Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)=[O:26]>>[OH:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)=[CH:4][CH:3]=1)[CH:31]=[CH:30]2)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)C1
Reactant: O=C(NCCO)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)NCCO)ccc43)nc2)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 3-((6-chloropyridin-3-yl)oxy)pyrrolidine-1-carboxylate and N-(2-hydroxyethyl)-1H-indole-5-carboxamide; MS: 466.5 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])=S)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[N:23][OH:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])=[CH:4][CH:3]=1
Reactant: Fc1cc(C(F)(F)F)ccc1C(=S)Nc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: ON=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzenecarbothioamide (2.50 g, 0.00663 mol), hydroxylamine hydrochloride (0.65 g, 0.00928 mol) and sodium bicarbonate (0.78 g, 0.00928 mol) was heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzeneamidoxime (2.35 g, 0.00625 mol) as an off-white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1Br)[CH3:7].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1.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>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:7]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cccc(OC)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(OC)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
2M Aqueous sodium bicarbonate (10 mL) was added to a suspension of 2-bromo-3-methoxybenzoic acid ethyl ester (2.06 g, 7.7 mmol), benzeneboronic acid (1.11 g), and tetrakis(triphenylphosphine)palladium(0) (0.30 g) in toluene (35 mL) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 2 hours, poured into water, and extracted with diethyl ether. The organic layer was evaporated, and the residue was chromatographed, eluting with hexane/acetone (3:1) to give a semisolid oil. Recrystallization from diethyl ether/hexane gave 3-methoxy-2-phenylbenzoic acid ethyl ester as colorless crystals (0.69 g, 34%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][N:22]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23]1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][N:22]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23]1)([OH:20])=[O:19]
Reactant: Cc1cc(C)n(CC(N)C(=O)O)n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Cc1cc(C)n(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)n1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3,5-dimethyl-pyrazol-1-yl)-propionic acid to provide the title compound in good yield.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:39])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30]COC)=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:25]=3)[CH3:18])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])C.Cl>>[OH:39][C@H:21]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:25]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[O:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7][O:8][C:9]=2[CH:15]=1
Reactant: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)COc3ccc(OCOC)c(NS(C)(=O)=O)c3)ccc2O1
Agent: Cl
Product: C[C@H](Cc1ccc2c(c1)OC[C@H](C(=O)O)O2)NC[C@H](O)COc1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 6-[2-(R)-[2-(S)-hydroxy-3-[3-methanesulfonamido-4-(methoxymethoxy)phenoxy]propylamino]propyl]-2,3-dihydro-1,4-benzodioxine-2-(R)-carboxylic acid ethyl ester (220 mg) obtained in Example 1 in 1N—HCl (9 mL) was stirred under reflux for 3 hours. After allowing to cool to room temperature, it was concentrated to dryness under reduced pressure. The residue was dissolved in water/acetonitrile=1/1(v/v) (10 mL) and the pH was adjusted to 6.0 by addition of saturated aqueous sodium bicarbonate. After concentrating under reduced pressure, the residue was purified by HP column chromatography and the title compound was obtained from the effluent with water/methanol=50/50 (v/v). Yield: 62%
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[Br:16].ClCCl.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.CO>[Br:16][C:3]1[C:4]2[O:8][CH2:7][CH2:6][C:5]=2[C:9]2[C:13](=[O:15])[CH2:12][CH2:11][C:10]=2[C:2]=1[Br:1]
Reactant: O=C(O)CCc1cc2c(c(Br)c1Br)OCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl)propionic acid (10.0 g, 28.6 mmols), dichloromethane (35 mL), thionyl chloride (5.11 g, 40.8 mmols) and N,N-dimethylformamide (30 mg) was heated to reflux for 1 hour. After cooling, aluminum chloride (4.66 g, 43.3 mmols) was added to the reaction mixture a trot more than 0° C. and then the mixture was stirred for 30 min. The reaction mixture was poured into precooled methanol (200 mL), then stirred for 30 min. Crystals precipitated were collected by filtration, washed with water (500 mL) followed by methanol (500 mL) to obtain 7.9 g (yield: 89%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]=[O:14].C(N(CC)CC)C>C(C(C)=O)C>[C:16]([CH2:15][NH:12][C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:14])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN=C=O
Reactant: O=c1oc2ccc(O)cc2s1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1ccc2oc(=O)sc2c1
