then was diluted with ethyl acetate, pouredinto 2M potassium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated. Purification of the residue by column chromatography on silica gel (elution: 10% ethyl acetate/hexane) gave 1-(1,1-dimethylethyl)-5-(2-methoxyphenyl)-2H-tetrazole (0.5102 g, 1.67 mmol), as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.Br[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: BrCC1CCCCO1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.45 mL), potassium carbonate (0.60 g) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 48%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([O:16]C)=[O:15])=[C:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:6]2=[O:26])[CH3:2].[OH-].[Na+].Cl>CC(C)=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:6]2=[O:26])[CH3:2]
Reactant: CCc1cc2c(=O)c(-c3ccc(OC)cc3)c(C(=O)OC)oc2cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1cc2c(=O)c(-c3ccc(OC)cc3)c(C(=O)O)oc2cc1O
Temperature: 25 °C

Procedure:
Methyl 6-ethyl-7-hydroxy-3-(4-methoxyphenyl)-4-oxo-chromene-2-carboxylate (13.6 g, 41.73 mmol) was dissolved in acetone (200 ml). Then a 2N aqueous solution of Sodium hydroxide (62.59 ml, 125.19 mmol) was added at room temperature. The resulting mixture was stirred at room temperature over night. After the reaction was complete the mixture was acidified under cooling with concentrated hydrochloric acid to pH 2.5. A solid precipitated from the solution. The solid was filtered off, washed with water and diethyl ether and dried at 40° C. under vacuum to yield the title product as an off white solid (11.2 g quantitative). The material was used directly without further purification in the next step. Mass Spectrum: (M+H+) 341.25, (M+H−) 339.19.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)CN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CC(C)C)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 7.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-isobutyl-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.5 mg) was obtained.