Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(Cl)Cl>CN(C)C=O.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (8.8 g, 0.05 mol) in dimethylformamide (25 mL) is added methyl 2-bromopropanoate (10.2 g, 0.06 mol) over 30 minutes and stirred at 80°-90° C. for 4 hours under nitrogen. The reaction is cooled to room temperature and methylene chloride (75 mL) and water (75 mL) are added. The organic phase is separated, washed with water (100 mL), dried and concentrated to give methyl 2-(4-acetylphenoxy)propanoate (8.5 g) (yield 76%). Methyl 2-(4-acetylphenoxy)propanoate (7.0 g, 31.5 mmol) is combined with 2N NaOH (20 mL) and refluxed overnight. Water (30 mL) is added to the reaction which is then washed with methylene chloride (50 mL). It is then acidified to pH=1 with concentrated hydrochloric acid and extracted with ethyl acetate (3×100 mL). The organic phase is dried and concentrated to provide 2-(4-acetylphenoxy)propanoic acid (5.0 g) (yield 92%): m.p. 104.3° C., IR (KBr) 3000 (br, vs), 2940 (br,s), 1754 (vs), 1650 (vs); 1H NMR (CDCl3) delta 1.69 (d, J=6.8 Hz, 3H), 2.55 (s, 3H), 4.8 (q, J=6.8 Hz, 1H), 6.92 and 7.93 (dd, J=9.0 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Product: Fc1cc(Br)ccc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Analogously to the synthesis described above (under Example 2.1 or 872.1), 250 g (1.31 mol) of 4-bromo-2-fluorophenol and 179 ml (1.51 mol) of benzyl bromide gave 366 g (97%) of 1-benzyloxy-4-bromo-2-fluorobenzene as colourless crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1>CS(C)=O>[Cl:21][C:16]1[CH:17]=[C:18]([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[CH:7]3)[N:19]=[C:14]([NH2:13])[N:15]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(Cl)cc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.1 %