Reaction time: 15 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (14.0 grams), was mixed with ethyl isocyanatoacetate (11.9 grams) and 0.84 gram of triethylamine in 165 milliliters of methyl ethyl ketone. The resulting mixture was then heated at reflux temperature for one hour and ten minutes and was allowed to cool and stand at ambient temperature for 15 hours. The solvent was then removed by evaporation in vacuo. The white, solid residue was recrystallized from a solution of 2% ethyl acetate in carbon tetrachloride. The resulting white crystalline solid had a melting point of 94.5°-96.5° C. This product was then recrystallized from a mixture of ethyl acetate and methylcyclohexane to give the desired purified product, 5-[(carbethoxymethyl)-carbamoyloxy]-1,3-benzoxathiol-2-one as colorless crystals having a melting point of 97.5°-98.5° C. Elemental analysis calculated for C12H11NO6S (percent): carbon--48.48; hydrogen--3.73; nitrogen--4.71. Found: carbon--48.6; hydrogen--3.84; nitrogen--4.80.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([CH:24]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:25][CH:26]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:19]1)=[O:17])C1C=CC=CC=1>CO>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([CH:24]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:25][CH:26]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:19]1)=[O:17]
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCNC(=O)OCc3ccccc3)CC2O)c2ccc(OC)cc2)cc1
Solvent: CO
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN)CC2O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Compound 64 (5.9 g, 8.84 mmol) was dissolved in methanol (10 mL) and purged with argon. To the solution was added 10% palladium on carbon (0.6 g). The flask was purged with hydrogen 2 times and stirred further at room temperature under hydrogen atmosphere for overnight. The disappearance of the starting material was confirmed by the TLC. The reaction mixture was filtered through a pad of Celite and washed with methanol. The combined organic layer was concentrated under reduced pressure to afford compound 65 (4.3 g, 92%) as white solid. This was used as such for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)Cc1cnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Yield: 88.6 %

Procedure:
5.00 g of 4,6-dichloropyridine-3-carboxyamide synthesized according to the method described in US 2006/0217417 was dissolved in 50 mL of ethanol, to which 3.37 g of benzylamine and 4.40 g of N,N-diisopropylethylamine were added, and heated at reflux for 12 hours. After cooling, the solvent was evaporated, and 100 mL of water was added to the residue. After cooling with ice, the deposited crystals were filtered, washed with water and hexane, and air-dried. It was further dried under reduced pressure (100° C., 2 hours) to obtain the title compound (5.96 g, 87%) as light yellow needle crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-fluoro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M34) (489 mg, 0.787 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (87 mg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:3]>CO.Cl>[NH:16]1[CH2:17][CH2:18][CH:13]([C:9]2[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[C:6]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:7]=3)[NH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1
Agent: Cl
Solvent: CO
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-(2-thienyl)-1H-indol-3-yl]-1-piperidinecarboxylate (90 mg, 0.22 mmol) in MeOH (3 mL), HCl (4.0M in dioxane, 2.06 mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours, after which time the solvent was removed under reduced pressure and the resulting residue was partitioned between ethyl acetate (10 mL) and 10% sodium hydroxide (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2) and the combined organic phase was dried over MgSO4 and concentrated to give a crude product (53 mg, 77%). This was used directly in the next step without further purification.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:24][CH2:23][C:22]2[C:13](=[N:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]=2Cl)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)[CH:28]=[O:29].C[O-].[Na+].[Na]>CO>[CH2:3]([N:10]1[CH2:24][CH2:23][C:22]2[C:13](=[N:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]=2[O:29][CH3:28])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: Clc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
19.9 gm (50 millimols) of 3-benzyl-11-chloro-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline dihydrochloride and 500 ml of dimethyl formamide were added to dry sodium methylate, prepared from 23 gm of sodium and 1600 ml of methanol. The mixture was stirred at 100° C for 3 hours, evaporated, the residue was introduced into water, and the aqueous mixture was extracted with ether. The 3-benzyl-11-hydroxy-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline formed at the same time remained undissolved.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[O:18][CH3:19].[F-].[K+].[OH-].[Na+]>CN(C=O)C.CN1C(=O)CCC1.[Cu]I.O>[CH3:19][O:18][C:12]1[C:13]([CH2:17][C:3]([F:6])([F:5])[F:4])=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1c(C)cccc1CBr
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)cccc1CC(F)(F)F
Temperature: 55 °C
Yield: 90.4 %

Procedure:
Trimethyl(trifluoromethyl)silane (25.39 mL, 162.5 mmol) was added to a stirred mixture of 1-bromomethyl-2-methoxy-3-methyl-benzene(19 g, 65 mmol), KF (9.44 g, 162.5 mmol), CuI (37.10 g, 195 mmol) in DMF (75 mL) and NMP (75 mL). The reaction mixture was heated to 55° C. under N2 for 15 hours. The mixture was poured into water, made basic with 1 N NaOH and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a black oil. Flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as a yellow oil (12.0 g). LCMS: APCI−VE=203
Reaction SMILES: CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.[CH3:22][O+:23]([CH3:25])C.[N+:26]([C:29]1[CH:30]=[C:31]2[CH:37]=[C:36](CO)[N:35]([S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:32]2=[N:33][CH:34]=1)([O-:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][O:23][CH2:25][C:36]1[N:35]([S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:42])[C:32]2=[N:33][CH:34]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=[C:31]2[CH:37]=1
Reactant: C[O+](C)C
