Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.C1(B(O)O)C=CC=CC=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: OB(O)c1ccccc1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and phenylboronic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18](=O)[CH2:17][CH:16]([C:20](OC)=[O:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold (0° C.) suspension of lithium aluminum hydride (2.44 g, 64 mmol) in THF (40 mL) was added methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (5.00 g, 21 mmol). The reaction mixture was stirred at room temperature for 5 hrs. To the reaction mixture were added water (2.5 mL), 15% aqueous sodium hydroxide solution (2.5 mL), and water (7.5 mL), successively. The mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give (1-benzyl-3-pyrrolidinyl)methanol. (4.16 g, yield; quant.)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.[H-].[Na+].[CH3:14][CH:15]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH3:16]>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:14])[C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]ccc2n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)n1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (4.0 g, 27.0 mmol) in THF (50 mL) was added NaH (60%, 1.30 g, 32.4 mmol) in small portions at 0° C. over 10 min. The resulting mixture was stirred under N2 for 1 hr, followed by dropwise addition of TIPS-Cl (6.86 mL, 32.4 mmol) in neat through an syringe at 0° C. over 2 min, and stirred for additional 1 hr. The reaction was quenched with sat. NH4Cl (50 mL), extracted with Et2O (500 mL). The extract was washed with brine (50 mL), dried (MgSO4), concentrated on rotary vacuo, and the residue was purified on Biotage Flash Collector eluting with 20-75% EtOAc/Hexanes (1600 mL) to afford the expected product, 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridine (8.25 g, 100%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.11 (d, J=7.55 Hz, 19 H) 1.57-1.67 (m, J=7.55, 7.55, 7.55, 7.55 Hz, 3 H) 3.98 (s, 3 H) 6.54 (d, J=9.06 Hz, 1 H) 6.67 (d, J=3.02 Hz, 1 H) 7.35 (d, J=3.27 Hz, 1 H) 7.65 (d, J=9.06 Hz, 1 H); Mass spec 305.1 (MH+) calc. for C17H28N2O Si 304.2.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[C:11]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[C:11]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:3]([O-:5])(=[O:4])[CH:2]([CH3:1])[OH:9]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: C=C(C)C(=O)OCCO
Product: CC(O)C(=O)[O-]

Procedure:
Dextran-(2-hydroxyethylmethacrylate)-lactate (Dex-lactateHEMA) macromer was synthesized according to a published method (Wolthuis, et al. Polymer, 1997, 38, 6235-6242). For example, L-lactide and 2-hydroxyethyl methacrylate (HEMA) with 1:1 molar ratio were first reacted at 110° C. for one hour in the presence of catalyst SnOct2 to obtain HEMA-lactate. Secondly, N,N′-carbonyldiimidazole (CDI) was reacted with the above HEMA-lactate product at 1:1 feeding molar ratio at room temperature in THF for 16 h to obtain HEMA-lactateCI. Finally, a calculated amount of dextran was reacted with HEMA-lactateCI (HEMAlactateCI:glucopyranose=7:1 molar ratio) in the presence of catalyst 4-(N,N-dimethylamino) pyridine (DMAP) in dimethyl sulfoxide (DMSO) at room temperature for four days to obtain the Dex-lactateHEMA macromer. The average length of lactate spacer (DPav) is equal to 3, and degree of substitute (DS; amount of methacrylate groups per 100 dextran glucopyranose residues) is equal to 4.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:22]N1C(=O)CCC1=O>C1COCC1>[Cl:22][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=3)[N:9]=[N:10][C:11]=2[C:16]=1[OH:17]
Reactant: COc1ccc(Cn2nnc3c(O)cccc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc3c(O)c(Cl)ccc32)cc1

