Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([C:25](=[CH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:31][CH:25]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Reactant: NCCCCNC(=O)OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CNCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A mixture of 20 g of 4-benzyloxycarbonylamino-1-butylamine, 21.04 g of ethyl α-(phenethyl)acrylate and 200 ml of ethanol was stirred at room temperature for 8 days and evaporated to dryness. The residue was dissolved in ethyl ether and the solution was extracted three times with 100 ml of 2N hydrochloric acid. The aqueous layer was basified with 2N sodium hydroxide and extracted three times with methylene chloride, dried over magnesium sulfate and evaporated to give the ethyl 2-(4-benzyloxycarbonylaminobutyl)aminomethyl-4-phenylbutyrate having signals in the NMR spectrum at δ=7.4, 7.25, and 5.1 ppm.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][N:14]=[C:13]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=1)([CH3:38])[CH3:37]>CN(C=O)C.[Cu]I.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>[CH:36]([O:39][C:40]1[N:41]=[C:42]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:15][N:14]=[C:13]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)[N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1)([CH3:38])[CH3:37]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Reactant: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cccc(OC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.8 g, 1.29 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (0.83 g, 1.95 mmol) in DMF (8 mL) was bubbled with Argon for 15 min. To the above mixture was added CuI (0.124 g, 0.65 mmol) and Pd(PPh3)4 (0.15 g, 0.13 mmol) and argon gas was purged for another 15 min. The reaction was heated at 90° C. for 1 h. The mixture was treated with ice cold water (20 mL) to obtain off white precipitate. The precipitate was filtered, washed with H2O (20 mL) and dried. The solid was purified by basic alumina chromatography (eluent: 20% EtOAc in petroleum ether) to give 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.35 g, 43%) as a white solid. MS (ESI, pos. ion) m/z: 625.2 (M+1); 1H-NMR (400 MHz, CDCl3): δ 9.02 (d, J=1.2 Hz, 1H), 8.10-8.08 (m, 2H), 7.96 (dd, J=8.8, 2.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.64 (t, J=8.0 Hz, 1H), 7.34-7.24 (m, 2H) 4.62 (d, J=5.6 Hz, 2H), 3.80 (s, 3H), 2.35 (s, 3H), 1.46 (d, J=5.6 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[O:13][CH2:12][C@H:11]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[CH2:29](N(CC)CC)[CH3:30].C(O)(=O)C>O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C@H:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][C:29]([CH3:30])=[N:2][C:3]=4[CH:4]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH2:12][O:13]2)=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc(O)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc2oc(C)nc2c1
Temperature: 25 °C

Procedure:
To a stirred mixture of (±)-cis4-(3-amino-4-hydroxyphenyl)-7-methoxy-3-(4-methylphenyl)-chromane hydrochloride (0.475 g, 1.19 mmol), triethylamine (0.173 ml, 1.25 mmol) and acetic acid (15 ml) was heated to gentle reflux for 18 h., giving a deep red coloured mixture. This was cooled to room temperature, poured into water (100 ml) and the product extracted into ethyl acetate (2×100 ml). The combined extracts were washed with water (6×50 ml), brine, dried over magnesium sulfate and evaporated to give a dark gum. This was purified by column chromatography on silica gel 60, with a 1:1 petrol/ethyl acetate eluent. This gave the product, on vacuum drying, as a stable pale pink coloured foam.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:37])=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][C:32]([CH3:37])=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (190 mg, 0.50 mmol), (prepared as described for the starting material in Example 4), 5-hydroxy-2-methylindole (81 mg, 0.55 mmol), (WO 00/47212, Example 48), and potassium carbonate (76 mg, 0.55 mmol) in DMA (6 ml) was stirred at 85° C. for 3 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) to give a white solid. This was triturated with a mixture of ether and acetone, filtered and dried to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (130 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Reaction time: 8 h
Yield: 38 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with pyridine-2-carbonyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred overnight. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (15 mg, 37%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[NH:7][O:8][C:4]=2[C:3]=1[F:12].O=P(Cl)(Cl)[Cl:15]>CCOCC>[Cl:15][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([F:12])[C:4]=2[O:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]oc2c(F)c(F)ccc12
Solvent: CCOCC
Product: Fc1ccc2c(Cl)noc2c1F
Temperature: 140 °C
Yield: 74 %

Procedure:
TEA (5.6 ml, 40.2 mmol) was added to an ice bath cooled mixture of 6,7-difluoro-1,2-benzisoxazol-3(2H)-one (Intermediate 528, 6.88 g, 40.2 mmol) and POCl3 (13.1 ml, 141 mmol) (exotherm results) in a microwave reactor vessel and the mixture was heated at 140° C. for 6 hours in a microwave reactor. The mixture was taken up in ether and washed with Na2CO3 (2×) and brine. The combined aqueous layers were twice more extracted with ether, which was washed with Na2CO3 and brine. The combined ether layers were dried (MgSO4) and concentrated to give an oil that slowly solidified. The material was chromatographed on silica gel (hexanes followed by gradient elution to 50% CH2Cl2 in hexanes) to afford 5.64 g of product as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[OH-:14].[Na+].OO>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]([NH2:11])=[O:14]
Reactant: [OH-]
Reactant: CC(C)(C#N)c1c(F)cccc1F
Agent: OO
Agent: [Na+]
Product: CC(C)(C(N)=O)c1c(F)cccc1F

