Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:33]([O:35][C@H:36]1[CH2:40][CH2:39][O:38][CH2:37]1)=[O:34]>C(Cl)Cl>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:33](=[O:34])[O:35][C@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (907.2 mg, 2.16 mmol) was added 4 mL of 1:1 TFA:CH2Cl2. The mixture was stirred at room temperature for 5 hours. The reaction was diluted with a solution of saturated aqueous NaHCO3 and CH2Cl2. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol. To this free amine (640 mg, 2 mmol) was added 8 ml of CH2Cl2 and triethylamine (335 μL, 2.4 mmol). After cooling the mixture to 0° C., (S)-tetrahydrofuran-3-yl chloroformate (271 mg, 1.8 mmol) was added, and the reaction was allowed to stir for 30 minutes. Purification on silica gel using 30-100% ethyl acetate/hexanes gave (S)-tetrahydrofuran-3-yl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, CDCl3) δ 14.8 (bs, 1H), 8.34 (d, J=6.4 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.48 (bs, 1H), 7.27 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.5 Hz, 1H), 5.21 (s, 1H), 5.06 (s, 1H), 4.37 (s, 1H), 4.15 (m, 1H), 4.02 (s, 1H), 3.97 (d, J=5.6 Hz, 1H), 3.87-3.77 (m, 5H), 2.42 (s, 3H), 2.24 (t, J=6.0 Hz, 1H), 2.15-2.06 (m, 1H), 1.98 (q, J=9.3 Hz, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1.[Cu](C#N)[C:19]#[N:20].C(N)CN>CN(C=O)C>[C:19]([C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: O=C(NC1CCCCC1)c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc(C(=O)NC2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Heat a mixture of 4-bromo-N-cyclohexyl-2-fluoro-benzamide (1.24 g, 4.13 mmol) and copper cyanide (740 mg, 8.26 mmol) in DMF (20 mL) to reflux for 16 h. Cool the mixture to ambient temperature, add aqueous ethylenediamine and stir for 30 min. Extract the mixture with hexane/EtOAc (1:1), dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give the desired intermediate as a white solid (620 mg, 61%). MS (ES−) m/z: 245 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[CH:23][N:24]([CH3:26])[CH3:25])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ccc(OCc3ccccc3)cc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CCc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
7-Benzyloxy-3,4-dihydro-2-dimethylaminomethylene -1(2H)naphthalenone was prepared from 7-benzyloxy-3,4-dihydro-1(2H)naphthalenone (6.0 g, 23.8 mmol) and N,N-dimethylformamide diethylacetal (20 ml, 119.4 mmol) to give the desired compound as a pale yellow solid (4.56 g) m.p. 85-86°. MS(ES+) 308 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: Nc1cccc2ccccc12
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3cccc4ccccc34)nc2N1c1ccccc1
Temperature: 130 °C
Yield: 40.8 %

