Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1.Cl.[Br:28]C1C=CC=C2C=1NC=C2CCN>Cl>[ClH:1].[Br:28][C:10]1[CH:11]=[CH:3][CH:4]=[C:5]2[C:9]=1[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1
Reactant: NCCc1c[nH]c2c(Br)cccc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3Cc1cccc2ccccc12
Agent: Cl
Product: Brc1cccc2c3c([nH]c12)C(Cc1cccc2ccccc12)NCC3
Temperature: 25 °C
Yield: 11.2 %

Procedure:
A suspension of azalactone (prepared as described in Example 5) (55 g, 6.53 mmol) and 7-bromotryptamine hydrochloride (1.50 g, 5.44 mmol) in 1N HCl (100 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The brown solid was triturated with isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50 mL). Recrystallization from ethanol afforded 260 mg of desired product as the hydrochloride salt. (mp=231°-233° C., dec.)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15]CC2C=CC(OC)=CC=2OC)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.CO.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Br:1][C:2]1[N:3]=[C:4]2[NH:15][C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCc1ccc(OC)cc1OC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNc2ncc(Br)nc2N1
Temperature: 75 °C
Yield: 96 %

Procedure:
Ethyl 2-(5-bromo-3-(2,4-dimethoxybenzylamino)pyrazin-2-ylamino)acetate (0.484 g, 1.138 mmol), methanol (0.461 mL, 11.38 mmol) and TFA (7 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 75° C. in an oil bath for 25 min. The resulting mixture was diluted with water (14 mL) and stirred at room temperature for 5 min. Solids were collected by vacuum filtration, washed with water and diethyl ether and dried under high vacuum to give the desired product (0.375 g, 1.093 mmol, 96% yield) as a pink solid. MS (ESI) m/z 229.0 [M]+, 231.3 [M+2]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:12](I)=[CH:13][C:14](=O)[C:15]2[NH:16][CH:17]=[C:18]([CH3:21])[C:19]=2[CH3:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][SH:35])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][S:35][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[C:18]([CH3:21])[C:19]=2[CH3:20])[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1c[nH]c(C(=O)C=C(I)c2c(F)ccc3c2CC(=O)N3)c1C
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Product: Cc1c[nH]c(-c2cc(SCCNC(=O)OC(C)(C)C)c3c(F)ccc4c3c2C(=O)N4)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-fluoro-4-[1-iodo-3-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 48 above) (1.58 g, 4.0 mmol) in tert-butyl-N-(2-mercaptoethyl)-carbamate (Aldrich, 8 mL) was added NaH (Aldrich, 95%, 0.3 g, 11.8 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 3 hours. The reaction was quenched by adding brine and ethyl acetate. The organic layer was dried over an hydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, 4:1 hexaneslethyl acetate) afforded [2-[6-fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester as an orange oil. (Yield 66 mg, 31%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[ClH:1].[C:35]([C:34]1[CH:37]=[CH:38][C:31]([CH2:30][O:18][C:12]2[CH:11]=[C:10]3[C:15]([C:6]([NH:5][C:4]4[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=4[F:2])=[N:7][CH:8]=[N:9]3)=[CH:14][C:13]=2[O:16][CH3:17])=[CH:32][CH:33]=1)#[N:36]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (187 mg, 0.75 mmol), (prepared as described for the starting material in Example 22), 4-bromomethylbenzonitrile (147 mg, 0.75 mmol) and potassium carbonate (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 50° C. for 1 hour. Methanol (5 ml) and potassium carbonate (138 mg, 1 mmol) were added and the mixture stirred at 65° C. for 2 hours. The solvent was removed by evaporation, water was added to the residue and the mixture adjusted to pH7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was triturated with ether, collected by filtration and dried. The solid was dissolved in methylene chloride/isopropanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate collected by filtration, washed with methylene chloride and dried under vacuum to give 7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (60 mg, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9](Cl)=[CH:10][C:11]=1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:27]([CH2:26][C:25]2[CH:40]=[CH:41][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1NC(=O)C(F)(F)F
Reactant: COc1ccc(CNc2ccc(N3CCOCC3)nc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1NC(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
