Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: Cn1cnnc1S
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cn1cnnc1Sc1nccnc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to Example 1 by using 4-methyl-4H-1,2,4-triazole-3-thiol (230.5 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 4 hr.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O>[Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Cc1cnc(Cn2c(C)cc(O)c(Br)c2=O)cn1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To a mixture of 3-Bromo-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (0.45 g, 0.0015 mol), and potassium carbonate (0.25 g, 0.0018 mol) in dimethylacetamide (5.0 mL) was added 2,4 difluorobenzyl bromide (0.25 mL. 0.0019 mol)and stirred at room temperature under argon for 1 h. Dimethylacetamide was distilled in vacuo and the residue was partitioned between CH2Cl2 (20 mL) and water (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. The resulting material was purified by flash chromatography (EtOAc/hexane 4:1 v/v) as the eluent. The appropriate fractions (m/z=451/453) were combined and concentrated under reduced pressure to give a white (0.25 g, 38%)solid. 1H NMR (CD3OD/400 MHz) δ 8.49 (s, 1H), 8.40 (s, 1H), 7.60 (m, 1H), 6.99 (m, 2H), 6.51 (s, 1H), 5.42 (s, 2H), 5.29 (s, 2H), 2.54 (s, 3H), and 2.50 (s, 3H); 19F NMR (CD3OD/400 MHz) δ−117.70 (m), and −116.09 (m); ES-HRMS m/z 436.0439 (M+H C19H17N3O2BrF2 requires 436.0467).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(=O)c4ccccc4oc23)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)4acetylxanthen-9one (2.4 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%, the addition being performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized with methanol to give 1.9 g of product m.p. 134-36° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H); 1.72 (s, 3H); 3.84 (s, 3H); 4.71 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 6.95-6.98 (m, 1H); 7.05-7.15 (m, 2H); 7.08 (d, 1H, J=8.8 Hz); 7.09 (d, 1H, J=16 Hz); 7.23-7.42 (m, 4H); 7.65-7.72 (m, 1H); 8.32-8 (d, 1H. J=8.8 Hz); 8.42(d, 1H. J=8.9 Hz).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[N:28]3[C:23]([CH:24]=[CH:25][CH:26]=[C:27]3[CH3:29])=[C:22]([C:30]#[N:31])[CH:21]=2)[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[C:30]([C:22]1[CH:21]=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:11]2=[O:32])[N:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[CH3:29])#[N:31]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C#N)c3cccc(C)n23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C#N)c3cccc(C)n23)c2ccccc21
Reaction time: 12 h

Procedure:
To a solution of 3-[3-(1-Cyano-5-methyl-indolizin-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (30 mg, 0.067 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (3.2 mg, 0.14 mmol) at room temperature. The solution was stirred at the same temperature for 12 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that precipitate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product 1 (19 mg, 67%). LCMS (ESMS): m/z 417.28 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:8][NH:7]1.Cl[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18].[OH-].[Na+]>O1CCCC1.O>[CH2:20]([O:19][C:17]([N:7]1[CH2:8][C@H:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][C@H:6]1[CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:18])[CH:21]=[CH2:22]
Reactant: CS(=O)(=O)O[C@H]1CN[C@H](COCCO)C1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCO

Procedure:
To a solution of (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (30.5 g) in a mixture of tetrahydrofuran (120 ml) and water (120 ml) was dropwise added a solution of allyl chloroformate (14.5 ml) in tetrahydrofuran (14.5 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for one hour and extracted with ethyl acetate (200 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (400 g) and eluted with a mixture of methanol and dichloromethane (2:98 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (28.03 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH2:31]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(COc2cccc3c2CCNC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3c(cccc3OCc3ccccc3)C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A suspension of 0.098 g (0.00051 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 2 ml of dimethylformamide was treated with 0.21 ml (0.0015 mol) of triethylamine and 0.145 g (0.00061 mol) of 5-benzyloxy-1,2,3,4-tetrahydro-isoquinoline (WO 94/20459) and the mixture was stirred at room temperature under argon for 18 hours The solvent was distilled off in a high vacuum. The residue was partitioned between dichloro-methane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.153 g (84%) of 5-(5-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a yellowish oil. MS (ISP): me/e=361 (C22 H25N4O+).
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=23)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.C(O)=O.[H][H]>CN(C)C=O.[Pd]>[C:4]1(=[O:22])[N:5]([CH2:6][CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[C:1](=[O:27])[C:2]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]12
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CC1=c2ccccc2=Cc2ccccc2N1
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1Nc2ccccc2Cc2ccccc21
Temperature: 50 °C

