Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]([I:27])=[C:13]([C:25]=1[I:26])[C:14]([NH:16][CH2:17][CH:18]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[OH:19])=[O:15])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+].[C:46](OCCBr)(=[O:48])[CH3:47]>CC(N(C)C)=O>[OH:24][CH:21]([CH2:22][OH:23])[CH2:20][CH:18]([OH:19])[CH2:17][NH:16][C:14](=[O:15])[C:13]1[C:25]([I:26])=[C:9]([N:8]([CH2:47][CH2:46][OH:48])[C:6](=[O:7])[CH2:5][OH:4])[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]=1[I:27]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(NCC(O)CC(O)CO)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(N(CCO)C(=O)CO)c1I
Temperature: 25 °C

Procedure:
5-Acetoxyacetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 3, Step B, (89 g, 0.1 g-mole) is mixed with K2CO3 (27.6 g, 0.2-g mole) and 2-bromoethyl acetate (33.4 g, 0.2 g-mole) in DMAc (200 ml). The mixture is stirred at 35°-40° C. until the reaction is complete (approximately 8-12 hours). The solution is then cooled to room temperature and the inorganic salts are filtered. The filtrate is then evaporated under vacuum at 70° C. to yield a thick oil. The oil is triturated with isopropyl alcohol to dissolve the residual DMAC and bromoethyl acetate. The supernatant is decanted and the residual solid is evaporated to dryness to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]([C:23](=O)[C:24]([F:27])([F:26])[F:25])=[CH:19][N:20](C)C)[O:11][N:10]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([NH:45]N)[O:38][N:37]=2)=[CH:32][CH:31]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:45]([C:39]3[O:38][N:37]=[C:36]([C:33]4[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][CH:34]=4)[C:40]=3[C:41]([O:43][CH3:44])=[O:42])[C:23]=2[C:24]([F:25])([F:26])[F:27])[O:11][N:10]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)noc1NN
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(=CN(C)C)C(=O)C(F)(F)F
Solvent: CCO
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2onc(-c3ccc(Cl)cc3)c2C(=O)OC)c1C(F)(F)F
Temperature: 60 °C
Yield: 37.2 %

Procedure:
The mixture of methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate (157 mg, 0.37 mmol) and methyl 3-(4-chlorophenyl)-5-hydrazinoisoxazole-4-carboxylate (0.1 g, 0.37 mmol) in ethanol (1 mL) was heated at 60° C. for 5 h, the solution was evaporated and the product was crystallized from methanol to give 86 mg (37%) of example 131. 1H NMR (DMSO-D6, CCl4): 3.69 (3H, s, OCH3), 3.71 (3H, s, OCH3), 7.35 (1H, dd, CH-arom.), 7.47 (1H, d, CH-arom.), 7.57 (2H, AB-syst., CH-arom.), 7.63 (1H, m, CH-arom.), 7.84 (2H, AB-syst., CH-arom.), 8.74 (1H, s, CH pyrazol.).
Reaction SMILES: B#B.C1COCC1.[CH3:8][C:9]([C:16]([F:19])([F:18])[F:17])([C:13]([NH2:15])=O)[C:10]([NH2:12])=O.[ClH:20]>>[ClH:20].[CH3:8][C:9]([C:16]([F:19])([F:18])[F:17])([CH2:13][NH2:15])[CH2:10][NH2:12]
Reactant: CC(C(N)=O)(C(N)=O)C(F)(F)F
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CC(CN)(CN)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of diborane in THF (56.2 ml, 1.78 mmol/ml, 150 mmol) is put into a 100 ml three neck flask equipped with a Dimroth condenser, and cooled in an ice bath. Subsequently, thereto is added gradually with stirring methyl-trifluoromethylmalonamide (8.0 g, 43.5 mmol) prepared in the above (1) in the form of a crystal, and the mixture is reacted at room temperature for 3 hours. After refluxing for 5 hours, the mixture is acidified with 1N aqueous hydrochloric acid solution with cooling, and THF is distilled off under reduced pressure. The reaction mixture is heated at 70° C. for 30 minutes, and thereto is added KOH with cooling until it saturates. The mixture is extracted with diethyl ether twice, and diamine and water are removed from the residue by azeotropic distillation under reduced pressure. The ether layer and aqueous layer are combined, acidified with 5N aqueous hydrochloric acid solution, and the aqueous layer is distilled off under reduced pressure to give 2-methyl-2-trifluoromethyl-1,3-propanediamine hydrochloride.
Reaction SMILES: [CH2:1]([NH:8][C:9](OC1C(O)=C(C2C=CC=CC=2)S(=O)(=O)C=1C1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC1C=CC=CC=1Cl>[CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)OC1=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1O
Solvent: Clc1ccccc1Cl
Product: O=C=NCc1ccccc1

