Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([NH:19][CH2:20][CH:21]=[O:22])[CH:17]=[CH2:18]>C(O)C.O>[CH2:16]([N:19]([CH2:20][CH:21]=[O:22])[C:8]([NH:7][C:5]1[S:6][C:2]([F:1])=[CH:3][N:4]=1)=[O:9])[CH:17]=[CH2:18]
Reactant: C=CCNCC=O
Reactant: O=C=Nc1ncc(F)s1
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: C=CCN(CC=O)C(=O)Nc1ncc(F)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Fluorothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-allylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-fluorothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[C:41]=1[NH2:47].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[C:41]=1[NH2:47])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(N)c1N
Reactant: CN(CCCC(=O)O)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cccc(NC(=O)CCCN(C)C(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.40 g 4-(benzyloxycarbonyl-methyl-amino)-butyric acid (obtained from 4-(methylamino)butyric acid and benzylchloroformate) in 25 mL THF were added 2.9 mL of DIPEA, 0.97 g of HOBt and 1.38 g EDC. After stirring for 5 min 0.80 g of 3-methoxy-benzene-1,2-diamine were added and the mixture was stirred for 3 h at rt. Sat. aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25].Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:22]([CH2:23][CH:24]([CH3:26])[CH3:25])=[O:27]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(C)CC(=O)c1ccc(O)cc1O

Procedure:
Resorcinol, 5.506 g (50.00 mmol), was added to 45 ml of nitrobenzene and stirred cooling with cold water and 13.3 g (100 mmol, 2.00 equivalents) of aluminum chloride was added piecemeal and they were stirred, with a calcium chloride tube attached. Then, 6.03 g (50.0 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise, stirred at room temperature for one hour, and further heated stirring at 90° C. for six hours. When the evolution of an acidic gas ceased, the resultant mixture was poured into dilute hydrochloric acid (prepared from 40 ml of concentrated hydrochloric acid and 160 ml of cold water) with stirring, and then extracted by ether. The ether layer was washed with saturated brine and removed by distillation under a reduced pressure. The residue, with water added piecemeal, was distilled under a reduced pressure and distilled off nitrobenzene by steam distillation method. The residue was extracted again by ether, washed with saturated brine, dried over sodium sulfate, and distilled to remove the solvent and obtain 8.952 g of a red viscous oily substance. This oily substance was purified by silica gel column chromatography (20 g of Wako Gel C-200, eluted with hexane:ether at varying ratios=8:2-7:3) to obtain 4.37 g of (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) in the form of light yellow crystals.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:19])[CH2:16][CH2:17]Cl)[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])([O-:5])=[O:4].O>CS(C)=O.O1CCCC1>[N+:3]([C:6]1[CH:7]=[C:8]([N:14]2[CH2:17][CH2:16][C:15]2=[O:19])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])([O-:5])=[O:4]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1NC(=O)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N1CCC1=O

Procedure:
5 g of sodium hydride (in the form of a 55% strength dispersion in oil) are stirred in 100 ml of dimethylsulphoxide until no further evolution of gas can be detected. 21.5 g (0.084 mol) of N-(3-nitro-4,6-dimethylphenyl)-β-chloropropionamide, suspended in 500 ml of tetrahydrofurane, are then added in the course of 5-10 minutes. The reaction temperature is kept at 15° for 1/2 an hour and water is then added dropwise in order to destroy excess sodium hydride. The reaction solution is taken up in methylene chloride and washed with water and saturated NaCl solution, dried (MgSO4) and evaporated. The crude product is subjected to fractional filtration on silica gel in chloroform. This gives 14.5 g (78%) of product; melting point 102°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH2:38]C)=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH2:26]O)=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.C(P(CCCC)CCCC)CCC.[NH:53]1[CH:57]=[N:56][CH:55]=[N:54]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]([N:53]4[CH:57]=[N:56][CH:55]=[N:54]4)[CH:25]=[CH2:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: CCc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2/C=C/CO)cc1OC
Reactant: c1nc[nH]n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: C=CC(c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)n1cncn1