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-ol (0.984 g, 3.85 mmol) at 0° C. in THF (15 mL) was added 1N NaOH (3.85 mL, 3.85 mmol). The resulting mixture was then stirred for several minutes, after which N-chloro-succinimide (0.515 g, 3.85 mmol) was added in one portion. The stirred reaction mixture was quenched after 5 minutes at 0° C. with aqueous ammonium chloride (25 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were concentrated under reduced pressure. The resulting residue was subjected to reverse phase chromatography (5-95% MeCN/H2O, 0.1% TFA). The product fractions were combined and extracted with dichloromethane (2×100 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product. 1H NMR (DMSO d6) δ 11.61 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 5.84 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C1COCC1>[C:16]1([C:13]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:15][CH2:14]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Diketene (1.50 mL, 19.2 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(2-aminoethyl)-4,4-diphenylpiperidine (3.60 g, 12.8 mmol, 1.00 equiv) in anhydrous THF (40 mL) under argon, and stirring was continued at room temperature for 1 hour. The mixture was concentrated to give 4.10 g (88%) of white solid, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Br:36][C:37]1[N:38]=[C:39]([C:42](Cl)=[O:43])[S:40][CH:41]=1.BrC1N=C(C(O)=O)SC=1>>[Br:36][C:37]1[N:38]=[C:39]([C:42]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][N:7]=2)=[O:43])[S:40][CH:41]=1
Reactant: COc1cc2c(Oc3ccc(N)nc3)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1nc(Br)cs1
Agent: O=C(O)c1nc(Br)cs1
Product: COc1cc2c(Oc3ccc(NC(=O)c4nc(Br)cs4)nc3)ccnc2cc1OCC1CCNCC1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X15 was prepared from tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate and 4-bromothiazole-2-carbonyl chloride, which was prepared similar to Preparative Example 16 step 4 from commercially available 4-bromothiazole-2-carboxylic acid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.53 (m, 2H), 1.98 (d, J=12.5 Hz, 2H), 2.18 (m, 1H), 2.95 (m, 2H), 3.33 (m, 2H), 3.94 (s, 3H), 4.08 (d, J=6.3 Hz, 2H), 6.58 (d, J=5.2 Hz, 1H), 7.45 (s, 1H), 7.54 (m, 1H), 7.87 (dd, J=2.9 Hz, J=9.0 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.31 (s, 1H), 8.45 (d, J=2.9 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 10.61 (br s, 1H). MS (ES) C25H24BrN5O4S requires: 570. Found: 570/572 (M−1-H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C@@H:19]3[O:23][CH2:22][C@@H:21](Br)[CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)(=O)C.CCCCCC>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C@@H:19]3[O:23][CH2:22][C@H:21]([S:27][C:25](=[O:28])[CH3:26])[CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC([O-])=S
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H]2C[C@H](Br)CO2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1CO[C@@H](C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Yield: 82.4 %

Procedure:
The title compound is prepared by the procedure of Example 139 using 1.14 g of product from Example 151, 0.393 g of potassium thioacetate, 0.1517 g of 18-crown-6 and 10 ml of acetonitrile to give 0.928 g of the desired product after chromatography (silica gel: 10-60% ethyl acetate/hexane).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([S:11]([C:13]([F:16])([F:15])[F:14])=[O:12])=[C:9]([CH3:17])[N:8]([C:18]2[C:23]([F:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)=[O:5])C.[OH-].[Li+].Cl>C(O)(C)C.O>[Cl:29][C:19]1[CH:20]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:23]([F:24])[C:18]=1[N:8]1[C:9]([CH3:17])=[C:10]([S:11]([C:13]([F:14])([F:15])[F:16])=[O:12])[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(C)c1S(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(S(=O)C(F)(F)F)c(C(=O)O)nn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g, 2.6 mmol) in isopropanol (10 mL) and water (2.5 mL) was added lithium hydroxide (0.2 g, 8.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. To the reaction mixture was added aqueous hydrochloric acid (37 wt %, 0.9 mL) and water (7 mL). The resulting mixture was extracted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to give 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid as an off-white solid (1.1 g). This material was used without purification for the next step. 1H NMR (400 MHz, CDCl3) δ ppm 2.52 (s, 3H), 7.56 (dd, J=8.3, 1.5 Hz, 1H), 7.73 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −113.4 (d, J=8.6 Hz, 0.5F), −112.9 (d, J=7.9 Hz, 0.5F), −73.9 (s, 1.5F), −73.7 (s, 1.5F), −63.8 (s, 3F).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)(C)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(C)c1ccc(CBr)cc1
Yield: 97 %