Procedure:
A suspension of 110.0 kg of 6-phthalimidomethyl-5H-dibenz[b,e]azepine in 911.4 liters of dimethylformamide, 28.7 kg of formic acid and a suspension of 12.5 kg of 10% palladium charcoal in 25 liters of dimethylformamide is fed into a 1200 liter VA-propulsive jet loop reactor. The reaction mixture is heated to 70° C. and hydrogenated under 7 bar of absolute hydrogen pressure. After the catalyst has been filtered off and the reaction equipment and catalyst have been washed with 80 liters of dimethylformamide, 960 liters of dimethylformamide are distilled off from the combined filtrates at 70° to 80° C. After cooling to 50° C., 150 liters of acetone are added, then after further cooling to 15° C. the precipitated crystals are centrifuged off, washed with acetone and dried.
Reaction SMILES: [OH-].[K+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1)([CH3:5])[CH3:4].OC[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.[N+](C1C=CC(OC(=O)NC2C=CC(OC(C)C)=CC=2)=CC=1)([O-])=O>O>[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH2:33][CH2:36][CH2:37][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[O:15])=[CH:11][CH:12]=1)([CH3:5])[CH3:4]
Reactant: COc1ccc2c(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)ncnc2c1
Reactant: OCCCN1CCCCC1
Agent: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCN5CCCCC5)ccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
Solid KOH (112 mg, 2 mmol) was added to a mixture of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 82 mg, 0.2 mmol), prepared as described in Example 29, and 3-hydroxypropylpiperidine (0.25 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and diluted with water. The mixture was extracted with DCM and the organic layer was drawn off and washed with water thrice, with brine once, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3 mL of 3M HCl/MeOH and the mixture was stirred at rt for 2 h and then concentrated in vacuo. This was suspended in anhydrous MeOH (3 mL), and to it DIEA (1.75 mL, 0.6 mmol) was added followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (96 mg, 0.3 mmol), as prepared in Example 1a, and the mixture was stirred at rt overnight. It was then concentrated in vacuo and the residue was dissolved in DCM and washed extensively with water thrice and brine once and then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH4OH) to obtain 14 mg (13% overall yield from 29a) of pure 4-(7-(3-piperidin-1-yl-propoxy)-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.13 (s, 1H), 8.05 (d, 1H), 7.35-7.21 (m, 4H), 6.84 (d, 2H), 6.33 (s, 1H), 4.48 (m, 1H), 4.32-4.15 (m, 4H), 3.68 (m, 1H), 3.13 (m, 2H), 2.7-2.45 (m, 6H), 2.20-1.90 (m, 8H), 1.75-1.58 (m, 4H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 531.3, found 532.6 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.[C:22]1(OC)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>ClCCl>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])[C:4]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole was cooled to 0° C. and 112 ml of trifluoroacetic acid was added. The solution was stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue was dissolved in 70 ml of acetone and the solution was adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate was added over 1 hour at pH 6.5-7.5. The mixture was stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation was chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gave 2.19 g of compound. Crystallization from ether-hexane yielded 1.125 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:27]2[CH2:28][CH2:29][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:17])[CH2:25][CH2:26]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: Cc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)c2c(C)noc2-c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.100 g, 0.35 mmol), 1-(2-methylphenyl)piperazine (0.092 g, 0.52 mmol), and 1-hydroxybenzotriazole (0.096 g, 0.71 mmol) in 5:1 CH2Cl2:DMF was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.136 g, 0.71 mmol), and the reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and washed twice with H2O, once with brine, and then dried over Na2SO4, filtered, and concentrated to give the title compound, which was used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=12.[H-].[Na+].I[CH3:21]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH3:21])[C:6]=12
Reactant: Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)nn2c1N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-2-(pyridine-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-one (50 mg, 0.22 mmol) in DMF (5 mL) was added NaH (13 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and then iodomethane (47 mg, 0.33 mmol) was added and stirred at room temperature for 30 minutes. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layers were dried, filtered, concentrated in vacuo and re-crystallized from MeOH to give 3,4-dimethyl-2-(pyridine-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4 H)-one: MS (m/z): 243.1 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.55 (d, 1 H, J=4.0 Hz), 8.03 (d, 1 H, J=8.0 Hz), 7.54 (dd, 1 H, J=4.8 Hz, J=8.0 Hz), 4.35 (t, 2H, J=6.8 Hz), 3.50 (s, 3 H), 2.95 (t, 2 H, J=6.8 Hz), 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=1.[CH3:30][O:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[C:34]([O:41][CH3:42])[N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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:26]([C:4]1[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=[C:2]([C:37]2[C:32]([O:31][CH3:30])=[N:33][C:34]([O:41][CH3:42])=[CH:35][CH:36]=2)[CH:3]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(Br)cc(C(C)(C)C)c1OC
Reactant: COc1ccc(B(O)O)c(OC)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: ClCCl
Solvent: CO
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)nc2OC)cc(C(C)(C)C)c1OC
Yield: 79.2 %

