Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:14]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[N:15]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C1C=CC=CC=1>[C:42]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[C:14]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)=[N:15][C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(OCCC(c1ccccc1)c1ccccc1)C1=C(COCCC2CCCCC2)NC(c2ccccc2)=NC1c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCCC(c1ccccc1)c1ccccc1)c1c(COCCC2CCCCC2)nc(-c2ccccc2)nc1-c1cccc(Cl)c1

Procedure:
89.8 mg (0.14 mmol) of 4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy) methyl]-2-phenyl-1,4-dihydropyrimidine-5-carboxylic acid 3,3-diphenylpropyl ester and 94.3 mg (0.42 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzochinon (DDQ) were refluxed in 20 ml of benzene for 3 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:57])[N:46]([C:48]1C=C(N)C=[CH:50][C:49]=1OC)C)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:57])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:48][CH2:49][CH3:50])([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1ccc(N)cc1N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (5-amino-2-methoxy-phenyl)-methyl-carbamic acid tert-butyl ester (prepared in two steps from 2-methoxy-5-nitrophenylisocyanate) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41, step b. 1H NMR (CDCl3) 11.00-10.00 (1H, br s), 8.16-8.12 (1H, m), 7.61-7.27 (5H, m), 7.02-6.89 (2H, m), 4.74-4.68 (2H, m), 4.37 (1H, d, 16.8), 4.18 (1H, d), 3.90 (3H, s), 2.99 (3H, s), 2.84 (1H, m), 2.05-1.70 (6H, m), 1.36-1.12 (13H, m). Found: C, 61.98; H, 7.12; N, 11.65%; C30H39N5O4.1.4HCl requires: C, 61.66; H, 6.97; N, 11.99%.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:2].[O-]CC.[Na+].[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=O)[CH:23]=1>C(O)C>[Br:17][C:18]1[CH:23]=[C:22](/[CH:24]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])[CH:21]=[N:20][CH:19]=1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: O=Cc1cncc(Br)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#C/C(=C\c1cncc(Br)c1)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of 3-cyanomethylindole (156 mg, 1.0 mmol) in anhydrous ethanol (1.5 mL) at room temperature was treated with 21% sodium ethoxide in ethanol (450 μL), stirred for 1 hour, treated with 3-bromopyridine-5-carboxaldehyde (J. Heterocycl. Chem., 1995, 32, 1801.) (187 mg, 1.0 mmol), stirred overnight, and concentrated. The residue was purified by flash column chromatography on silica gel with 2% methanol/dichloromethane to provide the desired product (52 mg, 16%). MS (DCI/NH3) m/e 325 (M+H)+.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])=[CH:5][CH:4]=1.[CH3:23]NCC#C.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15](=[O:16])[N:17]([CH3:18])[CH2:21][C:20]#[CH:23])=[CH:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Reactant: C#CCNC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C)C(=O)/N=C1\SCCN1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1-({[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (97 mg, 0.216 mmol, Example 25B), N-methylprop-2-yn-1-amine (0.020 mL, 0.238 mmol) and diisopropylethylamine (0.041 mL, 0.238 mmol) were heated in acetonitrile at 65° C. After 1 hour, the mixture was concentrated and the residue was purified by chromatography over silica using dichloromethane:methanol 95:5 as eluant to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[OH-].[Na+:46]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:23][CH:24]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[Na+:46]
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)[O-])c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1

Procedure:
3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid (14.2 g) was dissolved in ethanol (233 ml) and 1N NaOH in water (23.75 ml) was added. After removal of the solvent, 15.7 g of sodium 3-[5-(pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionate was obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]([C:27](O)=[O:28])[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[CH:21][C:20]([F:26])=[CH:19][CH:18]=3>>[F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH:8][C:27]([CH:16]2[C:17]3[CH:18]=[CH:19][C:20]([F:26])=[CH:21][C:22]=3[O:23][C:24]3[C:15]2=[CH:14][CH:13]=[C:12]([F:11])[CH:25]=3)=[O:28])=[N:5][CH:4]=1
Reactant: Nc1ncc(C(F)(F)F)o1
Reactant: O=C(O)C1c2ccc(F)cc2Oc2cc(F)ccc21
Product: O=C(Nc1ncc(C(F)(F)F)o1)C1c2ccc(F)cc2Oc2cc(F)ccc21