Procedure:
A solution of methyl 2-(4-methylphenyl)-2-methylpropionate (58.5 g), N-bromosuccinimide (54.2 g), benzoyl peroxide (1.2 g) and carbon tetrachloride (300 ml) was refluxed for 40 min. After being cooled, the reaction mixture was filtrated. The filtrate was washed with an aqueous sodium sulfite solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 2-(4-bromomethylphenyl)-2-methylpropionate (80.0 g) as a pale-brown oil. To a solution of this oil in dimethylformamide (500 ml) was added sodium azide (21.14 g) and the mixture was stirred at 80° C. for 40 min. The reaction mixture was poured into water (1000 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane,hexane:ethyl acetate=20:1) to give the title compound (48.1 g) as a pale-yellow oil.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])(=[O:12])=[O:11])=[N:8][N:9]=1)(=O)C>Cl>[NH2:4][C:5]1[S:6][C:7]([S:10]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])(=[O:11])=[O:12])=[N:8][N:9]=1
Reactant: CCC(CC)NS(=O)(=O)c1nnc(NC(C)=O)s1
Agent: Cl
Product: CCC(CC)NS(=O)(=O)c1nnc(N)s1
Temperature: 25 °C

Procedure:
2-Acetamido-5-[N-(1-ethylpropyl)aminosulfonyl]-1,3,4-thiadiazole (0.1 mole), and concentrated hydrochloric acid (500 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and reflux condenser. The mixture is refluxed for a period of about 2 hours, it is then cooled to room temperature, filtered and solvent removed from the filtrate by use of a rotary evaporator. The solid residue is washed with, 10% aqueous sodium carbonate, air dried and then crystallized from isopropanol to yield the desired product 2-amino-5-[N-(1-ethylpropyl)aminosulfonyl]-1,3,4-thiadiazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-chloropyridazine-3-carbaldehyde (2.50 g, 17.5 mmol) in 30 mL of methanol (30 mL) at 0° C. was added sodium borohydride (0.26 g, 7.02 mmol). The reaction mixture was warmed to room temperature. After 2 hours, the reaction mixture was concentrated in vacuo and triturated with 20% MeOH in dichloromethane to provide (6-chloropyridazin-3-yl)methanol.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]([OH:7])[CH2:2]1.[H-].[Na+].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>O1CCCC1>[Cl:11][C:12]1[CH:19]=[C:18]([O:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:1]([OH:8])[CH2:2]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: O[C@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(O[C@@H]2CCC[C@@H](O)C2)cc1Cl
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
A commercial mixture of cis/trans 1,3-cyclohexanediol (7.77 g, 66.9 mmol) was dissolved in 50 mL anhydrous THF (tetrahydrofuran), under a nitrogen atmosphere, and cooled in an ice/acetone bath. NaH (60% suspension in oil, 2.69 g, 6.725 mmol) was then added and the solution stirred approximately 10 min. Then a solution of 2-chloro-4-fluorobenzonitrile (1.06 gms, 6.79 mmol)(in 20 mL anhydrous THF was added in a slow, steady stream (not dropwise). The cold bath was removed, and allowed to stir at room temperature overnight. The reaction was quenched with approximately 10 mL 5% citric acid and the THF was removed by rotovap. off. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the organic layers were combined. The combined organic layers were washed twice with brine, then dried over magnesium sulfate, filtered and rotovapped. The resulting product was triturated with hexane, and the hexane decanted off. The crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate), and the desired fractions were combined, and the solvent removed. The results of two such runs were combined, and submitted for preparative reverse phase HPLC. The title compound (0.1575 g) was returned. HNMR (CDCl3, ppm) 7.5 (1H, d, J=8.8 Hz), 6.96 (1H, s), 6.82 (1H, d, J=8.8 Hz), 4.8-4.6 (1H, m), 4.2-4.1 (1H, m), 2.1-1.4 (9H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]1([C:44]2[O:48][N:47]=[C:46]([C:49]3[C:54]([Cl:55])=[CH:53][N:52]=[CH:51][C:50]=3[Cl:56])[C:45]=2[CH2:57]O)[CH2:43][CH2:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:41]1([C:44]2[O:48][N:47]=[C:46]([C:49]3[C:50]([Cl:56])=[CH:51][N:52]=[CH:53][C:54]=3[Cl:55])[C:45]=2[CH2:57][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:43][CH2:42]1
