Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH:18]([CH2:39][C:40]([O:42]CC)=[O:41])[S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH:18]([CH2:39][C:40]([OH:42])=[O:41])[S:17]2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)CC1SC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N(CCCN(C)CCOc2ccc3c(c2)OCO3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(CCCN1C(=O)C(CC(=O)O)SC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
In ethanol (5 ml) was dissolved 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-5-ethoxycarbonylmethyl-1,3thiazolidin-4-one (100 mg) prepared in Example 46, and a solution of sodium hydroxide (200 mg) in 20% water-containing ethanol was added, then the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. To the residue was added a mixture of water (50 ml) and chloroform (50 ml), and the mixture was stirred. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with n-hexane to afford 80 mg (84%) of the title compound as a pale yellow solid. NMR (CDCl3) (200 MHz) δ: 1.41 (18/2H, s), 1.42 (18/2H, s), 1.4-2.4 (2H, m), 2.85 (3/2H, s), 2.90 (3/2H, s), 2.7-3.8 (8H, m), 4.1-4.7 (3H, m), 5.2-5.4 (1H, m), 5.66 (1/2H, brs), 5.81 (1/2H, brs), 5.89 (2H, s), 6.2-6.7 (3H, m), 7.13 (2/2H, s), 7.14 (2/2H, s)
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1cccc(-c2ccccc2)n1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3cccc(-c4ccccc4)n3)CC2)cc1
Yield: 22.7 %

Procedure:
A mixture of 12.77 g (37.5 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 7.13 g (37.6 mmol) of 2-chloro-6-phenylpyridine, 8 g (58 mmol) of K2CO3 and 145 ml of absolute DMF were refluxed for 24 hours with stirring. The DMF was then removed by distillation in vacuo. CH2Cl2 /water was added to the residue, the mixture was shaken thoroughly, the phases were separated, and the aqueous solution was extracted repeatedly with CH2Cl2. After drying and filtering, the combined CH2Cl2 extracts were evaporated. The residue was taken up in ethyl acetate, whereupon a crystalline precipitate was produced, which was filtered off under suction. This solid (4.89 g) was a byproduct, to be precise 1-(4-hydroxyphenyl)-4-formylpiperazine. The ethyl acetate solution (filtrate) was evaporated, and the residue remaining (12 g) was chromatographed on a silica gel/CH2Cl2 /petroleum ether 1:2 column (diameter 2.2 cm, height 44 cm). Elution was effected using CH2Cl2 /petroleum ether 1:2, 1:1 and 2:1 mixtures, with CH2Cl2, and with CH2Cl2 /C2H5OH mixtures (0.5-2.0% by volume of C2H5OH). After preliminary fractions, 2.82 g (=22.7% yield) of 1-(4-hydroxyphenyl)-4-(6-phenylpyrid-2-yl)piperazine were obtained as a highly viscous oil;
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:8]([CH3:26])([CH3:25])[O:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([NH2:24])[CH:11]=2>N1C=CC=CC=1>[F:6][C:7]1[C:8]([CH3:26])([CH3:25])[O:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[CH:14][CH:13]=[C:12]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=2
Reactant: CC1(C)Oc2cc(N)ccc2C(c2ccc(F)cc2)=C1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2C(c2ccc(F)cc2)=C1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (4 mL) and Methanesulfonyl chloride (60 μL) were added dropwise to a solution of [3-fluoro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 7(7), 105 mg) in pyridine (4 mL) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, the residue was diluted with ethyl acetate, and the solution was washed successively with a saturated aqueous solution of citric acid, water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was filtered through a column of porous diatomite (Chem Elut), and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (105 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.C([BH3-])#N.[Na+]>CO>[N:21]1([CH:2]([CH3:4])[CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2=C(CC(C)N3CCCCC3)C(=O)NCCC2)c1
Reaction time: 24 h

