Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][CH:29]([NH:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6])[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NCC[C@@H](O)CO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC[C@@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously starting from 22 mg (0.21 mmol) of (R)-4-aminobutane-1,2-diol and 80 mg (0.21 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4C)c3O2)cc1
Product: CNCC1Cc2ccc(F)c(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.053 g, 72%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.24 mmol) and methylamine (0.31 g, 10.0 mmol). mp 200-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1CCOCC1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:31]4[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[N:29][CH:30]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4ccc(C#N)nc4)cnc3s2)cc1OC
Temperature: 120 °C
Yield: 26.6 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.10 g, 0.3 mmol, 1 eq), dioxane (5 mL), 2-cyanopyridine-5-boronic acid pinacol ester (0.155 g, 0.64 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.018 g, 0.1 eq), potassium carbonate (0.178 g, 1.3 mmol, 5 eq), and water (2 mL) was heated in the microwave oven (120° C., 30 min) and was left to cool to RT. A precipitate formed that was filtered off (0.048 g) and washed with a mixture of Et2O and little MeOH to afford the desired product (white solid, 0.029 g, 31%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=5.37 min, [M+H]+ m/z 364.1; 1H NMR (300 MHz, DMSO) d 9.47-9.39 (m, 1H), 8.68 (dd, J=8.3, 2.3, 1H), 8.23-8.10 (m, 2H), 7.60 (dd, J=8.3, 2.3, 1H), 7.51 (d, J=2.1, 1H), 7.17 (d, J=8.5, 1H), 3.91 (s, 3H), 3.87 (s, 3H);
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[F-].[K+].[Sn](C)(C)(C)[CH3:18].CCOC(C)=O>CN(C=O)C.[Cu]I.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>[CH3:18][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: C[Sn](C)(C)C
Reactant: O=C1CCC(=O)c2ccc(I)cc2N1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)NC(=O)CCC2=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 31.7 %

Procedure:
To a degassed solution of 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.3 g, 1.0 mmol) in DMF (5 mL) was added CuI (19 mg, 0.1 mmol), KF (116 mg, 2.0 mmol), Me4Sn (0.28 mL, 2.0 mmol), and Pd(PPh3)4 (116 mg, 0.1 mmol). The reaction mixture was allowed to stir at 120° C. for 4 h. After being allowed to cool to rt, EtOAc (50 mL) and a 1M aqueous KF solution (25 mL) were added and the solution was allowed to stir for an additional 40 min. The mixture was filtered over Celite®. The organic solution was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to provide 8-methyl-3,4-dihydro-1H-1-benzazepine-2,5-dione (60 mg, 32%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([C:12]#[C:13][Si](C)(C)C)[C:5]=2[N:6]=[CH:7][N:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:12]([C:9]1[C:5]2[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=2[S:11][CH:10]=1)#[CH:13]
Reactant: CSc1ncnc2c(C#C[Si](C)(C)C)csc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1csc2c(SC)ncnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
4-(Methylthio)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidine (500 mg, 1.8 mmol) was dissolved in THF (5 mL) at 1.0M and then tetrabutylammonium fluoride solution (3.6 mL, 3.6 mmol) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The resulting mixture was purified by silica gel chromatography (ethyl acetate/hexane=2:8˜3:7) to obtain the title compound (340 mg, 91% yield) as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][NH:16]3)=[O:10])[CH:7]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][NH:16]3)=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=O)Nc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a mixture of 1-(5-chloro-2-methoxyphenyl)-3-(1H-indol-4-yl)urea (6.3 g, 20 mmol) in acetic acid (50 mL) was added portionwise NaBH3CN (1.9 g, 30 mmol), and the resulting mixture was stirred at rt for 1 h. The solvent was evaporated and residue was diluted with water, neutralized with NaHCO3 and extracted with EtOAc. The combined organic phase were washed with brine, dried and evaporated to give crude 1-(5-chloro-2-methoxyphenyl)-3-(2,3-dihydro-1H-indol-4-yl)urea (6.3 g, 100%), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]([F:51])([F:50])[C:6]1[CH:7]=[C:8]([C@H:16]2[O:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=3[C:33]3[CH:34]=[C:35]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]=[O:47])=[CH:42][C:41]=4[CH3:48])[CH:36]=[CH:37][C:38]=3[Cl:39])[C@H:17]2[CH3:49])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[Cl-].[NH4+]>C1COCC1>[F:51][C:5]([F:4])([F:50])[C:6]1[CH:7]=[C:8]([C@H:16]2[O:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[CH:25][C:24]=3[C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[C:35]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]([OH:47])[CH3:1])=[CH:42][C:41]=4[CH3:48])[CH:34]=3)[C@H:17]2[CH3:49])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: Cc1cc(C=O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
MeMgBr (0.274 ml, 0.274 mmol, 1 M solution) was added to a solution of aldehyde from Example 50 (160 mg, 0.229 mmol) in THF (3 ml) at −78° C. The solution was stirred at −78° C. for 2 h. Saturated ammonium chloride solution was added. The mixture was extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.89 (s, 1H), 7.72 (m, 4H), 7.58 (d, J=8.5 Hz, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.32-7.20 (m, 4H), 5.62 (d, J=8.0 Hz, 1H), 5.00 (d, J=15.5 Hz, 0.5H), 4.93 (m, 1H), 4.82 (d, J=16.0 Hz, 0.5H), 4.10 (d, J=15.5 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 3.88 (m, 0.5H), 3.87 (m, 0.5H), 2.34 (s, 1.5H), 2.33 (s, 1.5H), 1.55 (m, 3H), 0.61 (d, J=6.5 Hz, 1.5H), 0.58 (d, J=6.5 Hz, 1.5H). LC/MS: M+−18: 698.16.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14](Br)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:46]2[CH2:47][CH2:48][N:43]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:44][CH2:45]2)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Product: Cc1c(N2CCN(Cc3ccccc3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 120 °C
Yield: 62.3 %