Reactant: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (81 mg, 0.29 mmol), triphenylphosphine (84 mg, 0.32 mmol) and [5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (83 mg, 0.29 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.058 mL, 0.32 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes and then allowed to stand overnight. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-1.25% methanol in chloroform gradient elution) to afford methyl 6-[4-({[5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (70 mg, 44%). 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 2H), 8.39-8.33 (m, 2H), 8.22 (d, J=9 Hz, 1H), 8.01-7.96 (m, 2H), 7.60 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.90 (s, 2H), 4.09 (s, 3H), 2.22-2.15 (m, 1H), 1.33-1.13 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.[Li+].[OH-].O.Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(N(CCCl)CCCl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added methyl 2-(4-(bis(2-chloroethyl)amino)phenyl)acetate (B-4) (3.4 g, 11.68 mmol), LiOH (1.7 g, 70.83 mmol), H2O (100 mL) and THF (50 mL). The reaction mixture was stirred at 50° C. for 2 h. After cooled down to r.t., the reaction mixture was adjusted with HCl (1 N) to pH7 and extracted with EtOAc (100 ml*2), the mixture was dried over Na2SO4 and concentrated under reduced pressure. The crude product (2.8 g) was used next step without further purification. LC-MS: (M+H)+=277;
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30]>>[C:22]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)(=[O:20])=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)(=O)c3ccccc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)c1ncc2cc(S(=O)(=O)c3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) from 7-benzenesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and L-alanine MS-(−)-ion: M−1=399.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:2].CS(O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37]COC)[C:28]=1[CH:41](OC)[O:42]C)(=O)=O>>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[C:29]([OH:37])[C:28]=2[CH:41]=[O:42])=[CH:18][CH:19]=1)[CH3:2]
Reactant: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Reactant: CCc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Product: CCc1cc(CC(=O)OC)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C=O)cc1
Yield: 79 %

Procedure:
According to a method similar to Example (40-2) and Example (8-3), from methyl (2-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (4.90 g, 18.1 mmol) obtained in Example (26-4) and 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate (8.35 g, 21.5 mmol) obtained in Example (26-5), methyl (2-ethyl-4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate was obtained as a colorless solid (6.77 g, two-step total yield: 79%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[S:22]1[CH2:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:25]3[CH2:26][CH2:27][S:22][CH2:23][CH:24]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Product: CNC(=O)c1c(C2=CCSCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 100 °C
Yield: 34 %

Procedure:
To a solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (800 mg, 1.6 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (371 mg, 1.6 mmol) and Cs2CO3 (1.07 g, 3.28 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl2 (50 mg) and tri-o-tolylphosphine (50 mg) under nitrogen. The reaction mixture was heated at 100° C. for 4 h, concentrated in vacuo to remove 1,4-dioxane and purified by column chromatography (PE:EA=3:1) to give the compound 5-bromo-2-(3,6-dihydro-2H-thiopyran-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (250 mg, yield: 33%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.59 (s, 1H), 6.73 (s, 1H), 6.06 (brs, 1H), 3.38 (t, J=2.0 Hz, 2H), 3.30 (s, 3H), 3.05 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.87 (t, J=5.6 Hz, 2H), 2.70˜2.76 (m, 2H). MS (M+H)+: 459/461.