Reaction time: 15 h
Yield: 44.9 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-ethyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propen-1-ol (1.00 g), tributylphosphine (0.77 g), 1H-1,2,4-triazole (0.26 g) and tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.95 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 1-(1-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenyl)-1H-1,2,4-triazole as crystals (0.48 g, yield 45%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])([CH3:15])[CH2:9][S:10][CH2:11][C:12](O)=[O:13])[CH:7]=1.C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@@:8]2([CH3:15])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:12](=[O:13])[CH2:11][S:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CSCC(=O)O)c2cc(Br)ccc2F)c(OC)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)CSC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Yield: 92.8 %

Procedure:
To a solution of (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)acetic acid (3.3 g, 6.99 mmol, Eq: 1.00) and N,N-diisopropylethylamine (2.71 g, 3.66 ml, 21.0 mmol, Eq: 3.0) in ethyl acetate (194 ml) was added at 23° C. 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (6.67 g, 6.23 ml, 10.5 mmol, Eq: 1.5) and the colourless reaction solution was stirred at 23° C. for 2 hours. The reaction mixture was washed with sat NaHCO3-sol., water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the nearly pure (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-5-methylthiomorpholin-3-one (2.95 g, 6.49 mmol, 92.9% yield) as a colourless oil, which crystallized in the fridge and was used without further purification. MS (ISP): m/z=454.0 [M+H]+ and 456.1 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:20]([C:19]([F:23])([F:24])[C:18]([F:25])([F:26])[C:17]([F:28])([F:27])[F:16])[NH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1N
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2ccc(-c3ccc(Cl)cc3)cc2[nH]1
Yield: 18 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (2 g, 11.59 mmol) in dioxane (100 ml) and water (10 ml) was added (4-chlorophenyl)boronic acid (3.6 g, 23.02 mmol), K3PO4 (5.01 g, 23.18 mmol) and Pd(PPh3)4 (0.7 g, 0.58 mmol) with stirring for 4 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 5% ethyl acetate in petroleum ether to afford 4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (2.0 g, 69%). Next, to a solution of 5-(4-chlorophenyl)-2-nitroaniline (300 mg, 1.21 mmol) in ethanol (10 ml) was added hydrogen chloride (0.5 ml, 3.63 mmol) and Zn powder (800 mg, 12.3 mmol) in portions at room temperature and stirred for 2 h at 85° C. The resulting mixture was concentrated under vacuum to give a residue and dissolved in water (100 ml), adjusted to pH 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml) and dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% to 20% ethyl acetate in petroleum ether to produce 4-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (200 mg, 76%). Finally, a solution of 4-(4-chlorophenyl)benzene-1,2-diamine (150 mg, 0.69 mmol) in heptafluorobutanoic acid (2 ml) was stirred for 8 h at 120° C. Then the reaction was quenched with water (50 ml), adjusted to pH 7 with sodium bicarbonate and extracted with ethyl acetate(3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (49.5 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([N:7]([C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>CC#N.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:4]2[C:3]=1[C:17]1([CH:22]=[CH:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5]2=[O:6]
Reactant: COc1ccc(CN(C(=O)c2cccc(Br)c2I)C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN2C(=O)c3cccc(Br)c3C23C=CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 50.1 %

Procedure:
A solution of tert-butyl 4-(3-bromo-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6-dihydropyridine-1(2H)-carboxylate (30 g, 0.048 mol) in CH3CN (500 mL) was stirred for 0.5 h under nitrogen. K2CO3 (13 g, 0.096 mol), PPh3 (6 g, 20%), tetra-butylammonium chloride (15 g, 0.048 mol) and Pd(OAc)2 (3 g, 0.0048 mol) were added. The resulting mixture was heated to reflux for 12 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography to afford tert-butyl 7-bromo-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate (12 g, 50%). 1H NMR: (400 MHz, CDCl3): δ=1.51 (s, 9H), 1.73 (m, 2H), 2.83-3.08 (m, 2H), 3.79 (s, 3H), 4.00 (m, 1H), 4.30 (m, 1H), 4.42 (d, 1H), 5.02 (d, 1H), 6.83 (d, 2H), 7.201 (d, 2H), 7.45 (m, 1H), 7.70 (d, 1H), 7.88 (d, 1H).
