Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]1([C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N+]=[N-])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[C:17]1([CH:23]([O:11][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of freshly prepared diphenyldiazomethane22 (3.50 g, 18.0 mmol) in ethyl acetate (20 ml) was added N-Boc-trans-4-hydroxy-L-proline (3.25 g, 14.0 mmol) in ethyl acetate (30 ml). Nitrogen gas was slowly evolved from the solution and the intense purple colour of diphenyldiazomethane was gradually discharged. The solution was stirred at room temperature overnight using a CaCl2 guard tube. Evaporation of the solvent followed by precipitation of the product from ethyl acetate-petroleum ether b.p. 40-60° C. gave a white solid, N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline diphenylmethyl ester (2a), (5.10 g, 91%), m.p. 93-95° C. (lit.9 m.p. 103-104° C.), δH (200 MHz; CDCl3) 1.22 and 1.47 (9H, 2×s, Boc rotamers), 1.95-2.50 [3H, br m, CH2(3) and OH], 3.45-3.74 [2H, br m, CH2(5)], 4.40-4.65 [2H, br m, CH(2)and CH(4)], 6.95 (1H, br s, CHPh2), 7.25-7.55 (10H, br m, phenyl CH); νmax (KBr)/cm−1 3491br (O—H), 1728s (C═O ester), 1693s (C═O urethane); m/z (ES MS) 436 (M+K+, 55%), 420 (M+Na+, 100), 415 (M+NH4+, 15), 398 (M+H+, 72); [α]D25−54.3 (C=1.0, EtOH).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)=[O:2].[H][H]>O1CCCC1.[Ni]>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([B:9]([OH:11])[OH:10])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: OCc1ccc(B(O)O)cc1
Yield: 97 %

Procedure:
15 g (100 mmol) of 4-formylphenylboronic acid were dissolved in 200 ml of tetrahydrofuran, and 0.25 g of Raney nickel were added. A stream of hydrogen was passed through the reaction mixture for 8 hours, giving 14.8 g (97 mmol) of 4-(hydroxymethyl)phenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:23].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]([O-:42])=[O:41].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:42][C:40](=[O:41])[CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][C:26]2[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:31])=[O:7])=[CH:4][C:3]=1[Br:23]
Reactant: Nc1c(Br)cc(C(=O)OCCCCCl)cc1CN1CCOCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCOCC1

Procedure:
This compound was prepared from 4-(4-amino-3-bromo-5-morpholinomethyl-benzoyloxy)-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[Li]C(C)(C)C.CN([CH:28]=[O:29])C>CCOCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:9]([NH:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:28]=[O:29])[CH2:10][CH3:11])=[CH:13][C:14]=1[CH3:19]
Reactant: CN(C)C=O
Reactant: CC[C@@H](Nc1cccc(Br)c1)c1ccc(Cl)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of INT 6 (5.00 g, 14.8 mmol) in Et2O (148 mL) at −78° C. was added tBuLi (1.7 M in pentane, 34.7 mL, 59.0 mmol) dropwise. The mixture was stirred at −78° C. for 40 minutes and DMF (2.5 mL) was added. The reaction mixture was stirred at −78° C. for an additional 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 7.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.B(Br)(Br)Br>C(Cl)Cl>[C:28]1([S:34]([N:9]2[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[CH2:10]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(C2CNCc3cc(OC)ccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1Cc2cc(O)ccc2C(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline (0.103 g, 0.382 mmol, 1.0 eq., see Preparation 64) and triethylamine (0.107 ml, 0.764 mmol, 2.0 eq.) in CH2Cl2 (2 ml) was added to a vial containing benzenesulfonyl chloride (0.101 g, 0.573 mmol, 1.5 eq.). The reaction mixture was stirred overnight at RT. To this mixture was added BBr3 as a 1.0M solution in CH2Cl2 (1.15 ml, 1.15 mmol, 3.0 eq.). The reaction mixture was again stirred overnight at RT, then cooled to −78° C. and quenched with MeOH (1.5 ml). The reaction mixture was evaporated under a stream of nitrogen and purified by reverse phase HPLC (gradient elution 98:2 H2O:0.1% TFA, then 2:98 MeCN:H2O). The exact yield was not determined.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:13][CH2:14][CH3:15])(=[O:12])[C:7]([O:9]CC)=O.[CH3:16][C:17]([CH3:19])=[O:18].S(=O)(=O)(O)O>C(O)C.O>[OH:9][C:7](=[CH:16][C:17](=[O:18])[CH3:19])[C:6]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)=CC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
In a 2-liter three-neck round-bottom flask equipped with a dropping funnel and a paddle stirrer a solution of sodium ethoxide is prepared by reacting metallic sodium (7.74 g, 340.00 mmol, 1.2 eq) in anhydrous ethanol (800 ml) at ambient temperature until the metallic sodium has been completely consumed. A solution of diethyl oxalate (37.20 mL, 280.00 mmol, 1.0 eq) in acetone (10.30 mL, 280.00 mmol, 1.0 eq) is subsequently added dropwise at ambient temperature. The reaction medium is maintained with vigorous stirring for 2 hours. The reaction medium is subsequently concentrated under vacuum. The crude reaction product is diluted in water (200 ml). Ice (100 g) is added, followed by concentrated sulfuric acid (20 ml) in small portions, until a clear orange solution is obtained. The resulting aqueous phase is extracted with ethyl acetate (3×300 mL). The organic phases are combined, dried over MgSO4 and then concentrated under vacuum. The crude reaction product is dried under vacuum to give, quantitatively, the expected product (m=44.71 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(OC(CO)CO)no1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OC(CO)COC2CCCCO2)no1

