Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1cc(OC)nc(Oc2cc3c(cc2OC)CCN(CC(=O)NC2CCc4ccccc42)C3Cc2ccc(OC)c(OC)c2)n1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-4,6-dimethoxy-pyrimidine
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]([CH3:19])[C:17]#[N:18])=[CH:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]([CH3:19])[CH2:17][NH2:18])=[CH:8]1
Reactant: CC(C#N)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CN)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred suspension of LAH (3.4 g, 90 mmol) in THF (40 mL, anhyd) chilled to 0° C. was added a solution of 2-(1H-indol-3-yl)propionitrile (2.5 g, 14.7 mmol) in THF (40 mL, anhyd). The reaction mixture was allowed to warm to ambient temperature and then heated at reflux. After 1 hour, the reaction mixture was cooled to 0° C. and quenched cautiously with wet THF (5-10% H2O) until gas evolution had ceased. The resulting mixture was filtered through Celite™ and concentrated to give a brown residue. The filtering agent was rinsed with Et2O (100 mL), which was combined with the residue, dried (Na2SO4), and concentrated under reduced pressure to yield 2-(1H-indol-3-yl)propylamine (2.1 g, 82%) as a pale amber oil; 1H-NMR (CDCl3): δ 8.28 (1H, br s), 7.61 (1H, d), 7.36 (1H, d), 7.16 (1H, app t), 7.08 (1H, app t), 6.96 (1H, br s), 3.41 (2H, br s), 3.19 (1H, q), 2.95 (2H, app d), 1.35 (3H, d).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)([O-:13])=[O:12]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCSc1ncc[nH]1
Product: CSC(=C[N+](=O)[O-])NCCCSc1ncc[nH]1

Procedure:
By the procedure of Example 4(i), 2-(3-aminopropylthio)-imidazole (from the dihydrobromide (3.8 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[3-(2-imidazolylthio)propylamino]ethylene which, on treatment with methylamine according to the procedure of Example 3(ii) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH2:38].C(N(C(C)C)CC)(C)C>CC#N>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10]([NH:38][C:34]2[S:33][CH:37]=[N:36][N:35]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc(Cl)nc1
Reactant: Nc1nncs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc(Cl)nc1
Yield: 79.3 %

Procedure:
A solution of 3-(6-chloro-pyridin-3-yl)-2,2-dimethyl-3-phenyl-propionic acid (Preparation 4, 100 mg, 0.345 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (132 mg, 0.69 mmol) and 1-hydroxy-7-benzotriazole (HOBt) (93 mg, 0.69 mmol), 1,3,4-thiadiazol-2-amine (103 mg, 1.04 mmol) and diisopropylethyl amine (0.21 ml, 1.21 mmol) in CH3CN (1 mL) was heated at 75° C. for 12 hours. The reaction mixture was filtered, concentrated and purified by silica gel flash chromatography using 50% ethyl acetate in hexanes to give 3-(6-chloro-pyridin-3-yl)-2,2-dimethyl-3-phenyl-N-[1,3,4]thiadiazol-2-yl-propionamide as a white solid. (102 mg, 79.3% yield).). 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H), 1.32 (s, 3H), 4.57 (s, 1H), 7.15 (m, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.85 (m, 1H), 8.26 (br s, 1H), 8.90 (s, 1H). LC/MS (m/z) 373.19 [(M+H)+]; HPLC Rt: 2.913 min.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][CH:46]([N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCC(N3CCCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 86 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(piperidine-1-yl)piperidine (30.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(piperidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine (85.3 mg, 86%).
Reaction SMILES: BrCCBr.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH:13]([CH3:15])[CH3:14].[C:16]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17].Cl>CCOCC>[C:16]([N:21]1[CH2:22][CH2:23][C:24]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH:13]([CH3:15])[CH3:14])([OH:27])[CH2:25][CH2:26]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CC(C)Oc1ccccc1Br
Agent: Cl
Solvent: CCOCC
Solvent: BrCCBr
Product: CCOC(=O)N1CCC(O)(c2ccccc2OC(C)C)CC1
Temperature: 22 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a suspended solution of Mg chips (10.07 g, 0.414 mol) in anhydrous ether (150 mL) at 22° C. under argon was added ca. 0.15 mL of 1,2-dibromoethane. Then 43.7 g (0.200 mol) of XIV in 200 mL of ether was added dropwise. After 50% of the aryl halide was added, the reaction began to reflux vigorously. The flask was cooled in an ice bath. After the refluxing had subsided somewhat, the ice bath was removed and the remaining aryl halide was added over a 1.5 h period. The resultant Grignard reagent was cooled in a dry ice/ether bath for 2 h and then treated with 34.0 mL (0.221 mol) of 98% 1-carbethoxy-4-piperidone. Upon complete addition of ketone, the reaction mixture was allowed to warm to 22° C. and stirred for 2 h. The reaction was then quenched with cold aqueous ammonium chloride which resulted in an emulsion. Addition of 1M aqueous HCl solution separated the two layers. The aqueous phase was extracted with additional ether and the combined organic solution was washed with 10% aqueous sodium bisulfite, 1.0M HCl, saturated NaHCO3, and dried (K2CO3). Filtration concentration yielded 56.36 g of XV as a yellow viscous oil which was carried on without further purification The structure of this oil was supported by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:20][CH2:21][C:22]([OH:24])=[O:23]>CN(C)C=O>[C:22]([CH2:21][S:20][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1)([OH:24])=[O:23]
Reactant: O=C(O)CS
Reactant: CCOC(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCC(=O)O)cc1Cl
Temperature: 80 °C