Procedure:
Hydrolysis of 2-(2,6-difluorophenyl)-2-methylpropionitrile was performed according to the procedure of Example 10 using sodium hydroxide in the presence of hydrogen peroxide to provide 2-(2,6-difluorophenyl)isobutyramide [1H-NMR (CDCl3): δ 7.34-7.29 (m, 1H), 6.91-6.85 (m, 2H), 6.43 (br s, 1H), 5.73 (br s, 1H), 1.68-1.66 (m, 6H)].
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:17])[CH2:13][CH2:14][CH2:15][CH3:16]>O1CCOCC1>[NH2:11][C:4]1[N:3]=[C:2]([NH:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=1
Reactant: CCCCCN
Reactant: CCc1c(C)nc(N)nc1Cl
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CC
Reaction time: 17 h
Yield: 58.1 %

Procedure:
A mixture of 4-chloro-5-ethyl-6-methylpyrimidine-2-ylamine (400 mg,33 mmol), amylamine (1.35 ml) and dioxane (5 ml) was kept at 95-100° C. for 17 hours. The procedure according to pro-treatment of Example 23 was carried out to give the object compound (301 mg, 58.1%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:13][CH:14]([CH2:18][CH2:19][Br:20])[C:15](Cl)=[O:16]>C(OCC)C.O>[Br:13][CH:14]([CH2:18][CH2:19][Br:20])[C:15]([NH:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=1)=[O:16]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Solvent: O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of (4-(trifluoromethyl)phenyl)methanamine (3 g, 17 mmol) in diethyl ether (60 mL) under nitrogen at 0° C. was added 2,4-dibromobutanoyl chloride (2.3 mL, 17 mmol) and the reaction mixture was stirred for 1 h at rt. The mixture was then diluted with water and extracted with 200 mL of ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to afford 2,4-dibromo-N-(4-(trifluoromethyl)benzyl)-butanamide (6.5 g, 87%). LCMS (method F) RT 2.01 min, m/z 434.8, 483.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.47 (m, 2H) 3.50-3.67 (m, 2H) 4.41 (dd, J=13.05, 6.02 Hz, 2H) 4.59-4.64 (m, 1H) 7.49 (d, J=7.53 Hz, 2H) 7.71 (d, J=8.03 Hz, 2H) 9.06 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:12])=[C:6]([O:20][CH3:21])[CH:5]=1.O.O.[OH-].[Li+]>CO>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)=[O:12])[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnccn2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnccn1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
To a stirred suspension of 3-methoxy-4-(3-pyrazin-2-yl-ureido)-benzoic acid methyl ester (6.07 g, 20 mmol) in 200 mL 3:1 MeOH:H2O at room temperature under nitrogen was added lithium hydroxide monohydrate (8.4 g, 200 mmol) and the reaction heated to 65° C. overnight. The reaction was then cooled to room temperature and most of the methanol removed by rotary evaporation. The remaining suspension was neutralized to pH about 4 with concentrated HCl. The formed precipitate was isolated by filtration and rinsing with H2O and then drying under high vacuum to give the desired acid as a white solid (5.34 g, 93%).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:4]=2[CH2:3][CH2:2]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CC(C)=O>[C:21]1([C:19]2[C:10]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[C:5]3[N:6]([CH:18]=2)[CH:7]=[CH:8][C:9]2[O:1][CH2:2][CH2:3][C:4]3=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)NCCCc1nccc2c1CCO2
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)NCCc1c(-c2ccccc2)cn2ccc3c(c12)CCO3
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A mixture of N-[3-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)propyl]acetamide (24.5 mg, 0.111 mmol) and 2-bromo-1-phenylethanone (44.2 mg, 0.222 mmol) in acetone (3 mL) was heated under reflux for 13 hr. The reaction mixture was allowed to cool to room temperature and the resulting crystals were collected by filtration and washed with acetone. The crystals were dissolved in ethanol (3 mL), sodium hydrogen carbonate (50 mg) was added, and the mixture was heated under reflux for 1 hr. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/50) to give the title compound (12.7 mg, yield 36%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:7].[F:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:27][C@@H:28]1[CH2:31][CH2:30][NH:29]1>>[F:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:27][C@@H:28]1[CH2:31][CH2:30][N:29]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:7]
Reactant: Cc1ccc(C[C@@H]2CCN2)cc1F
Reactant: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Product: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CC[C@H]1Cc1ccc(C)c(F)c1
Yield: 46 %