Procedure:
A solution of 11.26 g of 2-O-(5-methyl-3-isoxazolyl)glycerol (prepared as described in Preparation 20), 5.93 ml of dihydropyran and 0.15 g of pyridine p-toluenesulfonate in 110 ml of methylene chloride was stirred at room temperature for 14 hours. The solvent was removed by evaporation under reduced pressure, and then the residue was subjected to column chromatography through 350 g of silica gel. 3.32 g of the 1,3-ditetrahydropyranyl compound was first eluted with a 1:4 by volume mixture of ethyl acetate and hexane, and then 9.67 g of the title compound were isolated as a colorless oil from the fractions eluted with a 1:1 by volume mixture of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:8][CH:7]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].N1C=CC=CC=1>>[CH3:17][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH:13][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)=CCOc1ccc(OC(C)CN)cc1
Solvent: c1ccncc1
Product: CCOC(=O)NCC(C)Oc1ccc(OCC=C(C)C)cc1

Procedure:
Following the procedure of Example 8, the above propylamine (2.0 g, 8.5 mmol) and ethyl chloroformate (1.01 g, 9.35 mmol) are reacted together, in the presence of pyridine (0.74 g, 9.35 mmol), to give ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]propyl}carbamate, MS m/e 307 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.N>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: CC(=O)c1cc(Oc2ncccc2C(=O)O)ccc1Cl
Agent: N
Product: CC(=O)c1cc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)ccc1Cl

Procedure:
Prepared from 2-(3-Acetyl-4-chloro-phenoxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. MS (m/e): 456/458 (M++NH3, 100). NMR (CDCl3): 8.64 (dd, J=2,8 Hz, 1H), 8.18 (dd, J=2,5 Hz, 1H), 7.95 (m, 1H), 7.46 (m, 3H), 7.31 (m, 3H), 7.19 (m, 2H), 4.68 (d, J=6 Hz, 2H), 2.66 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=1[C:26]([F:29])([F:28])[F:27]>>[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[CH:20][C:19]=1[C:26]([F:27])([F:29])[F:28]
Reactant: CSc1ccc(CCl)cc1C(F)(F)F
Reactant: Sc1nnc(-c2ccc3ncsc3c2)o1
Product: CSc1ccc(CSc2nnc(-c3ccc4ncsc4c3)o2)cc1C(F)(F)F
Yield: 94 %

Procedure:
In the same manner as in Example 7 and using 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 4-(methylthio)-3-(trifluoromethyl)benzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 94%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH:11]=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:26])[CH:4]=1.O.NN>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:26])[CH:4]=1
Reactant: COc1ccc(-c2c(C)ccn2N2C(=O)c3ccccc3C2=O)c(C)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(C)ccn2N)c(C)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a suspension of 2-[2-(4-methoxy-2-methylphenyl)-3-methyl-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)-dione (0.40 g, 1.15 mmol) in EtOH was added hydrazine monohydrate (0.14 mL, 2.89 mmol) at room temperature. The reaction mixture was heated at reflux for 1 h. After cooling down to room temperature, the mixture was filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 0.233 g (93%) of clear oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8 Hz, 1H), 6.89 (s, 1H), 6.84–6.79 (m, 2H), 6.00 (s, 1H), 3.87 (s, 3H), 2.16 (s, 3H), 1.93 (s, 3H); MS m/z 217.1 (M++H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26](C)(C)C)=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[Cl:40]CCl.Cl>C(OCC)C>[ClH:40].[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@H:18]3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 44 mg, 0.08 mmol), methanol (0.1 ml), dichloromethane (0.6 ml) and 1M HCl in diethyl ether (1 ml) was kept at room temperature for 3 weeks. The mixture was concentrated to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2C)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-4-yl]-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-4-yl]-propionic acid as light brown oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:24])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]3[CH2:21][O:20][CH2:19][CH2:18][O:17]3)=[C:10]([O:22][CH3:23])[CH:9]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)(Cl)Cl.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>[NH2:37][C:36]1[CH:38]=[CH:39][C:33]([C:2]2[C:3]([NH2:24])=[N:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]4[CH2:21][O:20][CH2:19][CH2:18][O:17]4)=[C:10]([O:22][CH3:23])[CH:9]=3)[CH:7]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COc1cc(-c2cnc(N)c(Br)c2)ccc1OC[C@H]1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OC[C@H]1COCCO1
Yield: 60.1 %