Procedure:
{(R)-2-[5-bromo-3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (45 mg, 0.082 mmol), 1-benzyl-piperazine (216 mg, 1.23 mmol), and acetonitrile (500 μl) were placed in a microwave vessel and heated at 120° C. for 1 hr by microwave irradiation with stirring. Following concentration, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford the 33 mg of the compound as a colorless oil (yield 62%).
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[C:8]([OH:32])[C:9]([C:11]3(O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]([OH:32])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.1 %

Procedure:
To a solution of 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (2.50 g, 5.32 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was added triethylsilane (4.2 mL, 26 mmol) and trifluoroacetic acid (12 mL). The reaction mixture was allowed to warm to ambient temperature and was stirred for 72 h and was concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 0% to 30% gradient of ethyl acetate in hexanes afforded 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (1.81 g, 75%) as a colorless amorphous solid: MS (ES+) m/z 454.2 (M+1).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:19])([CH3:18])[CH2:10][N:11]1[CH:15]=[C:14](I)[N:13]=[C:12]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26]>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:19])([CH3:18])[CH2:10][N:11]1[CH:15]=[C:14]([Sn:25]([CH3:27])([CH3:26])[CH3:24])[N:13]=[C:12]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1nc(I)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1nc([Sn](C)(C)C)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 26.8 %

Procedure:
To a mixture of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-2-methyl-1H-imidazole (1.5 g, 3.8 mmol) in DCM (15 mL) was added ethylmagnesium bromide (1.9 mL, 3 mol/L, 5.7 mmol) at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride (6.5 ml, 1 mol/L, 6.5 mmol) was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM, The organic was washed with water twice, dried over anhydrous Na2SO4, concentrated to give 0.44 g of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole. Yield=63%. 1H NMR (CDCl3, 400 MHz): δ 7.04 (s, 1 H, ArH), 3.74 (s, 2 H), 2.43 (s, 3 H), 1.24-1.20 (m, 6 H), 0.88 (s, 9 H), 0.29 (s, 6 H), 0.03 (s, 8 H). LC-MS: m/z=375 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH:43][CH2:44][CH:45]([CH2:48]O)[CH2:46][OH:47].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:48][CH:45]([CH2:46][OH:47])[CH2:44][OH:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)CO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCC(CO)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 50.1 %