Procedure:
A mixture of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 320 mg (2.2 mmol) of 1-aminonaphthalene was heated at 130° C. for 4 hours. The mixture was left to cool and was then partitioned between 10 ml of ethyl acetate and 2M hydrochloric acid. The insoluble 1-aminonaphthalene hydrochloride was removed by filtration. The ethyl acetate phase was separated, washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution. Product-containing fractions were evaporated to give 46 mg (40%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(1-naphthylamino)-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a pale pink solid of melting point 213-214° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].C[Si]([C:34]([F:37])([F:36])[F:35])(C)C>CN(C)C=O.[Cu]Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(C(F)(F)F)c23)C1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution of Intermediate 1a (200 mg) prepared in Example 1-1, Step A in N,N-dimethylformamide (5 ml) was added with potassium fluoride (30.8 mg, Aldrich), trimethylsilyltrifluoromethane (0.196 ml, Aldrich), and copper(I) chloride (65.2 mg, Wako Pure Chemical Industries), and the mixture was stirred at 60° C. for 15 hours. The reaction mixture was cooled to room temperature, and then the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was separated and purified by HPLC to obtain the title compound (16.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(C)(C)N
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C(C)(C)NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (100.3 mg, 0.268 mmol) and methyl 2-amino-2-methylpropanoate hydrochloride (41 mg, 0.268 mmol) according to Reference R and the general procedure for reductive amination to give methyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)benzylamino)-2-methylpropanoate as a yellow-orange oil. MS (ESI) m/z: Calculated: 475.2; Observed: 476.1 (M++1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[O:12]=[C:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[C:24]2[CH:25]=[CH:26][C:21]([S:18]([NH2:17])(=[O:20])=[O:19])=[CH:22][CH:23]=2)[NH:7]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Product: NS(=O)(=O)c1ccc(-c2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Yield: 1.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 171 using Compound 83 (100 mg, 0.43 mmol) and 4-(aminosulphonyl)benzeneboronic acid (174 mg, 0.87 mmol) to provide 177 (2 mg, 2% yield) as a grey solid. LC-MS (M+H=352, obsd.=352).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[F:7][C:8]([F:58])([F:57])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:49]([CH3:50])=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:51])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:56])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:41]([CH3:51])=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][C:49]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)[N:27]=3)[C@H:20]2[CH3:56])[CH:10]=[C:9]([C:8]([F:7])([F:58])[F:57])[CH:14]=1
Reactant: FC1CNC1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
3-Fluoroazetidine hydrochloride (26.7 mg, 0.239 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 44, 60 mg, 0.080 mmol), THF (800 μl) and triethylamine (55.6 μl, 0.399 mmol) were stirred at 100° C. for 10 minutes in the microwave reactor. Once complete, the reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ8.15 (s, 1H), 68.02 (d, 1H), 67.89 (s, 1H), 67.80 (s, 2H), 67.74 (s, 2H), 67.28 (d, 1H), 65.71 (d, 1H), 65.51 (m, 0.5H), 65.40 (m, 0.5H), 64.71 (d, 1H), 64.45 (m, 3H), 64.30 (m, 2H), 64.00 (d, s, 4H), 63.93 (s, 3H), 62.14 (d, 6H), 60.74 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]2[CH2:39][CH2:38][C@@H:37]([CH2:40][C:41](O)=[O:42])[N:29]3[C:30](=[O:36])[C:31](=[O:35])[NH:32][C:33]([CH:34]=1)=[C:28]23>>[Br:24][C:25]1[CH:26]=[C:27]2[CH2:39][CH2:38][C@@H:37]([CH2:40][C:41](=[O:42])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=3[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:29]3[C:30](=[O:36])[C:31](=[O:35])[NH:32][C:33]([CH:34]=1)=[C:28]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC(=O)CCCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Product: COC(=O)CCCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 45.8 %

Procedure:
A procedure similar to that described in Example 9-7) was performed with 4-tert-butoxycarbonylaminomethyl-2-(3-methoxycarbonylpropyl)aniline (130 mg, 0.4 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (136 mg, 0.4 mmol) to give 118 mg of the title compound (62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([OH:33])[CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:28]=[C:27]([C:26]([F:34])([F:25])[F:35])[CH:32]=[CH:31][N:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cc(C(F)(F)F)ccn1
Product: CC(NC(=O)c1coc(Oc2cc(C(F)(F)F)ccn2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 30.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-trifluoromethyl-pyridin-2-ol (43 mg, 0.26 mmol) to give the title compound (20 mg, 30%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>C(NCC)C.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.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][C:21]3([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CCCC1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC3(O)CCCC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
9.57 g (25.5 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 3 hours with 3.52 g (32 mmol) of 1-ethynylcyclopentanol, 170 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 30 mg of copper(I) iodide in 60 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After crystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-[(1-hydroxycyclopentyl)ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-208°.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9])=[O:7])([CH3:4])[CH3:3].[CH3:21][S:22][CH2:23][CH2:24][NH2:25]>>[CH3:21][S:22][CH2:23][CH2:24][NH:25][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH3:9]
Reactant: CSCCN
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Product: CSCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C