Procedure:
The solution of 8.0 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 14.95 g of piperidine, 6.6 ml of 5 N methanolic hydrogen chloride and 1.9 g of sodium cyanoborohydride in 120 ml of methanol is refluxed overnight. An additional portion of 0.95 g of sodium cyanoborohydride is added and refluxing continued for 24 hours. The mixture is cooled to 0°, 30 ml of concentrated hydrochloric acid are added and the solution concentrated. The concentrate is diluted with 100 ml of water, the solution washed with benzene and rendered basic with 70 ml of 3 N aqueous sodium hydroxide. It is extracted with diethyl ether, the extract evaporated and the residue crystallized from petroleum ether and hexane, to yield the 3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone of the formula ##STR7## melting at 97° to 99°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: COC(=O)C(C)(C)NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (100.3 mg, 0.268 mmol) and methyl 2-amino-2-methylpropanoate hydrochloride (41 mg, 0.268 mmol) according to Reference R and the general procedure for reductive amination to give methyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)benzylamino)-2-methylpropanoate as a yellow-orange oil. MS (ESI) m/z: Calculated: 475.2; Observed: 476.1 (M++1).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=O)[CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]12([CH2:11][NH:12][CH2:13][CH2:14][S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(CSc1ccccc1)NCC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(SCCNCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of Example 68A in THF (5 mL)was treated with 1M LAH in THF (20 mL, 20.0 mmol), heated to reflux, stirred for 24 hours, cooled to room temperature, treated sequentially with water (0.8 mL), 15% NaOH (0.8 mL), and water (2.4 mL), stirred for 30 minutes, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-100% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2ncccc2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc2ncccc2c1
Yield: 85.6 %

Procedure:
A solution of 2.50 g (15.7 mmol, Aldrich) of 6-methoxyquinoline in 10 ml of 48% aqueous HBr was refluxed for 24 hours. The reaction mixture was cooled, added slowly to a 150 ml stirred solution of saturated aqueous sodium bicarbonate and then extracted with two 100 ml portions of ethyl acetate. The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give a solid. The crude material was recrystallized (EtOAc/petroleum ether) to afford 1.95 g (84%) of title compound as white crystals, m.p. 194°-195°.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=1.O=S(Cl)[Cl:23].C(OC(=O)C)C>C(Cl)Cl.CCCCCC>[F:6][C:7]([F:20])([F:19])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([Cl:23])=[O:17])=[CH:10][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
DMF (0.3 mL) was added to a solution of 3-(4-trifluoromethyl-phenyl)-acrylic acid (I-29a: 4 g, 0.018 mol) in DCM (30 mL). The reaction mixture was stirred at 0° C. under nitrogen atmosphere. This was followed by the addition of SOCl2 (2.62 g, 0.022 mol) and the resulting mixture was refluxed at 75° C. for 3 hours. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was cooled to room temperature and concentrated to afford the crude product which was dissolved in 1,4-dioxane and used in the next step without further purification.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH2:25][CH3:26])[N:21]=3)=[O:18])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>C1COCC1.CO>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH2:25][CH3:26])[N:21]=3)=[O:18])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO)c2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A solution of 3-{[4-(azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzamide (246 mg, 0.504 mmol) and triethylamine (0.42 mL, 3.02 mmol) in THF (6 mL) and methanol (6 mL) was evacuated and purged with argon (×3). Palladium on carbon (10% w/w, 52 mg) was added and reaction mixture was evacuated and finally filled with hydrogen gas. The reaction mixture was left to stir at ambient temperature under hydrogen for 2 hours. The Pd/C was filtered off and mixture partitioned between ethyl acetate and 1M hydrochloric acid solution. The organic phase was dried (MgSO4) and the filtrate concentrated in vacuo to give the product (170 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[Li+].[Br-].Br[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>COCCOC.CN(C=O)C.C1COCC1.CCCCCC.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: COc1ccc2c(OCCBr)ccnc2c1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
In a 2-L RBF, a mixture of 5-bromopyridin-2(1H)-one (30 g, 172 mmol) in DME (250 mL) and DMF (70 mL) was purged with nitrogen and cooled in an ice bath. NaH (60% dispersion, 8.0 g, 200 mmol) was added in small portions to the mixture (over 2 h), resulting in a yellow suspension. LiBr (35 g, 403 mmol) was added and the mixture was stirred at room temperature for 15 min before 4-(2-bromoethoxy)-7-methoxyquinoline (40.0 g, 142 mmol) was added. The mixture was then heated to 60° C. in an oil bath for 5 days. The mixture was cooled to room temperature. CH2Cl2 (300 mL) was added and the slurry was filtered through a pad of Celite. The filtrate was washed with NaOH (0.5 N, 3×150 mL), H2O (100 mL), and dried over Na2SO4. The solution was concentrated to give a soft sludge which was stirred with a mixture of hexane (150 mL)-THF (150 mL) at reflux. The mixture was let cooled to room temperature overnight. The soft cake was filtered and washed with 1:1 hexane-THF (100 mL) to afford the product as a white solid (35.5 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>O1CCOCC1.CCOC(C)=O.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([F:34])([F:33])[F:22])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (186 mg, 0.937 mmol) in 1,4-dioxane (5 mL) was treated with K3PO4 (1.00 g, 5.10 mmol), 2-trifluoromethylphenylboronic acid (178 mg, 0.937 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (60.5 mg, 0.128 mmol) and Pd(OAc)2 (28.6 mg, 0.128 mmol). The resulting mixture was stirred 80° C. overnight. The cooled mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The aqueous layer was extracted twice with EtOAc (30 mL) and the combined extracts were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified on silica (0:100-100:0 EtOAc-hexanes) to yield 4-amino-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridine-2-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ: 7.79 (m, 1H), 7.67 (m, 4H), 7.52 (m, 1H), 7.04 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 510.3 and 512.2 (M+H)+, 410.1 and 412.1 ((M-Boc)+H)+ (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]([OH:17])=[O:16])[CH2:9][CH2:10][C:11]2([O:32][CH2:31][CH2:30][O:14]2)[CH2:12][CH2:13]1
Reactant: OCCO
Reactant: O=C1CCC(C(=O)O)(c2ccccc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1(c2ccccc2F)CCC2(CC1)OCCO2