Procedure:
By using ethyl (4E)-5-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)pent-4-enoate which had been obtained in Example 13 (13a) and (2R)-2-(3-fluoro-4-methylbenzyl)azetidine which had been obtained in Example 14 (14e), the reaction was carried out in the same manner as the method described in Example 1 (1f) to give the title compound as a colorless oily substance (yield 46%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=1.01 min; [M+H]+=426.06.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[O:9]>[Ag]=O.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:8]([OH:1])=[O:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (12g.; 0.3m) was dissolved in 200 ml. of water, silver oxide (11.6g.; 0.05m) added and the resulting mixture warmed to 50° C, 3-methoxy-4-benzyloxybenzaldehyde (12.1g; 0.05m) added in one portion and the mixture heated to 60° C with stirring for 1 hour, stirred 18 hours at room temperature, filtered and acidified to give the acid which was recrystallised from glacial acetic acid, m.p. 172°-3° C.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#[N:12])=[C:5]([CH3:13])[CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#[N:12])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1cc(C)c(CC#N)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(CC#N)c(C)cc1O
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of (4-methoxy-2,5-dimethylphenyl)acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 ml) was cooled to −80° C. and treated with a solution of boron tribromide in dichloromethane (14.3 ml of a 1M solution, 14.3 mmol). The reaction mixture was stirred at −80° C. for a further 30 minutes and then gradually allowed to warm to room temperature over a period of 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 ml) and the organic phase separated. The organic phase was washed with saturated aqueous sodium chloride (20 ml), dried (sodium sulfate) and the solvent removed in vacuo to give a pale brown solid. Purification by column chromatography on silica gel eluting with ethyl acetate:pentane (1:4 changing to 1:2) gave the title compound as a colourless solid (0.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:30][C:31]#[CH:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:32][C:31]#[CH:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 63 %

Procedure:
Six hundred milligrams (600 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.57 mmol), 0.14 g (1.89 mmol) of 3-chloropropyne, 280 mg (2.05 mmol) of potassium carbonate and 10 ml of anhydrous N,N-dimethylformamide were mixed and stirred at room temperature. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 415 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1196).
Reaction SMILES: [Li+].[OH-].C1COCC1.O.C([O:11][C:12]([C:14]1[S:18][C:17]([NH:19][C:20](=[O:46])[C@@H:21]([NH:29][C:30](=[O:45])/[CH:31]=[CH:32]/[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[N:40]2[CH:44]=[N:43][N:42]=[N:41]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:16][CH:15]=1)=[O:13])C.ClCl>>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([N:40]2[CH:44]=[N:43][N:42]=[N:41]2)=[C:33](/[CH:32]=[CH:31]/[C:30]([NH:29][C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20]([NH:19][C:17]2[S:18][C:14]([C:12]([OH:13])=[O:11])=[CH:15][N:16]=2)=[O:46])=[O:45])[CH:38]=1
Reactant: CCOC(=O)c1cnc(NC(=O)[C@H](Cc2ccccc2)NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)s1
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/c1cc(Cl)ccc1-n1cnnn1)N[C@@H](Cc1ccccc1)C(=O)Nc1ncc(C(=O)O)s1

Procedure:
LiOH/THF/water hydrolysis of 2-{(S)-2-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-3-phenyl-propionylamino}-thiazole-5-carboxylic acid ethyl ester (Example 19) afforded Example 21. HPLC purity: >98%. LCMS m/z 524.2 (M+H, chlorine isotope). 1H NMR (400 MHz, CD3OD) δ: 9.48 (s, 1H), 8.02 (s, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.68 (dd, J=2.3 & 9.2 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.31-7.19 (m, 5H), 7.10 (d, J=15.7 Hz, 1H), 6.75 (d, J=15.6 Hz, 1H), 4.9 (t, 1H), 3.30 (m, 1H), 3.11 (m, 1H) ppm. Analytical HPLC RT: 5.48 min (Method C, 8 min gradient).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([CH3:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]>COCCO>[CH3:1][C:2]1([CH3:28])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:3][CH2:10][O:12][CH3:13])[C@H:3]1[C:10]([O:12][C@H:13]([CH3:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)=[O:11]
Reactant: C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C)c1cccc(Oc2ccccc2)c1
Solvent: COCCO
Product: COCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
The product of Step C was reacted with 2-methoxyethanol to obtain (R)α-methyl-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-methoxyethoxy)-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]([CH:26]=1)=[N:23][O:24][N:25]=2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[C:22]([CH:26]=2)=[N:23][O:24][N:25]=3)[N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nn2cncn2)cc1
Reactant: BrCc1ccc2nonc2c1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc3nonc3c2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-nitrophenyl)amino]-1H-1,2,4-triazole and 5-bromomethylbenzofurazan
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][C@H:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:19][C@H:20]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:24][CH:23]=2)[CH3:21])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)nicotinic acid and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (step 3): 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.14 (1H, br.s), 8.13 (1H, d, J=2.7 Hz), 7.95 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.17–7.11 (4H, m), 5.36 (1H, dq, J=7.2, 7.0 Hz), 1.59 (3H, d, J=7.0 Hz), 1.58 (9H, s); MS (ESI) m/z 415 (M+H)+.