Procedure:
This was prepared by coupling of BOC Me Phe OH with 2-methylthioethylamine by the method of Example 1(b) The product was obtained as an oil. Rf1G=0.71 Rf32A=0.48
Reaction SMILES: [CH2:1]([C@@H:7]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.O=[Pt]=O>[CH2:1]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC1CC(=O)[C@@H](CCCCCC)C(=O)O1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H]1C[C@H](O)[C@H](CCCCCC)C(=O)O1
Reaction time: 12 h

Procedure:
M)c) 8 g of an isomer mixture of tetrahydro-3-hexyl-4-oxo-(R)-6-undecyl-2H-pyran-2-one were dissolved in 2 l of ethyl acetate and 3 g of PtO2 were added. The mixture was then hydrogenated (50 bar) for 12 hours. The catalyst was filtered off and the solution was evaporated. After recrystallization there were obtained 7 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2 H-pyran 2-one. m.p. 108°-109° C.
Reaction SMILES: [O:1]=[C:2]1[CH:16]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:15]2[N:14]=[CH:13][N:6]3[CH2:7][C:8](=[O:12])[CH2:9][CH2:10][NH:11][C:4]([C:5]=23)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15]2[N:14]=[CH:13][N:6]3[CH2:7][C:8](=[O:12])[CH2:9][CH2:10][NH:11][C:4]([C:5]=23)=[CH:3]1
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate from Step D (15 mg, 0.045 mmol) in CH2Cl2 (3 mL) was added TFA (1 mL). After 2 h, the mixture was concentrated under reduced pressure to give the title compound. MS: m/z=276 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:35][CH2:34]4)=[CH:41][CH:40]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
2.64 (192 mg, 0.581 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (355 mg, 1.16 mmol), K3PO4 (400 mg, 1.9 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (21 mg, 0.029 mmol) were taken up in 1,4-dioxane (10 mL) and water (1 mL). The stirred reaction mixture was heated to 100° C. for 1.5 h and was then cooled and partitioned between EtOAc (30 mL), water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-12.5% MeOH in DCM) to provide tert-butyl 4-(4-(3-(difluoromethyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H35F2N6O4: 557.3; found: 557.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:23])[CH3:22])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:22])[CH3:23])[N:5]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
Reaction of 1.15 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, 0.625 ml of triethylamine and 0.56 ml of n-valeryl chloride analogously to Example 1c) yields N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester after flash chromatography (N3). (TLC: N2) Rf : 0.63.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Product: CCOC(=O)C1CCN(CCOc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl piperidine-4-carboxylate.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2].[Cl:26]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)Cl>[Cl:26][C:9]1[CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]2([CH3:6])[C:4]=1[S:3][CH2:1][CH3:2])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCSC1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 100.5 %

Procedure:
A solution of 1.5 g of 17-(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4,16-trien-3-one in 70 ml of dry dichloromethane is stirred with 609 mg of N-chlorosuccinimide at room temperature under a nitrogen atmosphere for 2.5 hours. The resulting solution is diluted with 140 ml of chloroform; the chloroform solution is washed with saturated NaHCO3 solution and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.65 g of a foam. The foam is dissolved in chloroform-hexane (4:1) and chromatographed on a 60 g-silica gel column. Elution with chloroform-hexane (4:1) gives 1.2 g of a tlc-homogenous material. Crystallization from acetone-hexane gives 815 mg of an analytical specimen of the title compound, melting point 240°-241° C. (dec).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:22][CH2:23]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: C1CCC(C2CCNCC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl)piperidine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.5 g compound (I-121) with a yield of 63.7%. ESI-MS [M+H]+: m/z 341.3.