Reaction SMILES: [C:1]([CH:9]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C@H:10]1[CH2:11][CH2:12][C@@H:13]1[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:32])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH:20]=[O:21])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O1CCCC1.CCOCC>[C:1]([CH:9]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C@H:10]1[CH2:11][CH2:12][C@@H:13]1[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:32])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[C@@H:18]([CH3:19])[CH2:20][OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The (5α,20R)-4-benzoyl-3-oxopregnane-20-carboxaldehyde (436 mg, 1.0 mmole) in tetrahydrofuran:methanol (2.0 ml, 1:1) is mixed with sodium borohydride (9.5 mg, 0.25 mmole) at 0° C. for 1 hours. The mixture is then diluted with ether and washed with 0.5 N hydrochloric acid and brine and then dried and the solvent is evaporated to leave, as a resiue, (5α,20R)-4-benzoyl-21-hydroxy-20 -methylpregnan-3-one.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:40]([OH:42])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][O:28][C@@H:29]1[O:37][C@@H:36]([CH3:38])[C@@H:34]([OH:35])[C@@H:32]([OH:33])[C@@H:30]1[OH:31])=[O:24])=O)C1C=CC=CC=1>O>[C@@H:29]1([O:28][CH2:27][CH2:26][NH:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:40]([OH:42])=[O:41])[NH2:11])=[O:39])[O:37][C@@H:36]([CH3:38])[C@@H:34]([OH:35])[C@@H:32]([OH:33])[C@@H:30]1[OH:31]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Solvent: O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](N)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
In a 100 mL flask, N2-[(benzyloxy)carbonyl]-N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (200 mg, 0.335 mmol) was dissolved in water (5 mL). The flask was degassed and filled with N2. To the above mixture was added PdOH2 (48.7 mg, 0.069 mmol. The mixture was stirred under H2 balloon for 2 hr. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the title compound. UPLC Method B: m/e=464.2697 [M+1]; Rt=2.61 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].CC(C)([O-])C.[Na+].[CH3:36][C@H:37]1[C@H:41]([CH3:42])OS(=O)(=O)[O:38]1.Cl>CN(C)C(=O)C>[OH:38][C@@H:37]([CH3:36])[C@H:41]([N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[C:2]([CH3:1])[C:3]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:18])=[CH:4]1)[CH3:42]
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (28 g, 66 mmol) in anhydrous N,N-dimethylacetamide (DMA) (0.53 L) was added sodium tert-butoxide (15 g, 15 mmol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (15 g, 99 mmol) in anhydrous DMA (2.0 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (0.14 L) and concentrated on a rotary evaporator. To this residue was added anhydrous tetrahydrofuran (THF) (140 ml) and 5N HCl (0.14 L) and stirred at 60° C. for 90 min. The mixture was diluted with ethyl acetate and washed with water, saturated NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (9:1 to 1:1 dichloromethane:ethyl acetate) to give an atropisomeric mixture of title compound as a white solid (22.5 g, 69%).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)C)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)O)cn1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Ethyl 1-isopropyl-2-methyl-1H-imidazole-4-carboxylate (0.423 mmol, 83 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (2.115 mmol, 1.057 ml) was added and the resulting mixture was stirred at RT overnight. The pH of the reaction mixture was adjusted to about 5 with 1 M HCl and the mixture was evaporated. Ethanol was added and the salt was removed by filtration. The salt was flushed few times with ethanol. 51 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.38 (d, 6H), 2.39 (s, 3H), 4.35-4.49 (m, 1H), 7.97 (s, 1H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([CH3:26])([CH3:25])[CH2:9]1)=O)(C)(C)C.Cl>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:14]2[CH:15]=[C:16]3[NH:8][CH2:9][C:10]([CH3:26])([CH3:25])[C:11]3=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Agent: Cl