Procedure:
A mixture containing ethyl 2,4-dichlorobenzoate (10.0 g), potassium carbonate (9.44 g), dimethylformamide (50 ml), and mercaptoacetic acid (3.8 ml) was allowed to react with heat at 80° C. for 4 hours.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:26][C:27]([F:36])([F:35])[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].[CH:37]([C:40]1[CH:45]=[CH:44][C:43]([C:46]([CH3:49])=[CH:47][CH3:48])=[C:42]([O:50][CH3:51])[CH:41]=1)([CH3:39])[CH3:38].O>ClCCl>[CH:37]([C:40]1[CH:45]=[CH:44][C:43]([C:46](=[CH:47][CH3:48])[CH2:49][C:28]([OH:34])([C:27]([F:35])([F:36])[F:26])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:42]([O:50][CH3:51])[CH:41]=1)([CH3:39])[CH3:38]
Reactant: CC=C(C)c1ccc(C(C)C)cc1OC
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1ccc(C(C)C)cc1OC

Procedure:
Ytterbium(III) trifluoromethanesulphonate (3.25 g, 5.23 mmol) in 116 ml of dichloromethane is admixed dropwise at room temperature with ethyl trifluoropyruvate (9.55 ml, 78.5 mmol). Following the addition of 4-isopropyl-2-methoxy-1-(1-methylpropenyl)benzene (10.7 g, 52.37 mmol), in solution in 29.5 ml of dichloromethane, the reaction mixture is stirred at room temperature for two days. In parallel a second batch is carried out with the same quantities and under the same conditions. Water (100 ml) is added to each of the two reactions. For further working up, the two batches are combined. The dichloromethane phase is separated off and the aqueous phase is extracted a further time with dichloromethane (300 ml). The combined organic extracts are washed with water (100 ml) and brine (100 ml) and then dried (Na2SO4). After removal of the solvent on a rotary evaporator, the residue is purified by repeated chromatography on silica gel (eluent: ethyl acetate/hexane). The yield of ene product, which is used in the next stage, is 9.08 g, only 40% being the described compound and 60% being the corresponding ethyl 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pent-4-enoate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[CH:17]([O:20][C:21]([N:23]1[C:36]2[C:28](=[CH:29][C:30]3[CH2:31][CH2:32][CH2:33][C:34]=3[CH:35]=2)[C:27](=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])[CH3:18].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH:17]([O:20][C:21]([N:23]1[C:36]2[C:28](=[CH:29][C:30]3[CH2:31][CH2:32][CH2:33][C:34]=3[CH:35]=2)[CH:27]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)OC(=O)N1CCCC(=O)c2cc3c(cc21)CCC3
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)CCC3
Reaction time: 72 h
Yield: 61.1 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (187 mg, 0.77 mmol) followed by titanium isopropoxide (835 mg, 2.94 mmol) to 9-Oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (200 mg, 0.7 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 3 days. Add methanol (3 mL) and sodium borohydride (40 mg, 1.05 mmol) and stir the mixture under nitrogen at room temperature for 16 hours. Add sodium bicarbonate saturated solution. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by silica cartridge, eluting with hexanes/ethyl acetate 9:1, to afford of (+/−)-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (220 mg). Add acetic anhydride (0.22 mL, 2.33 mmol) dropwise to a solution of the amine (80 mg, 0.155 mmol) and pyridine (0.18 mL, 2.33 mmol) in dichloromethane (1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by silica gel cartridge, eluting with hexanes/ethyl acetate 4:1, to afford the title compound (64 mg, 74%); MS (ES+): 579 (M+H+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[C:23]1[CH3:31]>>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:29])=[O:28])[N:24]=[C:23]1[CH3:31]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cn(C)c(C)n2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.8 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (4 mg, 14%) as a brown solid. MS (ESI+) for C17H22N4O3S m/z 386 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCCCC)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([F:44])[C:36]=1[F:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=3)=[N:4][CH:3]=2)=[C:37]([F:44])[C:36]=1[F:45])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(-c2ncc(-c3ccc(OCc4ccccc4)c(F)c3F)cn2)cn1
Yield: 49.1 %