21.8 mg of 6-chloro-4-(trifluoroacetyl)aminopyridine-3-carboxylic acid ethyl ester and 22 mg of 3-(4-methoxybenzyl)amino-6-morpholinopyridine were dissolved in 1 mL of toluene, to which 1.7 mg of palladium (II) acetate, 9.2 mg of 2,2′-bis (diphenylphosphino)-1,1′-binaphthyl and 202 mg of sodium carbonate were added, and stirred overnight at 100° C. After cooling, water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:1) to obtain 5.7 mg (ylod 14%) of the title compound as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1ccccc1C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C=CCC(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
A sodium hydroxide solution (5.5 ml., 20%) is added to a solution of p-chlorobenzaldehyde (14.06 g., 0.1 mole) and 3-phenyl-6-(o-methylphenyl)-5-hexen-2-one (26.4 g., 0.1 mole) in ethanol (260 ml.) with stirring. The yellowish solid that separates on continued stirring is filtered and air-dried, yield 22.5 g., m.p. 60°-76°C. Recrystallization from hexane gives material with m.p. 79°-82°C.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:40])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClCCl.CN(C=O)C>[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH2:38][N:5]6[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]6)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:40])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: FC1(F)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCC(F)(F)C5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
3,3-Difluoropyrollidine hydrochloride (0.200 g, 1.39 mmol) was suspended in DCM and washed with 3M NaOH. The organic phase was separated, dried over anhydrous MgSO4 and filtered into a solution of aldehyde 47 (0.090 g, 0.20 mmol) and acetic acid (0.03 mL, 0.5 mmol) in a 10:1 dichloromethane/DMF mixture (45 mL), which was stirred for 20 min at RT. Then sodium triacetoxyborohydride (0.128 g, 0.60 mmol) was added and the reaction mixture was stirred at RT for 18 h and partitioned between dichloromethane and water. The organic phase was washed with saturated aqueous NaHCO3, then dried (anhydrous MgSO4) and concentrated. Silica gel chromatography (10% methanol/ethyl acetate), of the residue followed by a second column (10% methanol/chloroform) afforded title compound 315 (0.045 g, 42% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H); 8.57 (d, J=2.7, 1H); 8.52 (d, J=5.3, 1H); 8.34 (s, 1H); 8.26 (d, J=8.0, 1H); 7.88 (dd, J=8.2, 2.1, 1H); 7.73 (dd, J=13.7, 2.5, 1H); 7.38 (t, J=9.0, 1H); 7.22-7.19 (m, 1H); 6.65 (d, J=5.3, 1H); 6.60 (d, J=2.7, 1H); 3.71 (s, 2H); 2.92 (t, J=13.3, 2H); 2.73 (t, J=7.0, 2H); 2.57-2.52 (m, 1H); 2.27 (septet, J=7.0, 2H); 0.67-0.63 (m, 2H); 0.45-0.41 (m, 2H). MS (m/z): 540.6 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C@:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH:14]1([C@@:11]([OH:13])([CH3:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=3)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: C[C@@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Product: C[C@@](O)(CNC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 531.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl.CO>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
A solution of 95.0 mg (0.210 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with MeOH (1 drop) and TFA (1 mL). The mixture was stirred at RT for 2 days, and the solvents were evaporated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column with 25% EtOAc-hexane and RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 36.0 mg (39%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 9.02 (dd, 1H, J=8.4, 1.6 Hz), 8.44 (dd, 1H, J=5.2, 1.6 Hz), 8.06 (s, 1H), 7.76-7.71 (m, 1H), 6.22 (sept, 1H, J=2.0 Hz), 2.50-2.43 (m, 2H), 2.18-2.13 (m, 2H), 1.65 (t, 2H, J=6.4 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C18H19N5O, 322.1 (M+H), found 322.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1>>[CH:10]1([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])(=[O:21])=[O:22])[CH2:17][CH2:18]2)[CH2:11][CH2:12]1
Reactant: NCCS(=O)(=O)NC1CCN(C2CC2)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Product: O=C(NCCS(=O)(=O)NC1CCN(C2CC2)CC1)c1ccc(Cl)s1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [2-(1-cyclopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 1 iii) starting from 339 mg (2 equiv.) 5-chloro-thiophene-2-carboxylic acid and 258 mg (1.04 mmol) 2-amino-ethanesulfonic acid (1-cyclopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(1-cyclopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Product: CC(C)c1ccc(NC(=O)c2cccc(S(=O)(=O)c3ccccc3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:26])=[C:13]([CH:25]=1)[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH3:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:26][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:25][C:13]=1[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH3:16]
Reactant: C[C@@H](Nc1cc(O[Si](C)(C)C(C)(C)C)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(O)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