Procedure:
1-(2-Fluorophenyl)-4-oxocyclohexane-1-carboxylic acid (D20, 16.36 g, 69 mmol) was stirred with toluene-4-sulphonic acid hydrate (0.50 g, 3 mmol) and 1,2-ethanediol (35 ml) at reflux in toluene (500 ml), removing the immiscible 1,2-ethanediol/water distillate via a Dean-Stark trap until the distillate was homogenous. The solution was then evaporated, dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (19.94 g, quantitative) as an amber syrup, contaminated with some unidentified materials (NMR).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:23]CC2C=CC=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([OH:23])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OCCNC(=O)OC(C)(C)C)c(OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCc1cc(OCCNC(=O)OC(C)(C)C)c(O)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.5 %

Procedure:
To a solution of 3.8 g of (5-(benzyloxy)-4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridin-2-yl)methyl acetate in 91 mL of ethanol, 1.1 g of 10% palladium carbon was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. Thereto were added chloroform and diethyl ether, and the solid was filtered off to obtain 2.1 g of (4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-hydroxypyridin-2-yl)methyl acetate as a light brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Compound 454 (1.67 g, 6.00 mmol) and DMAP (36.7 mg, 0.300 mmol) were suspended in pyridine (24 mL), and cyclopropanecarbonyl chloride (1.09 mL, 12.0 mmol) was added thereto, followed by stirring at 60° C. for 90 minutes. The reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=99:1), followed by recrystallizing from ethanol to afford the entitled Compound 456 (1.35 g, 65%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@H:4]([NH:27][S:28]([C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36](Cl)[S:37][C:33]=2[CH:32]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.[CH2:49]([O:51][C:52](=O)[CH3:53])C>CC#N>[CH3:1][O:2][C:3](=[O:41])[C@H:4]([NH:27][S:28]([C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36]([S:28][C:31]3[CH:40]=[CH:53][C:52]([O:51][CH3:49])=[CH:33][CH:32]=3)[S:37][C:33]=2[CH:32]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)NS(=O)(=O)c1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)NS(=O)(=O)c1ccc2nc(Sc3ccc(OC)cc3)sc2c1

Procedure:
(2R)-2-[(2-Chlorobenzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl)propionic acid methylester (0.24 g, 0.39 mmol) prepared in a similar manner as in Example 59 was dissolved in MeCN (3 mL). K2CO3 (0.081 g, 1.5 equi.) were added to the solution in a solid form and then, 4-methoxybenzthiol (0.053 mL, 1.1 equi.) was added and refluxed for 3 hours. After starting material was exhausted, water/ethylacetate (5 mL/10 mL) was added and the product was extracted with an organic solvent. The organic phase was washed with NaCl solution, dried over anhydrous MgSO4, distilled under reduced pressure and then, purified on silica gel chromatography using ethylacetate/n-hexane (1/2) to prepare the titled compound, (2R)-2-[(2-(4-methoxyphenylthio)benzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl)propionic acid methylester (0.2 g, 70%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([N+:18]([O-])=O)[CH:13]=[CH:14][C:15]=2Br)[C:10]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:9]1[CH3:29])([CH3:4])[CH3:3].C(N(CC)CC)C>CCOC(C)=O.[Pt]>[NH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([O:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[C:9]([CH3:29])[N:8]2[CH2:7][C:6]([O:5][C:2]([CH3:3])([CH3:4])[CH3:1])=[O:30]
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])ccc(Br)c2n1CC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(N)cccc2n1CC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of the product from step (iii) (0.18 g) in EtOAc (30 ml) was added triethylamine (0.15 ml) and 5% Pt/C (36 mg) and the reaction stirred under hydrogen (1 atm) for 2 h. The reaction was filtered through celite and the filtrate evaporated under reduced pressure. Yield 0.139 g.