Procedure:
In a manner similar to the method described in Example 7, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.2 mg, 0.163 mmol) was reacted with N,N′-carbonyldiimidazole (Aldrich, 69.5 mg, 0.416 mmol) and then, a mixture of 2-(hydroxymethyl)-1,3-propanediol (Aldrich, 91.8 mg, 0.839 mmol) and sodium hydride (41.6 mg, 1.65 mmol) in tetrahydrofuran to give chiral 3-hydroxy-2-(hydroxymethyl)propyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white lyophilized solid (57.5 mg, 50% yield). MS (ES+) m/z calcd. for C35H38Cl2F2N3O6: [(M+H)+]: 704. found: 704.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][C:57]([CH3:62])([CH2:60][OH:61])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:31])([CH2:60][OH:61])[CH3:62]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CC(N)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NC(C)(CO)CO
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-amino-2-methyl-propane-1,3-diol (49 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 8 days, the reaction was concentrated, diluted with DCM and then added solid sodium bicarbonate. After stirring at rt for 15 mins, the resulted suspension was loaded onto a silica gel column to give the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>CC(C)=O>[C:2]1([NH:1][C:8](=[O:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
N,N'-diphenylterephthalamide (Structure I) is synthesized from aniline and terephthaloyl chloride using acetone as a reaction media and an aqueous solution of NAOH to neutralize the HCl generated. Terephthaloyl chloride (87.2 grams, 0.43 moles) is first added to a stirred, 2-liter reaction flask containing one liter of acetone. After the terephthaloyl chloride has dissolved, aniline (80.0 grams, 0.86 moles) is added dropwise using an addition funnel over a 30 minute period. During the course of this addition, a white precipitate is formed. A 200 ml aqueous solution of NaOH (34.3 grams, 0.86 moles) is then added, also using an addition funnel, over a 30 minute period. The reaction temperature during both the aniline and NAOH addition is maintained below 35° C. by blowing air onto the outside of the reaction flask. After the NAOH addition, the reaction mixture is stirred for three hours and then vacuum filtered (filtrate pH=7). The filter cake obtained is washed with 400 ml of acetone and then added to one liter of deionized water, stirred for 15 minutes and filtered. This filter cake is washed with 500 ml of acetone and then dried in a 105° C. vacuum oven to a constant weight. This final product (114.4 grams, yield=84.2%) exhibited a sharp melting endotherm by differential scanning calorimetry (DSC) at 346° C. Also Fourier transform infrared (FTIR) analysis showed the following absorbances which are indicative of the structure for the final product: 3329 cm-1 (N-H stretch), 1528 cm-1 (Amide II band) and 1650 cm--1 (Amide I band). ##STR9##
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3F)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(F)c4F)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(2,3-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.391 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.14 (1:2 EtOAc-heptane); Rt=5.81.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([CH3:24])([CH3:23])[C:14]([N:16]3[CH:20]4[CH2:21][CH2:22][CH:17]3[CH2:18][CH2:19]4)=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=2)[CH:34]=1.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)(=O)C>[CH:17]12[N:16]([C:14](=[O:15])[C:13]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[C:4]4[CH2:3][CH2:2][NH:1][CH2:43][C:42]3[CH:41]=[CH:40][C:39]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[CH:46][CH:45]=3)([CH3:24])[CH3:23])[CH:20]([CH2:19][CH2:18]1)[CH2:21][CH2:22]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCc2ccc(-c3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 28.8 %

Procedure:
To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2.1]hept-7-yl)-2-methyl-propan-1-one (20 mg in 1.5 mL dry, degassed tetrahydrofuran) was added 9.4 mg 4-pyridin-3-yl-benzaldehyde followed by 43 mg titanium (IV) isopropoxide and the mixture stirred at room temperature. After 60 hours, the reaction was cooled to 0° C. and a solution of sodium cyanoborohydride (9.0 mg in 0.50 mL methanol) was added along with 0.026 mL acetic acid and the mixture stirred at low temperature. The reaction was quenched after 45 minutes by the addition of saturated aqueous ammonium chloride and brine. This was then extracted with ethyl acetate and the organics washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash chomatography on silica gel (ethyl acetate:hexane, 75:25; then methylene chloride:10% ammonium hydroxide in methanol, 98:2; then 97:3; then 95:5) gave the title compound (8.0 mg). MASS: 597 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(O)(=O)CC(O)=[O:18].CCC1(CC)C(=O)NCCC1=O>N1C=CC=CC=1>[CH2:10]([O:9][C:7]([C:6]1[CH:13]=[CH:14][C:3]([C:1]([OH:18])=[O:2])=[CH:4][CH:5]=1)=[O:8])[CH:11]=[CH2:12]
Reactant: C=CCOC(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: CCC1(CC)C(=O)CCNC1=O
Solvent: c1ccncc1
Product: C=CCOC(=O)c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
17.2 g (90.5 mmol) of allyl 4-formylbenzoate, 24 g (230 mmol) of malonic acid, 8 ml of piperidione and 100 ml of pyridine are introduced into a round-bottomed flask. The reaction medium is heated at 100° C. for six hours and then evaporated to dryness. The residue is taken up in water and dichloromethane and acidified to pH 1, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The solid obtained is triturated from hexane, filtered off and dried. 16.7 g (80%) of 4-allyloxycarbonylbenzoic acid, with a melting point of 205-6° C., are collected.