Procedure:
step 1—A sealed tube containing 315 (117 mg, 0.243 mmol), 2,6-dimethoxy-pyridin-3-yl boronic acid (53 mg, 0.290 mmol, CASRN 221006-70-8), Pd(PPh3)4 (28 mg, 0.024 mmol), Na2CO3 (76 mg, 0.717 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave reactor at 115° C. for 30 minutes. The reaction mixture was concentrated, diluted with EtOAc, washed with brine and dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20% to 30% EtOAc) to afford 104 mg (79%) of N-(4-{(E)-2-[3-tert-butyl-5-(2,6-dimethoxy-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-3-methoxymethyl-phenyl) methanesulfonamide (322) as a colorless oil.
Reaction SMILES: COC1C=CC(C[N:8]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:23][C:17]=4[CH2:16]3)[CH:12]3[CH:10]([CH2:11]3)[C:9]2=[O:30])=CC=1.C1(OC)C(=CC=CC=1)OC.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[C:24]1([C:22]2[O:23][C:17]3[CH2:16][N:15]([C:13]4[CH:12]5[CH:10]([CH2:11]5)[C:9](=[O:30])[NH:8][N:14]=4)[CH2:20][CH2:19][C:18]=3[N:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2N=C(N3CCc4nc(-c5ccccc5)oc4C3)C3CC3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1OC
Product: O=C1NN=C(N2CCc3nc(-c4ccccc4)oc3C2)C2CC12

Procedure:
320 mg (0.75 mmol) 3-(4-methoxy-benzyl)-5-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one, 1 ml (7.84 mmol) Veratrol and 6 ml TFA are heated to 100° C. in a pressure vessel for 24 h. The cooled mixture is combined with sat. sodium carbonate solution and extracted with DCM, the org. phase is concentrated by rotary evaporation i. V. and the residue is purified by silica gel (eluant: DCM/methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[F:21][C:22]1[C:27](C(Cl)=O)=[CH:26][CH:25]=[CH:24][N:23]=1>C(#N)C>[F:21][C:22]1[C:27]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cccnc1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cccnc1F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Potassium 3-(ethoxy)-3-oxopropanoate (6.06 g, 35.6 mmol) was suspended in acetonitrile (100 mL), cooled to 0° C. and treated successively with triethylamine (4.96 mL, 35.6 mmol, 1 equiv) and anhydrous magnesium(II) chloride (3.39 g, 35.6 mmol, 1 equiv). The ice bath was removed and the mixture was warmed to ambient temperature and stirred for 2.5 hours. An acetonitrile (5 mL) solution of 2-fluoropyridine-3-carbonyl choride (5.68 g, 35.6 mmol) was added and the mixture was stirred for 72 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was concentrated from toluene (1×75 mL). The residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous). After 15 minutes, the mixture was warmed to ambient temperature and stirred for an additional 45 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH:15]=[CH2:16])[C:7]([OH:9])=[O:8])C=C>C(Cl)Cl.CCOC(C)=O.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:18][O:17][C:11]1[C:12]2[O:13][CH2:14][CH:15]=[CH:16][CH2:1][C:4]=2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1
Reactant: C=CCOc1c(CC=C)cc(C(=O)O)cc1OC
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)O)cc2c1OCC=CC2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of 3-allyl-4-allyloxy-5-methoxybenzoic acid (200 mg, 0.81 mmol) in CH2Cl2 (20 mL) at room temperature was added benzylidene-bis-(tricyclohexylphosphine)dichlororuthenium (Grubb's catalyst, 35 mg, 0.04 mmol, 0.05 eq.). After stirring for 2 h the reaction was diluted with EtOAc (150 mL) then extracted with 2.0 N NaOH (100 mL). Aqueous layer was treated with brine (100 mL) then acidified to pH 5 using 1.0 N HCl. The aqueous layer was then extracted with EtOAc (2×200 mL). The organic layer was dried over MgSO4 and then concentrated in vacuo to afford 9-methoxy-2,5-dihydrobenzo[b]oxepine-7-carboxylic acid (179 mg, 100%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:17][NH2:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([NH:18][CH3:17])=[O:7]
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3,4-dimethoxy-5-nitro-benzoyl chloride (0.50 g, 2.04 mmol) in dichloromethane (10 mL) at 0° C., was added dropwise methylamine (1.02 mL, 2.04 mmol, 2 M in THF). The reaction mixture was stirred at room temperature till all starting material disappeared, then diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to leave a crude residue that was recrystallised from a dichloromethane/isopropanol mixture to afford 3,4-dimethoxy-N-methyl-5-nitro-benzamide, 0.44 g (89%).