Reactant: O=[N+]([O-])c1cnc2c(c1)cc(CO)n2S(=O)(=O)c1ccccc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: COCc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N,N,N′,N′-Tetramethyl-1,8-naphthalenediamine (0.212 g, 0.99 mmol) and trimethyloxonium tetrafluoroborate (0.146 g, 0.99 mmol) were added to a solution of (5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol (0.11 g, 0.33 mmol) in DCM (3.3 mL). The reaction mixture was stirred at room temperature for 1 hour. It was then treated with saturated aqueous NaHCO3, and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 2-(methoxymethyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.11 g, 96%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:10](=[O:19])(=[O:18])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]1=2.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][S:10](=[O:19])(=[O:18])[C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]2=3)=[CH:27][CH:26]=1
Reactant: O=S1(=O)Cc2ccccc2N(C[C@@H]2CCCN2)c2ccccc21
Reactant: Oc1ccc(CCBr)cc1
Product: O=S1(=O)Cc2ccccc2N(C[C@@H]2CCCN2CCc2ccc(O)cc2)c2ccccc21

Procedure:
This was obtained by reacting (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine-10,10-dioxide (see Preparation 20) and 4-hydroxyphenethyl bromide by a similar method to that described in Example 28. The title compound was obtained as a colourless oil, (60 mg, 29%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][O:12][C:11]([C:4]2[CH:3]=[C:2]([O:1][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C:7]3[O:8][CH2:9][O:10][C:6]=3[CH:5]=2)=[O:13])[CH:18]=1
Reactant: Cc1cccc(CCBr)c1
Reactant: O=C(O)c1cc(O)c2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CCOC(=O)c2cc(OCCc3cccc(C)c3)c3c(c2)OCO3)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
2.5 g of 7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid, 6.8 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 7.6 g of potassium carbonate were stirred in 100 ml of anhydrous DMF for 10 h at 80° C. Then another 1.4 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 1.5 g of potassium carbonate were added and the mixture was stirred for 5 h at 90° C. The solvent was removed in vacuo and the residue dissolved in 200 ml of water and 200 ml of EA. The organic layer was separated, washed with 100 ml of a saturated aqueous sodium carbonate solution, dried with magnesium sulfate and evaporated to yield 4.5 g of the title compound.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[CH:18]([Si:21]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:22][CH2:23][C@@H:24]([OH:26])[CH3:25])([CH3:20])[CH3:19].[O:33]1[CH2:35][C@@H:34]1[C:36]([O:38][CH3:39])=[O:37]>C(OCC)(=O)C>[OH:33][C@H:34]([CH2:35][O:26][C@@H:24]([CH3:25])[CH2:23][O:22][Si:21]([CH:18]([CH3:20])[CH3:19])([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:32])[CH3:31])[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)[C@H]1CO1
Reactant: CC(C)[Si](OC[C@H](C)O)(C(C)C)C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
Magnesium trifluoromethanesulfonate (1.263 g, 3.92 mmol) was added to a mixture of (S)-1-(triisopropylsilyloxy)propan-2-ol (4.55 g, 19.59 mmol) and (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) in ethyl acetate (40 mL). The resulting suspension was heated to 80° C. for 72 hours. Further (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) was added and the mixture stirred at 80° C. for 48 hrs. Further (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) was added and the mixture stirred for 24hrs. The mixture was allowed to cool, filtered through a bed of silica (˜10 g), washed through with EtOAc and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% EtOAc in isohexane, to afford the product (2.7 g, 41%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](O)=[O:22])=[O:18])=[CH:11]2>>[CH2:24]([CH:20]([NH:19][C:17]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=2)=[O:18])[C:21]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC1CCNC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Racemic3-pyrrolidinol (2.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3phenyl-propionic acid (1 mmol) were coupled according to procedure A (0-25° C. reaction temperature, washing first with acid then base), and the product purified by column chromatography on silica gel eluted with 0.5-16% ethanol in dichloromethane to give a colorless foam: Yield 260 mg, 63%; HPLC (60/40) 100%, 3.86 minutes; PBMS 412/414 (MH+, 100%);
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34](=[O:45])[NH:35][CH:36]([CH3:44])[CH2:37][C:38](N(OC)C)=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:38](=[O:39])[CH2:37][CH:36]([NH:35][C:34](=[O:45])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:44])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)CC(C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of magnesium turnings (1.55 g; 63.76 mmol) in THF (50 mL) under an atmosphere of N2 was added 1,2-dibromoethane (135 uL). The mixture was heated to 75° C. and 3,5-bis(trifluoromethyl)bromo benzene (4.59 mL; 26.79 mmol) was slowly added to maintain a gentle reflux. The reaction was heated at gentle reflux for 2.5 h and then cooled to room temperature. In a separate flask, isopropyl magnesium chloride (18 mL; 36 mmol) was added dropwise to a stirred solution of benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate (Step B; 5 g; 17.86 mmol) in THF (30 mL) at −20° C. The resultant solution was stirred at −20° C. for 40 min prior to dropwise addition of the Grignard solution. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with 1 N HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% acetone/hexanes gradient) to afford benzyl {3-[3,5-bis(trifluoromethyl)phenyl]-1-methyl-3-oxopropyl}carbamate as a white solid. LCMS=434.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.39 (s, 2H), 8.07 (s, 1H), 7.37-7.29 (m, 5H), 5.16-5.04 (m, 3 h), 4.31-4.23 (m, 1H), 4.16-4.10 (m, 1H), 3.19 (dd, J=16.8, 6.5 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H).