Procedure:
2.16 g of 3-(benzylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 50 ml of o-dichlorobenzene are heated at 150° C. for 2 hours. The benzyl isocyanate formed is then distilled off under reduced pressure produced by a water pump.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N[C:16](N)=[O:17]>O>[CH2:13]([N:12]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=[C:16]1[OH:17])[CH3:14]
Reactant: NC(N)=O
Reactant: CCNc1ccc2cccnc2c1N
Solvent: O
Product: CCn1c(O)nc2c3ncccc3ccc21
Temperature: 140 °C

Procedure:
22.4 g (0.12 mol) of 8-amino-7-ethylaminoquinoline and 9 g (0.15 mol) of urea are heated at 160° C. for 2 h, stirring vigorously. The mixture is allowed to cool to 140° C., and 50 ml of water are slowly added dropwise. After further cooling to 100° C., another 100 ml of water are added. The precipitate is filtered off with suction, washed again with hot water and dried under reduced pressure.
Reaction SMILES: C([O:5][N:6]=[C:7]([C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:34])[C@@H:17]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][CH:14]=1)[CH3:8])(C)(C)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:19]1([CH2:18][C@H:17]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)[C:16]([NH:15][C:12]2[CH:11]=[N:10][C:9]([C:7](=[N:6][OH:5])[CH3:8])=[CH:14][N:13]=2)=[O:34])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(=NOC(C)(C)C)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=NO)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A solution of N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (342.6 mg, 0.704 mmol) in methylene chloride (1.4 mL) was cooled to 0° C. and then was treated with a 1.0M solution of titanium tetrachloride in methylene chloride (2.10 mL, 2.10 mmol). The resulting reaction solution was stirred at 0° C. for 2 h and then was stirred at 25° C. for 1 h 50 min. The reaction solution was concentrated in vacuo and then partitioned between ethyl acetate (210 mL) and water (150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/2 ethyl acetate/hexanes) afforded the 3-cyclopentyl-N-[5-(1-hydroxyimino-ethyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-phenyl)-propionamide (276.3 mg, 91%) as a white foam: mp 118.8–122.4° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26N4O4S (M+H)+ 431.1748, found 431.1752.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[NH:29])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1
Reactant: N
Product: N=C(Nc1ccc(C(F)(F)F)cc1)Nc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(3-benzyloxypyrid-2-yl)-N'-(4-trifluoromethylphenyl)thiourea (3.08 g, 0.0076 mol), yellow mercuric oxide (2 g, 0.0092 mol) and methanolic ammonia solution (40 ml) was stirred for 48 hours at room temperature, then the solvent was removed in vacuo and the residue extracted with boiling chloroform and filtered hot. Evaporation of the filtrate and recrystallisation from acetonitrile gave the desired product. Yield 2.05 g (70%), m.p. 154°-155 ° C.
Reaction SMILES: CC([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([NH:47][C:48](=[O:59])[C@H:49]([C:55]([CH3:58])([CH3:57])[CH3:56])[NH:50][C:51]([O:53][CH3:54])=[O:52])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C@H:41]([CH2:43][CH3:44])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[N:11]1)(C1C=CC=CC=1)C.S(=O)(=O)(O)O>>[NH:13]1[C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]([NH:47][C:48](=[O:59])[C@H:49]([C:55]([CH3:56])([CH3:58])[CH3:57])[NH:50][C:51]([O:53][CH3:54])=[O:52])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C@H:41]([CH2:43][CH3:44])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:20]=2)=[N:11][N:10]=[N:14]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Agent: O=S(=O)(O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn[nH]2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C