To a stirred solution of (R)-5-(t-butyldimethylsilyloxy)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)aniline (18.5 g, 43.0 mmol) in anhydrous tetrahydrofuran (THF) (100 mL) at 0° C. was added a solution of tetrabutylammonium fluoride (TBAF) (1 M solution in THF, 43.0 mL, 43.0 mmol). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature and stirred for an additional 4 h. The reaction mixture was diluted with deionized water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with deionized water, brine, dried (Na2SO4), filtered, and concentrated in vacuo to give (R)-4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenol as a brown solid (15.3 g). The solid compound was carried to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:32][CH3:33])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:32][CH3:33])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of (±)-cis-3-(4-fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane (1.0 g, 2.23 mmol) and powdered potassium hydroxide (0.25 g, 4.46 mmol) in dry DMSO (5 ml) was heated to 80° C. for 3 h. The mixture was diluted with water (100 ml) and the products extracted into ethyl acetate (3×100 ml). The combined extracts were washed with water, brine, dried over magnesium sulfate, and evaporated to give the crude multi-component product mixture as an orange gum. The title compound was partially purified by means of column chromatography on silica gel 60, with 5% methanol in dichloromethane as eluent. On evaporation the title compound was isolated as a mixture of the title compound with some of the unreacted cis-isomeric starting material. The title compound was fully purified by means of preparative HPLC: column: YMC 120 Å, 15 μm, 250×10 mm; eluent: 60% methanol in 50 mM aqueous ammonium acetate; flow: 10 ml/min; UV detection at 220 nm. Evaporation of the appropriate fractions gave the title compound as a colourless wax.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:33][CH2:32][CH:30]1[O:29][N:28]=[C:27]([C:25]2[S:26][C:22]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[CH:17][N:16]=[N:15]5)[O:10][C:9]4=[O:19])=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[CH2:31]1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)cc1
Temperature: 90 °C
Yield: 40.7 %

Procedure:
(5R)-3-(4-Iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (214 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (100 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[Cl:32][CH2:33][C:34](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Cl:32][CH2:33][C:34]1[O:31][C:3]2[CH:4]=[CH:5][C:6]3[NH:7][C:8]([C:14]4[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]5[C:22]([C:23]=4[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:9][S:10](=[O:12])(=[O:13])[C:11]=3[C:2]=2[N:1]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Reactant: COC(CCl)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4oc(CCl)nc34)N2)c(O)c2ccccc21
Yield: 51 %

Procedure:
A solution of Example 354 (0.030 g, 0.067 mmol) in dimethylformamide (3 mL) was treated with 2-chloro-1,1,1-trimeth oxyethane (0.50 mL) and a catalytic amount of para-toluenesulfonic acid at 60° C. for 4 hours. The solvent was removed under a stream of warm nitrogen and the resulting residue was triturated with water and filtered, then triturated with methanol and filtered to yield the title compound (22 mg, 51%). The sodium salt was made by the procedure of Example 1D. MS (ESI−) m/z 500 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, J=6.62 Hz, 6 H) 1.87 (m, J=20.04, 13.42, 6.99 Hz, 1 H) 2.63 (m, 2 H) 5.13 (s, 2 H) 5.95 (t, J=6.99 Hz, 1 H) 7.08 (t, J=7.54 Hz, 1 H) 7.36 (d, J=9.19 Hz, 1 H) 7.57 (m, 2 H) 7.99 (d, J=8.82 Hz, 1 H) 8.09 (dd, J=7.91, 1.29 Hz, 1 H) 16.59 (s, 1 H).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][OH:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][O:20][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@@H]1c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
To a stirred solution of N-Boc-2-(S)-hydoxymethyl-5-(R)-phenylpyrrolidine (1.10 g, 3.97 mmol), triphenylphosphine (1.25 g, 4.76 mmol) and methyl 4-hydroxybenzoate (724 mg, 4.76 mmol) was added diisopropyl azodicarboxylate (955 ml, 4.76 mmol) at rt, and the resulting mixture was stirred at 60° C. for 45 min. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give methyl 4-[N-Boc-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.31 g, 80%) as a colorless oil. 1H-NMR (CDCl3) δ 1.19 and 1.47 (br s, total 9 H), 2.09–2.15 (m, 3 H), 2.33–2.37 (m, 1 H), 3.94 (s, 3 H), 4.30 (br s, 1 H), 4.41 (br s, 2 H), 4.77 (br s, 1 H), 7.03 (d, J=8.8 Hz, 2 H), 7.24–7.36 (m, 5 H), 8.03–8.06 (m, 2 H); MS (ESI) m/z, 412 (M++H).