Solvent: CO
Product: CC1(C)CNc2cc(Cc3ccc(F)cc3)cnc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A solution of 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (9.0 g, 25 mmol) in methanol (62.5 mL) was treated with 5 M hydrochloric acid (62.5 mL) and the mixture stirred at 20° C. for 18 h then heated at 50° C. for 2 h. Solvent was evaporated and the residue was partitioned between water (200 mL) and EtOAc (3×). The aqueous phase was slowly poured into saturated aqueous NaHCO3 and the resulting solid collected by filtration to afford the title compound (3.45 g). 1H NMR (CDCl3): 7.81 (1H, s), 7.16 (2H, dd), 6.99 (2H, t), 6.58 (1H, d), 3.84 (2H, s), 3.38 (2H, s), 1.36 (6H, s). MS: [M+H]+=257. Further title compound (1.5 g) was obtained by aqueous acid extraction of the combined organic extracts and subsequent basificatioin of the combined aqueous extracts.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]2[C:8]=1[C:9]([CH3:30])=[C:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:11]([O:18][CH:19]([F:21])[F:20])=[N:12]2)[CH3:5].[OH-].[Li+].P([O-])(O)(O)=O.[Na+]>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:31])=[O:2])=[C:8]2[C:13]=1[N:12]=[C:11]([O:18][CH:19]([F:20])[F:21])[C:10]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[C:9]2[CH3:30]
Reactant: COC(=O)C(C)Oc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: O=P([O-])(O)O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2)c(OC(F)F)nc2c(Cl)ccc(OC(C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[8-chloro-3-(4-chlorobenzyl)-2-difluoromethoxy-4-methylquinolin-5-yloxy]propionic acid methyl ester (0.22 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 3 hours. The mixture was acidified by the addition of sodium dihydrogenphosphate, concentrated under reduced pressure and the residue extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 0.20 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][CH:9]1[C:38]([O:40]C)=[O:39].[OH-].[K+]>O.CO>[C:26]([CH2:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][CH2:14][C:13]([N:12]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH:11]2[C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:24]=[CH:23][CH:22]=1)([OH:28])=[O:27]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(C(=O)OC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CNC(=O)C1CC(C(=O)O)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 54 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.7 g of methyl (2RS,4RS,5SR)-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}pyrrolidine-4-carboxylate and 0.56 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.9 g of (2RS,4SR,5SR)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-(isobutylcarbamoyl)pyrrolidine-4-carboxylic acid Rf =0.155 eluant: methylene chloride/methanol (90/10)].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([I:13])=[C:6]([NH2:14])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[NH2:14][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]=1[I:13]
Reactant: CCOc1cc(C(=O)OC)cc(N)c1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(CO)cc(N)c1I
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 3-amino-5-ethoxy-4-iodo-benzoic acid methyl ester (0.18 g, 0.56 mmol, 1.0 equiv) in THF (5 mL) at 0° C. under Ar was slowly added diisobutylaluminium hydride (2.8 mL, 2.80 mmol, 5.0 equiv, 1 M solution in THF) over a time period of 30 min, the cooling bath removed on completion of addition and the reaction allowed to reach rt. After 2 h, the excess hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (50 mL). The solidified mixture was extracted with hot THF, the combined organic phases concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (2:1) providing 0.056 g (34%) of the title compound. 1H NMR (250 MHz, CDCl3): δ 1.47 (t, J=7.0 Hz, 3H), 4.08 (q, J=7.0 Hz, 2H), 4.23 (br s, 2H), 4.58 (d, J=6.0 Hz, 2H), 6.23 (s, 1H), 6.42 (s, 1H). MS (EI): 293.0 [M]+.