Procedure:
Sodium hydride (1.0 g, 25 mmol) was suspended in dimethyl sulfoxide (40 ml) under nitrogen atmosphere, and 5-hydroxyindole (3.33 g, 25 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 20 minutes, 2-amino-4,6-dichloropyrimidine (3.28 g, 20 mmol) was added. The reaction mixture was heated at 100° C. and was stirred for 3 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and 10% aqueous ammonia solution. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:hexane=2:1). The crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (1.15 g, 4.41 mmol, 22.0%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:8][O:9][C:16]2[CH:15]=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=2[I:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1Br
Reactant: Oc1cc(Cl)ccc1I
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Clc1ccc(I)c(OCc2ncccc2Br)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
(3-Bromo-pyridin-2-yl)-methanol (3.4 g, 18 mmol), and 2-iodo-5-chlorophenol 4.5 g, 18 mmol), are dissolved in benzene (60 mL) and cooled to 0° C. To the solution is added tributylphosphine (15 mL, 90 mmol), and 1,1′-(azodicarbonyl) dipiperidine (ADDP) (6.6 g, 18 mmol) and the mixture is heated at 40° C. for 3 h. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 15% ethyl acetate/hexane) to yield 3.77 g (51%) of the title compound as a white solid. GCMS m/e 296, 298 [M-I]−.
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[CH2:2][CH2:3][C:4]([O:6]C)=[O:5].C[O-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH:14](=[C:3]([CH2:2][C:1]([OH:9])=[O:8])[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC(=Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
700 mmol of dimethyl succinate and then 20 ml of methanol are added to 290 mmol of sodium methylate dissolved in 80 ml of methanol. The mixture is brought to reflux, and 236 mmol of benzaldehyde are slowly added, followed by 20 ml of methanol. The mixture is maintained at reflux, with stirring, for one hour, and then 100 ml of methanol are distilled off. 120 ml of water and 120 ml of 10N sodium hydroxide solution are added to the concentrated reaction mixture. The removal of the methanol by distillation is continued. The residue is diluted with 150 ml of water. After the addition of dichloromethane, the diacid is precipitated by the slow addition of 12N hydrochloric acid. The diacid is filtered and washed with dicliloromethane and then with water. Drying yields the expected product.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([OH:35])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[C:47]([O:50][CH2:51]Br)(=[O:49])[CH3:48]>CC(C)=O.C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([O:35][CH2:51][O:50][C:47](=[O:49])[CH3:48])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate (85 mg, 0.154 mmol) and K2CO3 (42.7 mg, 0.309 mmol) in acetone (2.0 mL) was added bromomethyl acetate (21.2 μL, 0.216 mmol), and the reaction was stirred vigorously at 50° C. under N2 for 1 h. The reaction was cooled to room temperature, diluted with CH2Cl2 (10 mL), filtered, and treated with Celite®. The solvent was removed under reduced pressure and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→50% acetone/hexanes) to afford (3S,6S,7R,8S)-3-(3-(acetoxymethoxy)-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate (70 mg, 0.112 mmol, 73% yield) as a white powder: mp 58-64° C.; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.1 Hz, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.02-7.94 (m, 1H), 7.89-7.81 (m, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.56-7.43 (m, 2H), 7.40 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (dd, J=7.1, 1.2 Hz, 1H), 6.92 (d, J=5.4 Hz, 1H), 5.71 (d, J=6.5 Hz, 2H), 5.17-5.06 (m, 3H), 4.04 (dd, J=11.6, 7.4 Hz, 1H), 3.89 (s, 3H), 3.60 (d, J=4.2 Hz, 2H), 3.40 (dd, J=11.7, 7.1 Hz, 1H), 3.23 (dd, J=14.2, 3.1 Hz, 1H), 2.77-2.63 (m, 2H), 2.29 (ddt, J=12.2, 8.1, 3.9 Hz, 1H), 2.04 (s, 3H), 1.39 (d, J=5.6 Hz, 3H), 1.29 (dd, J=7.0, 3.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.38, 171.75, 170.27, 163.15, 160.19, 145.74, 143.97, 142.01, 134.75, 133.97, 131.96, 128.95, 127.78, 127.32, 125.99, 125.54, 125.38, 123.50, 109.70, 89.40, 74.18, 72.32, 71.93, 56.18, 51.77, 44.97, 34.38, 32.25, 20.85, 19.14, 19.07, 18.28; HRMS-ESI (m/z) [M+H]+ calcd for C33H39N2O10 expected, 623.2599. found, 623.2611.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([Cl:8])([Cl:7])=[CH2:6].Cl[C:10]([CH3:15])([CH:12]([CH3:14])[CH3:13])[CH3:11]>C(O)(=O)C>[Cl:7][C:5]([Cl:8])=[CH:6][C:10]([CH3:15])([CH3:11])[CH:12]([CH3:14])[CH3:13]
Reactant: C=C(Cl)Cl
Reactant: CC(C)C(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC(C)C(C)(C)C=C(Cl)Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
20 g of anhydrous, powdered aluminum chloride are added in portions to 2,040 g (21 mols) of vinylidene chloride at -10° C., in a dry apparatus equipped with a drying tube. 837 g (7 mols) of 2-chloro-2,3-dimethylbutane are then added dropwise in the temperature range from 0° to 10° C. The mixture is allowed to warm up to 20° C., and further aluminum chloride portions (a maximum of 20 g) are added, while cooling, until the reaction is no longer exothermic. The mixture is stirred for a further 4 hours at room temperature, the catalyst is deactivated by dropwise addition of 70 ml of acetic acid, and the mixture is filtered over sodium sulphate. The volatile constituents are separated from the sparingly volatile constituents by continuous-feed distillation under 1 mbar. The distillate is fractionated in a column. 824 g (65% of theory) of 1,1-dichloro-3,3,4-trimethyl-pent-1-ene of boiling point 60°-75° C./20 mbar are obtained. ##STR19##
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:56])[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1.C(O)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: [Pd]
Agent: CCCC[SnH](CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 17-Allyl-1-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (as prepared in Example 14) (100 mg) in toluene (5 ml) and acetic acid (0.01 ml) was added tetrakis(triphenylphosphine) palladium(0) (0.01 g). After 5 minutes tri n-butyltin hydride (0.04 g) was added and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the reaction mixture was extracted with ether. The ether extracts were dried (magnesium sulphate), filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with ether gave the title compound as a low melting solid (70 mg).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18]S(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:24]1[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
A suspension of 1 mmol methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester [33301-41-6], 1 mmol 3-hydroxy benzotrifluoride, 0.05 mmol tetrabutyl ammonium bromide and 4 mmol sodium hydroxide in a mixture of 5 ml toluene and 0.2 ml water was refluxed overnight. The reaction mixture was cooled, diluted with 20 ml of water and extracted 3 times with dichloromethane. The organic phase was dried, concentrated and the crude product purified by chromatography (methanol/dichloromethane). MS (m/e): 442.3 ([M+CH3COO−]−, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([NH:1][C:2]3[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCC3(CC2)OCCO3)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (5.0 g, 25 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (5.86 g, 37.8 mmol) in dichloroethane (50 mL) was added acetic acid (9.0 g, 150 mmol) and the reaction mixture stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (15.9 g, 752 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to afford the title compound (6.6 g, 76%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.Cl.[NH:14]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19]2)[CH2:15]1>C(N(CC)CC)C>[N:8]1([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15]3)=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: c1ccc2c(c1)COC21CCNC1
Reactant: Clc1ccc(-n2ccnc2)nn1
Agent: Cl
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)COC21CCN(c2ccc(-n3ccnc3)nn2)C1