Procedure:
The title compound, white solid, m.p. 249° C. and MS: m/e=379.2 (M+H+), is prepared in accordance with the general method of example 3c from 5-trifluoromethyl-oxazol-2-ylamine and 3,6-difluoro-9H-xanthene-9-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].O1CCCC1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=[O:26].CN>C(N(CC)CC)C>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:5]2[CH2:4][CH2:3][NH:2][C:25](=[O:26])[NH:27][CH3:28]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (167 mg) were added tetrahydrofuran (2.00 mL), triethylamine (0.246 mL), and 1,1′-carbonyldiimidazole (143 mg), followed by stirring at room temperature for 15 minutes. Then, methylamine (2 M tetrahydrofuran solution, 1.77 mL) was added thereto, followed by warming to 50° C. and stirring for 1 hour. The reaction mixture was cooled to room temperature, silica gel was added thereto, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to obtain 5-methoxy-N-methyl-3-{2-[(methylcarbamoyl)amino]ethyl}-1H-indole-2-carboxamide (144 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:11]=[C:12]=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl>[CH2:14]([O:21][NH:22][C:12]([NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOCc1ccccc1
Reactant: CCCCCCCCCCN=C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)NOCc1ccccc1
Yield: 66.3 %

Procedure:
To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3].F[C:10]1[C:11]([CH3:30])=[N:12][C:13]2[C:18]([N:19]=1)=[C:17]([C:20]1[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=1)[CH:16]=[CH:15][CH:14]=2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:30][C:11]1[C:10]([N:7]2[CH2:8][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]2[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=2)[N:12]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CS(=O)(=O)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N1CC(S(C)(=O)=O)C1
Yield: 48.6 %

Procedure:
A solution of 3-methanesulfonyl-azetidine (10.95 mg, 0.08 mmol) (Pharmablock Co. Ltd, cat# PBJH0053), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (24 mg, 0.081 mmol) and DIEA (15.50 μL, 0.09 mmol) in 0.5 mL of NMP was heated in a microwave at 125° C. for 30 min. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM) gave 2-(2-methyl-3-(3-(methylsulfonyl)azetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16 mg, 48% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br.), 7.93 (1H, m, 7.65 (1H, m), 7.44 (1H, m), 7.14 (1H, s), 6.99 (1H, br.), 4.72 (2H, m), 4.60 (2H, m), 4.48 (1H, m), 3.43 (2H, m), 3.15 (3H, s), 2.89 (2H, m), 2.63 (3H, s). m/z (ESI, +ve) 12.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2(OC)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)[CH3:2].[ClH:34]>O1CCCC1>[CH2:1]([N:3]([CH2:32][CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([Cl:34])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Cl
Reactant: CCN(CC)c1ccc(C2(OC)c3ccccc3N(c3ccccc3)c3ccccc32)cc1
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C2(Cl)c3ccccc3N(c3ccccc3)c3ccccc32)cc1
Yield: 95.8 %

Procedure:
9(p-Diethylaminophenyl)-9-methoxy-10-phenylacridan (12.0 g, 0.0276 mole) is slurried in 150 ml of tetrahydrofuran while anhydrous hydrogen chloride is bubbled in with cooling. The hydrogen chloride is bubbled in until the slurry reaches a pH of 1.0 and a bright yellow color is obtained. The product is collected on a Buchner funnel, washed twice with 10 ml portions of tetrahydrofuran and dried at 50° C. to give 11.6 g (95.8% yield) of 9(p-diethylaminophenyl)-9-chloro-10-phenylacridan.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C:18]([CH3:17])([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: CC1(O)CCCNC1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(O)CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.50 g, 2.0 mmol), triethylamine (0.42 mL, 3.0 mmol) and 3-methyl-piperidin-3-ol (0.46 g, 4.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The reaction mixture was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.50 g, 88%). 1H NMR (CDCl3, 300 MHz): 7.49-7.43 (m, 2H), 7.23-7.15 (m, 2H), 3.78 (s, 2H), 3.69-3.59 (m, 2H), 2.63-2.51 (m, 2H), 2.14 (br s, 1H), 1.77-1.49 (m, 4H), 1.15 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16](Br)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1.C(OCC)C>[CH2:21]([C:16]1[CH:15]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 5-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g, 4.37 mmol, Example 12a above) in THF (30 mL) at 0° C. was added [1,3-bis(diphenylphosphino)-propane]nickel(II) (14.0 mg) followed by propylmagnesium chloride (5.50 mL of a 2 M solution in diethyl ether, Aldrich). The reaction mixture was refluxed for 3 h, cooled to ambient temperature and then quenched with saturated aqueous ammonia chloride. The desired product was extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1) to afford 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (292 mg, 22%): MS (CI/NH3) m/z: 307 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.95 (t, J=8.3 Hz, 3H), 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.60-1.70 (m, 2H), 2.22-2.40 (m, 2H), 2.56 (t, J=8.3 Hz, 2H), 3.70-3.80 (m, 2H), 3.90 (m, 1H), 4.13 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.3 Hz, 1H). To a 0° C. solution of 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (290 mg, 0.950 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After stirring for 30 min the reaction mixture was basified with 15% aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by chromatography (silica gel; CH2Cl2/MeOH, 10:0.5) afforded the free base of the title compound as an oil (103 mg, 53%): MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.94 (t, J=8.3 Hz, 3H), 1.58-1.70 (m, 2H), 2.30-2.48 (m, 2H), 2.55 (t, J=8.3 Hz, 2H), 3.57 (m, 1H), 3.76 (q, J=8.3 Hz, 1H), 4.04-4.10 (m, 2H), 4.39 (m, 1H), 7.03 (t, J=3.0 Hz, 1H), 8.04 (s, 1H), 8.14 (d, J=3.3 Hz, 1H). The free base was dissolved in Et2O and a saturated solution of HCl in Et2O was added dropwise carefully. The solvent was removed, and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a yellow hygroscopic solid: mp 79-80° C.; MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (D2O, 300 MHz) δ1.01 (t, J=3.05 Hz, 3H), 1.68-1.80 (m, 2H), 2.62-2.78 (m, 2H), 2.80 (t, J=7.1 Hz, 2H), 4.04-4.21 (m, 3H), 4.44-4.60 (m, 2H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). Anal. Calcd for C12H18N2O.2 HCl.H2O: C, 48.49; H, 7.46; N, 9.43. Found: C, 48.35; H, 7.23; N, 9.48.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:24][CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH2:25][CH3:26])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CCCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 97.5 %