Procedure:
Analogously to Example 26, 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane is deprotected with 80% sulfuric acid to form the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.Cl.[Cl:24][CH2:25][CH2:26][NH2:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][CH2:26][CH2:25][Cl:24])=[O:12])=[C:4]2[N:3]=1
Reactant: NCCCl
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCl)c1cnn2ccc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (284 mg, 1.31 mmol) in DCM (10 mL) was added DIEA (1.14 mL, 6.57 mmol). The solution was cooled to 0° C., then treated with 2-chloroethylamine hydrochloride (183 mg, 1.58 mmol) and stirred for 1 hour. The mixture was partitioned between water (30 mL) and DCM (30 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford 5-chloro-N-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (290 mg, 85% yield) as a beige solid. MS (apci) m/z=258.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9]C(=O)C2C=CC=CC=2)[CH:5]=[CH:4][N:3]=1.C[O-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(OCc1ccnc(F)c1)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1ccnc(F)c1
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a stirred solution of Benzoic acid 2-fluoro-pyridin-4-ylmethyl ester (36) (4.536 g, 19.62 mmol) in anhydrous methanol (40 ml) cooled in an ice bath, was added sodium methoxide (1.06 g, 19.62 mmol). After stirring for 30 min., excess ammonium chloride was added to the mixture. The mixture was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 2.34 g (94%) of a white solid; m.p. 70-71° C.; 1H NMR (200 MHz, CDCl3) δ: 2.40 (1H, t, J=4.0 Hz), 4.78 (2H, d, J=4 Hz), 6.97 (1H, s), 7.15 (1H, m), 8.15 (1H, d, J=5.0 Hz); m/z (EI): 127 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27].CN1CCOCC1>C1COCC1>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[CH2:13][NH:12][C:10]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:2][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])[N:5]=1)=[NH:11]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NCc1csc(NC(=N)NCc2c(OC)cccc2OC)n1

Procedure:
Reaction of 100 mg (0.33 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, with 60.4 mg butane sulfonic acid chloride in 5 ml THF with addition of 480 mg polymer-bound NMM (1.7 mmol/g; Argonaut) and chromatography of the crude product on silica gel dichloromethane/methanol 0-2%) yielded 46 mg; ESI-MS [M+H+]=442.05.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=[O:1]
Reactant: N#Cc1cccc2c1OCCC2CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc2c1OCCC2C=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(hydroxymethyl)-3,4-dihydro-2H-chromene-8-carbonitrile (210 mg, 1.11 mmol) in 10 mL of anhydrous DCM was added NaHCO3 (933 mg, 11.1 mmol), Dess-Martin reagent (942 mg, 2.22 mmol) at 0° C. The mixture was stirred at 0° C. for 1-2 hours. The reaction mixture was filtrated and purified by prep-TLC to give 4-formyl-3,4-dihydro-2H-chromene-8-carbonitile. 1H-NMR (400 MHz, CDCl3) δ ppm 9.67 (s, 1H), 7.43˜7.45 (m, 1H), 7.34˜7.36 (m, 1H), 6.93˜6.97 (m, 1H), 4.35˜4.39 (m, 1H), 4.0˜4.06 (m, 1H), 3.58˜3.6 (m, 1H), 2.4˜2.46 (m, 1H), 2.06˜2.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:20](=[O:21])[NH:19][C:18]([CH3:22])=[N:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:20](=[O:21])[NH:19][C:18]([CH3:22])=[N:17][C:7]=3[CH2:8][N+:9]([O-:33])=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2

Procedure:
A solution of 2.8 g (8.3 mmol) of 9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one and 2.5 g (11.5 mmol) of 85% m-chloroperbenzoic acid in 110 mL of methylene chloride was stirred at room temperature for 2.5 hr. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow solid. Recrystallization from methanol gave pale yellow prisms, mp 219°-221°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[CH3:13][N:14](C=O)C>CCOC(C)=O.[Zn].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]([CH3:11])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(C)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
Zinc cyamide (6.2 g, 52 mmol) and tetrakis(triphenylphosphine) palladium (0) (4 g, 3 mmol) was added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (20 g, 87 mmol) and DMF (100 mL) and stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc (700 mL), washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, 1:3 EtOAc:hexanes) provided the title compound (12.3 g, 39.8% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:38])[O:9][N:8]=[C:7]([C@@H:10]([NH:20][C:21]([O:23]CC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6]1)=[O:4].N1CCCCC1.[CH:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][C:46]=1C(O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:38])[O:9][N:8]=[C:7]([C@@H:10]([NH:20][C:21]([C:47]2[CH:46]=[CH:45][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:48]=2)=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CC([C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)=NO1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CC([C@H](CCC(=O)OC(C)(C)C)NC(=O)c2ccc3ccccc3c2)=NO1
Yield: 34.8 %