Procedure:
The object product (195 mg, 61%) was obtained in the same manner as in Example 165 and using 3-chloro-6-(1H-imidazol-1-yl)pyridazine (180 mg), 3H-spiro[2-benzofuran-1,3′-pyrrolidine] hydrochloride (200 mg) obtained in Example 43(5) and triethylamine (0.42 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[N:4][CH:3]=1
Reactant: N#Cc1cccc(Cc2ncc(Cl)cc2C(=O)O)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(C#N)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-cyanobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.58 (1H, d, J=2.4 Hz), 8.05–8.02 (2H, m), 7.66 (1H, d, J=2.4 Hz), 7.50–7.27 (6H, m), 6.01 (1H, d, J=8.1 Hz), 5.32–5.23 (1H, m), 4.30 (2H, s), 3.93 (3H, s), 1.54 (3H, d, J=7.0 Hz); MS (ESI) m/z 432 (M−H)−.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2ccccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccccc2c1Nc1ccccc1C
Yield: 59.1 %

Procedure:
3-Butyryl-4-chloroquinoline (2.33 g, 10 mmol), 2-methylaniline (1.60 ml, 15 mmol) and dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The hydrochloride salt was filtered off, converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4-(2-methylphenylamino)quinoline (1.80 g), m.p. 107°-109°. PG,35
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:24]([O-])=O)=[C:7]([NH:9][S:10]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:8]=1.[H][H]>CN(C)C(=O)C.[Pt](=O)=O>[NH2:24][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][S:10]([C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COc1ccc([N+](=O)[O-])c(NS(=O)(=O)c2ccc(OCC(N)=O)cc2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(N)c(NS(=O)(=O)c2ccc(OCC(N)=O)cc2)c1
Yield: 93 %

Procedure:
2-(4-{[(5-methoxy-2-nitrophenyl)amino]sulfonyl}phenoxy)acetamide (Intermediate A60, 2.0 g, 0.0052 mol) was hydrogenated in N,N-dimethylacetamide with platinum(IV)oxide catalyst (0.2 g) until hydrogen uptake ceased. The catalyst was removed by filtration and the resulting mixture was concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate to give 1.7 g (93%) of the title compound, “amine sulfonamide”.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([C:12](=[O:24])[C@H:13]([OH:23])[C@@H:14]([OH:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.CN(C=O)C>CC(O)(C)C.CS(C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:3][CH2:2][O:23][C@H:13]([C@@H:14]([OH:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]2=[O:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)N(CCCl)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(F)cc2)C1=O
Yield: 27.5 %

Procedure:
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 59-4 (1.62 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 59-5 (400 mg) as a colorless amorphous solid.
Reaction SMILES: C([O:4][CH:5]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:6]#[C:7][CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])(=O)C.C(OC(COC1C=CC(F)=CC=1)CCCNS(C)(=O)=O)(=O)C.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54]CC)=[O:53].BrCC#CCCCC(OCC)=O>>[OH:4][CH:5]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:6]#[C:7][CH2:8][N:9]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([OH:54])=[O:53])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC(=O)OC(C#CCNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CCOC(=O)CCCC#CCBr
Product: CS(=O)(=O)N(CC#CC(O)COc1ccc(F)cc1)CCCCCCC(=O)O

Procedure:
This compound is prepared by the procedure described in Example 2, Step I, except that N-[4-acetoxy-5-(4-fluorophenoxy)- 2-pentynyl]methanesulfonamide is substituted for the N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamide and ethyl 7-bromoheptanoate is substituted for ethyl 7-bromo-5-heptynoate. The product is thus ethyl 7-{N-[4 -acetoxy-5-(4-fluorophenoxy)-2-pentynyl]methanesulfonamide} -heptanoate. The subsequent hydrolysis (Example 2, Step J) affords the subject compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([NH:5][OH:6])=[O:4].[CH2:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:15][CH3:16].C(N(C(C)C)C(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[OH:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H](Cc1ccccc1)C(=O)NO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(S(=O)(=O)N[C@H](Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 400 mg (−0.33 mmol) resin from stage 1.1 are added successively dry dichloromethane (2 ml), 4-dimethylaminopyridine (4 mg, 0.033 mmol), 4-propoxy-benzenesulfonyl chloride (309.8 mg, 1.32 mmol) dissolved in dry dichloromethane (1 ml), and N-ethyl-diisopropylamine (0.28 ml, 1.64 mmol). After shaking for 15 h at r.t. the suspension is filtered and the resin washed with dichloromethane (3×), alternating with DMA and H2O (2×), 0.2M aequous citric acid, alternating with DMA and H2O (2×), alternating with 2-propanol and THF (3×), and with dichloromethane (4×). The resin is dried under reduced pressur to provid polymer-bound (R)-N-hydroxy-3-phenyl-2-(4-propoxy-benzenesulfonylamino)-propionamide.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[CH3:35][NH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Product: CN[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (5)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 102.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.89 min, m/z=459.0 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:15]=2)[C:10]([CH3:35])=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:35][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=4)=[N:21][C:20]=3[CH3:34])=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH:9]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(C)cn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(C)cn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {3-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {3-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as off-white solid.