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (1.0 g) and 1-iodopropane (838 mg) were used, whereby the title compound (1.11 g) was yielded.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[C:4]([O:3][C:1]([NH:8][C@H:9]([CH2:10][C:11]1[CH:12]=[C:13]([C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([Cl:21])[CH:23]=2)[CH:14]=[CH:15][CH:16]=1)[C:18]([OH:20])=[O:19])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccc(Br)c1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccc(-c2ccc(F)c(Cl)c2)c1)C(=O)O
Yield: 81.4 %

Procedure:
2-(R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-3-yl)-propionic acid (0.93 g ) was prepared from (R)—N-Boc-3-bromophenylalanine (1.0 g, 2.9 mmol) and 3-chloro-4-fluorophenylboronic acid (1.0 g, 5.8 mmol) following general procedure D.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7]1.ClC1[N:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:23]=1[C:24]([NH:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:25]>>[Cl:44][C:41]1[CH:42]=[N:43][C:11]([N:8]2[CH2:9][CH2:10][C@@H:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH2:7]2)=[C:23]([CH:40]=1)[C:24]([NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH2:29][CH2:28]1)=[O:25]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc(F)c2)C1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC[C@@H](Oc4cccc(F)c4)C3)CC2)cc1
Yield: 106.4 %

Procedure:
The title compound (D205) (96 mg) was prepared according to the experimental procedure described in Description 160 starting from (R)-tert-butyl 3-(3-fluorophenoxy)pyrrolidine-1-carboxylate (D47) (100 mg, 0.355 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (D021/056/3) (65 mg, 0.177 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO.O>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)c(O)cc1O
Temperature: 55 °C
Yield: 83.4 %

Procedure:
8.9 kg of 5-bromo-2,4-dihydroxybenzoic acid are dissolved in 70 l of methanol and heated to 55° C. 800 ml of sulfuric acid (w=95-98%) are subsequently metered in, and the mixture is stirred under gentle reflux for 4 days, with a further 500 ml of sulfuric acid (w=95-98%) being added daily (3 times). The reaction mixture is stirred into a cooled solution (5° C.) of 9 kg of sodium hydrogencarbonate in 100 l of water. Filtration and drying in vacuo at 50° C. gives 7.87 kg (83%) of methyl 5-bromo-2,4-dihydroxybenzoate (white crystals), MW 247.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH:11]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9](=[O:30])[CH:10]3[CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])=[CH:17][CH:16]=2)=[CH:35][CH:34]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(CBr)cc3)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.0 g of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one (11) 7.0 g of 1,4-bisbromomethylbenzene and 5.0 g of potassium carbonate were dissolved in 100 ml of dimethylformamide and stirred at room temperature for 90 min. After the reaction ended, the mixture was dissolved in ethyl acetate and extracted two times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (n-heptane/ethyl acetate). Yield 3.2 g of colorless crystals (12) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>C(OCC)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A solution of 25.82 g (100 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3 mL (20 mmol, 0.2 equiv) DBU was added to the reaction flask then the mixture was stirred at 0° C. for ten min. Slowly 15 mL (150 mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0° C. for 2 hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (<35° C.) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3″×10″ pad) in two batches eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a pale yellow oil. 1H-NMR (CDCl3): δ: 1.74 (3 H, d, J=6.5 Hz), 6.07 (1 H, q, J=6.5 Hz), 7.82 (1 H, s), 7.86 (2 H, s), 8.40 (1 H, br. s) ppm.