Procedure:
The compound obtained in Step 2 of Example 41 (2.05 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.14 g), tetrakis(triphenylphosphine)palladium (0.3 g), and potassium carbonate (2.15 g) were suspended in dioxane (30 ml) and water (6 ml), and the suspension was stirred at 100° C. for two hours. After leaving to cool, the reaction solution was diluted with chloroform, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate:hexane=1:1->chloroform:ethanol=19:1 (v/v)] to give 1.27 g of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:32]1([CH2:31][CH2:30][CH2:29][CH:28]([NH:38][C:15]([C@H:12]2[CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13]2)=[O:17])[CH2:27][CH2:26][CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(tert-Butoxycarbonyl)-cis-4-amino-1-cyclohexanecarboxylic acid (23) (1.00 g; 4.11 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.50 g; 4.93 mmol), N,N-diisopropylethylamine (1.70 g; 13.15 mmol) and PyBOP (2.57 g; 4.93 mmol) are added sequentially. The reaction is stirred 4 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (20%→40% ethyl acetate in hexanes) affording the desired product as a solid. CIMS: MH+ 493
Reaction SMILES: [CH2:1]([C:8]1([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26](CC3C=CC=CC=3)[CH3:27])[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[Pd]>[CH2:1]([C:8]1([OH:35])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[CH:21]=2)=[O:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)ccn1
Reaction time: 96 h

Procedure:
A suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-[2-(benzyl-methyl-amino)-pyridin-4-yl]-urea (Example 434., 0.3 g, 0.65 mmol), 2N aqueous HCl (0.65 mL, 1.3 mmol) and Pd—C 10% (30 mg) in MeOH (20 mL) is stirred under hydrogen atmosphere for 96 h. The catalyst is filtered off and the reaction mixture evaporated to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:18])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (4 g, 22.6 mmol) was dissolved in DMF (115 ml) and treated with NaH (1 g, 45.2 mmol) and CH3I (2.8 ml, 45.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. EtOAc was added to the mixture and extracted with 5% citric acid (2×10 mL), saturated NaHCO3 (2×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated to yield the desired product.
Reaction SMILES: Br[CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:9])[CH2:7][OH:8])=[O:4].[K].CCSC(N(CC(C)C)CC(C)C)=O.C([C@H]1OC[C@@](C2C=C(Br)C=CC=2F)(C)NC1=O)C1C=CC=CC=1.C([C@@H]1OC[C@](C2C=C(Br)C=CC=2F)(C)NC1=O)C1C=CC=CC=1>>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([F:17])=[C:10]([C:6]([NH:5][C:3](=[O:4])[CH:2]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:9])[CH2:7][OH:8])[CH:15]=1
Reactant: CC(CO)(NC(=O)C(Br)Cc1ccccc1)c1cc(Br)ccc1F
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: C[C@@]1(c2cc(Br)ccc2F)CO[C@@H](Cc2ccccc2)C(=O)N1
Agent: C[C@]1(c2cc(Br)ccc2F)CO[C@H](Cc2ccccc2)C(=O)N1
Product: CC(CO)(NC(=O)C=Cc1ccccc1)c1cc(Br)ccc1F
Yield: 30 %

Procedure:
In analogy to the cyclization reaction described for the preparation of Building block C, the reaction of (2RS)-bromo-N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide with potassium tent-butylate yielded besides the N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide (0.381 g, 30% of theory), (2R,5S)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one and (2S,5R)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one as the dominant diastereoisomer in form of a white foam (51% of theory). Mass (calculated) C18H17BrFNO2[378.244]; (found) [M+H]+=378, [M+2-H]+=380.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][C@@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:15]([CH2:26][CH2:27][C@@H](O[Si](C(C)(C)C)(C)C)CCCCC)[C@H:14]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[CH:44]=2)(=O)=O)=CC=1.[H-].[Na+].C([O:55][CH2:56][CH3:57])(=O)C>C1COCC1>[Si:19]([O:18][C@H:16]1[C@H:15]([CH2:26][CH2:27][C@@H:56]([O:55][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH2:57][CH2:15][CH2:14][CH2:13][CH3:12])[C@H:14]2[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[C:44]=3[CH2:12][C@H:13]2[CH2:17]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:20])[CH3:21]
Reactant: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(O)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](CC[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A degassed solution of ((1S,2S,3R,4R)-2-(3-hydroxybenzyl)-4-(tert-butyldimethylsilyoxy)-3-((S)-3-(tert-butyldimethylsilyoxy)octyl)cyclopentyl)methyl 4-methylbenzenesulfonate (12.4 g, 0.017 mol) in anhydrous THF (250 ml) at 0° C. under nitrogen was treated with 60% sodium hydride (2.04 g, 0.051 mol). The resulting suspension was stirred for 4 hr at reflux. The reaction was then cooled to 10° C., diluted with ice cold brine (250 ml) and ethyl acetate (500 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 87%.