Procedure:
A solution of 3-[(1S)-1-(9-fluorenylmethyloxycarbonylamino)-3-t-butoxycarbonyl-propyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester (440 mg, 0.842 mmol) in DMF (8.0 mL) at room temperature was treated with piperidine (2.5 mL) for 5 min. After concentration, the residue was dissolved in DMF (10 mL), and treated with 2-naphthoic acid (174 mg, 1.2 eq), EDC (210 mg, 1.3 eq), HOBt (148 mg, 1.3 eq) and triethylamine (0.35 mL, 3.0 eq), then sired overnight (0° C. to room temperature). Usual workup followed by chromatography gave 133 mg of the title compound and 260 mg (˜50% purity) mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:6](Br)[C:7]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:24](B(O)O)[CH:25]([CH3:27])[CH3:26].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C(OCC)(=O)C.ClCCl>[CH2:24]([C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:6]([CH2:3][CH:4]([CH3:18])[CH3:5])[C:7]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CB(O)O
Reactant: O=C(Nc1c(Br)cc(-c2ccccc2)cc1Br)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2ccccc2)cc(CC(C)C)c1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 171.1 %

Procedure:
A mixture of N-(3,5-dibromobiphenyl-4-yl)benzamide (8.52 g, 19.8 mmol), isobutyl boronic acid (8.06 g, 79.2 mmol), potassium phosphate monohydrate (13.7 g, 59.4 mmol), water. (50 mL) and toluene (150 mL) was purged with nitrogen for 20 min before addition of tris(dibenzylideneacetone) dipalladium(0) (0.27 g 3% Pd) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.49 g, 6 mol %). The reaction was stirred at reflux for 18 h. After cooling to ambient temperature the mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was concentrated and chromatographed on a silica gel column. Elution first with dichloromethane then dichloromethane and ethyl acetate (49:1) gave 6.53 g (86% yield) of the desired product as a solid. 1H NMR confirmed the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[BH4-].[Na+].O.[OH-].[Na+].[C:44](O)(=O)[CH3:45]>>[CH2:44]([N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:12]=[C:11]([CH3:13])[O:10][N:9]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1)[CH3:45]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)no1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4noc(C)n4)cc2C)cc1)CC3
Yield: 52 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E3, 100 mg, 0.20 mmole) in glacial acetic acid (2 ml) at room temperature under argon was carefully treated with sodium borohydride pellets (50 mg, 1.3 mmole) and stirred for 24 H. Additional sodium borohydride pellets were added (50 mg, 1.3 mmole) and reaction mixture stirred at room temperature for a further 72 h. The reaction mixture was then treated with water (20 ml), basified with 10% NaOH solution (20 ml) and extracted with dichloromethane. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 3% MeOH/CHCl3. Crystallisation of the product form ethyl acetate/60-80 petrol afforded the title compound as a white solid (55 mg, 52%) mp 202-204° C.
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>CO>[OH:1][CH:2]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)[CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.8 g, 26.6 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (26.6 ml, 53.2 mmol), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (9.0 g, 81%).
Reaction SMILES: C=O.[BH3-][C:4]#N.[Na+].[C:7]1([CH:13]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:14][NH:15][CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)=O.CO>[C:35]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][N:15]([CH3:4])[CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [BH3-]C#N
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCC(c2ccccc2)c2ccccc2)nc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CC(c1ccccc1)c1ccccc1)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
Add paraformaldehyde (57 mg) and NaBH3CN (46 mg, 0.734 mmol) to a solution of 6-[1-(2,2-Diphenyl-ethylamino)-indan-5-yloxy)-nicotinamide (example 9, 110 mg, 0.245 mmol) in 5% AcOH/MeOH (3 ml) and stir at ambient temperature for two days. Concentrate the reaction mixture and partition remaining residue between EtOAc and 1M aq. K2CO3. Separate layers and wash organic with 1M aq. K2CO3 and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 74 mg of the title compound as a white solid. Mass spectrum (ion spray): m/z=464 (M+1); 1HNMR (CDCl3): 8.54 (s, 1H), 8.15 (d, 1H), 7.30-7.15 (m, 10H), 6.95-6.81 (m, 4H), 5.81 (br. s, 2H), 4.39 (t, 1H), 4.20 (t, 1H), 3.02 (d, 2H), 2.94-2.75 (m, 2H), 2.27 (s, 3H), 2.06 (m, 2H).