Procedure:
The reaction of 6 mmol of 5-bromo-2-(6-dodecyloxypyridin-3-yl)pyrimidine, 6 mmol of 4-benzyloxy-2,3-difluorophenylboronic acid, 12 mmol of sodium carbonate 0.06 mmol of bis(dibenzylideneacetone)palladium(0) and 0.12 mmol of triphenylphosphine in 50 ml of toluene, 25 ml of ethanol and 25 ml of water is carried out analogously to the procedure indicated for Example 1a). Corresponding chromatographic purification gives 1.4 g (42%) of a colorless solid, m.p. 115° C., cl.p. 172° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([N:36]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]1[NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:46]([N:36]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:37]1[N:41]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3[nH]2)cc1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N(Cc4ccccc4)Cc4ccccc4)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.35 g) was reacted with N,N-dibenzyl-1H-benzo[d]imidazol-2-amine via General Procedure J for Buchwald coupling to give 255 mg of 2-(1-((2-(2-(dibenzylamino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol following flash chromatography.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[N:20]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([C:28](O)=[O:29])[C:26]=3[CH:27]=2)=[O:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].ClC1SC(C2ON=C(CN3C4C(=CC(C(O)=O)=CC=4)C=C3C(=O)NC3CCN(C(C)C)CC3)C=2)=CC=1>>[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[N:20]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:21]3[C:26]([CH:27]=2)=[C:25]([C:28]([N:5]2[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]2)=[O:29])[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: COC1CNC1
Reactant: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)cc3c(C(=O)O)cccc32)c1
Agent: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Product: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)cc3c(C(=O)N4CC(OC)C4)cccc32)c1

Procedure:
The title compound was prepared analogously to example 1 with the difference that 3-Methoxy-azetidine and 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-indole-4-carboxylic acid was used instead of Azetidin-3-ol and 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid. MS (ES+): m/e=519.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[Br:38][C:39]1[C:48]([O:49][C@H:50]2[CH2:55][CH2:54][C@H:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:52][CH2:51]2)=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][C:43]([C@:60]1([CH3:66])[CH2:64][O:63]C(=O)[NH:61]1)=[CH:44]2>>[NH2:61][C@@:60]([C:43]1[CH:42]=[CH:41][C:40]2[C:45](=[CH:46][CH:47]=[C:48]([O:49][C@H:50]3[CH2:51][CH2:52][C@H:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:54][CH2:55]3)[C:39]=2[Br:38])[CH:44]=1)([CH3:66])[CH2:64][OH:63]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2Br)CC1

Procedure:
(R)-2-amino-2-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 31% yield using (R)-4-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=419.29 [M-NH2]+. 1H NMR (MeOD) δ: 8.29 (d, J=9.0 Hz, 1H), 7.92-7.96 (m, 2H), 7.69 (dd, J=9.0, 2.0 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 4.37-4.47 (m, 1H), 3.96 (d, J=11.5 Hz, 1H), 3.85 (d, J=11.5 Hz, 1H), 2.20-2.29 (m, 2H), 1.90-1.97 (m, 2H), 1.78-1.83 (m, 3H), 1.50-1.63 (m, 2H), 1.10-1.30 (m, 3H), 0.94 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6]1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCO)cc1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a sol. of compound 4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (7.60 g, 15.4 mmol) in THF (150 mL) at 0° C. and under Ar was added TBAF (4.86 g, 15.4 mmol). After stirring the mixture for 1 h, aq. sat. NH4Cl (100 mL) was added, and the reaction mixture was extracted with EtOAc (2×). The org. layer was washed with water, brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:1→1:0) yielded the title compound (5.06 g, 87%). LC-MS: tR=0.91 min, ES+=380.30.
Reaction SMILES: ClC1C(O[C:9](=[O:24])[C@H:10]([CH2:22][OH:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=C(Cl)C(Cl)=C(Cl)C=1Cl.[NH2:29][C@H:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[CH2:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:29][C@H:30]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:24])[CH2:22][OH:23])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](CO)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 69.7 %

Procedure:
A solution of benzyloxycarbonyl-serine pentachlorophenyl ester (Z-Ser-OPcp, 19.5 g, 40 mmol) in distilled DMF (100 ml) is added at 0°-5° C. to a stirred solution of H-Leu-OBut (7.5 g, 40 mmol) and HOBt (100 mg) in distilled DMF. The solution is kept at 0° C. for two days and then evaporated to dryness under reduced pressure. The residue is subjected to chromatography on silica gel (1300 g) using hexane-ethyl acetate (1:3) as the eluant. The pure fractions are pooled and evaporated to dryness to yield 11.39 g of the title compound; NMR(CDCl3) δ 0.85 (m, 6H), 1.45 (s, 9H), 7.3 (s, 5H); amino acid analysis: Leu (1.00), Ser (0.93).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[N:15]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:36])[N:15]([C:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=3)[CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:11][CH:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)OCC)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)O)cc3)c2)cc1
Temperature: 50 °C
Yield: 81.8 %

Procedure:
380 mg (10 mmol, 10 eq) of sodium hydroxide are added to a solution of 436 mg (1.0 mmol, 1 eq) of ethyl 3-{3′-[3-(4-butylphenyl)-1-methylureido]biphenyl-4-yl}propanoate in 20 mL of ethanol. The reaction mixture is heated at 50° C. for 3 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and 352 mg of 3-{3′-[3-(4-butylphenyl)-1-methylureido]biphenyl-4-yl}propanoic acid are obtained in the form of white crystals (m.p.=157-158° C.). Yield=86%