Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC(C)C)=[CH:4][C:3]=1[F:16].Cl[CH2:18][C@@H:19]([OH:22])[CH2:20][OH:21].CC([O-])(C)C.[K+].C(=O)([O-])N>C1COCC1.CCOC(C)=O.CCCCCC.O.CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:18][C@H:19]([CH2:20][OH:21])[O:22][C:9]2=[O:10])=[CH:4][C:3]=1[F:16]
Reactant: CC(C)COC(=O)Nc1ccc(Br)c(F)c1
Reactant: OC[C@H](O)CCl
Agent: CC(C)(C)[O-]
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: O=C1O[C@@H](CO)CN1c1ccc(Br)c(F)c1
Yield: 86.7 %

Procedure:
To a solution of 1056 g (3.64 mol) of 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate in 6.65 L of THF cooled to −15° C. in a 22 L round bottom flask was added a solution of 428 g (4.55 mol, 1.25 equiv.) of lithium t-amylate over 10 min via an addition funnel, maintaining −15° to −12° C. In a separate 5 L flask, a solution of 438 g (4.37 mol, 1.20 equiv.) of (S)-3-chloro-1,2-propanediol in 1.75 L of THF was cooled to −25° C. and treated with a 20% t-BuOK solution in THF (2645 mL, 4.29 mol, 1.18 equiv) over 25 min, resulting in a thick but stirrable slurry. This was allowed to warm to 10° over 75 min and then poured into the 22 L flask containing the carbamate solution. The resulting slurry was allowed to warm from −7° to 7° over 1.5 h, monitoring reaction progress by HPLC. Upon completion (˜2.5% each of remaining 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate and the over addition product) a quench solution composed of 1.05 AcOH and 3.5 L of water was added. The layers were separated. The aqueous layer was back-extracted with 1 L of THF, and the combined organic layers were washed with brine. The volatile were removed, giving white solids wet with acetic acid. This material was slurried in 1.6 L of EtOAc. Hexane (4L) was added over 1 h. The resulting slurry was cooled to 2° over 1 h and filtered, giving 916 g (87%) of (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one as coarse white crystals: TLC Rf=0.008 (50% EtOAc/hexane); HPLC rt=2.55 min; mp 114-121 °; [α]D=+52.2° c=1, MeOH); 1H NMR (DMSO) δ7.49 (m, 2H), 7.15 (d,1H, J=8.5 Hz), 5.30 (br s, 1H), 4.54 (m, 1H), 3.89 (t, 1H, J=8.6 Hz), 3.67 (m, 1H), 3.50 (dd, 1H, J=3.0, 11.8 Hz), 3.39 (dd, 1H, 3.8, 11.8 Hz); 13C NMR (DMSO) δ158.1 (s, JCF=241 hz), 154.2 (S), 139.7 (S, JCF=10 hz), 133.3 (D), 114.9 (D), 105.9 (d, JCF=29 Hz), 100.9 (s, JCF=21 Hz), 73.3(d), 61.5(t), 45.9 (t); Anal. calc'd for C10H9BrFNO3: C, 41.40; H, 3.13; N, 4.83: Br, 27.55; found: C, 41.11; H, 3.06; N, 4.83: Br, 26.97.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[N+:12]=[N-:13]
Reactant: OCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCCCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
8-Bromo-octan-1-ol (2.61 g, 12.5 mmol) was dissolved in Dmf (30 mL) and sodium azide (0.89 g, 13.75 mmol) was added. The reaction was heated to 90° C. and stirred overnight. The solution was then cooled to room temperature and poured onto ice. The aqueous was extracted with DCM (3×200 mL) and the combined extracts were washed with brine (2×200 mL), then dried over MgSO4. The solution was filtered and the solvent was removed in vacuo to give a yellow oil, 1.99 g (93% yield);
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][C:16]=2[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35]C)=[C:31]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[CH:30]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:35][C:32]1[CH:33]=[CH:34][C:29]([C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][C:16]=3[CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:8])[CH3:7])=[CH:30][C:31]=1[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2CC(C)C)cc1Cc1cccc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(O)c(Cc3cccc4ccccc34)c2)c(CC(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
1.02 ml (1.02 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 192.9 mg (0.34 mmol) 3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile (76) in 20 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 12 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 117.9 mg (0.21 mmol, 62.85%) 3-(4-Hydroxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile (32) as a colorless oil. Rf (hexanes/EtOAc (2+1))=0.37. 1H-NMR (500 MHz, CDCl3): δ=0.59 (d, 6H, J=6.62 Hz, 2*CH3), 0.70 (d, 6H, J=6.78 Hz, 2*CH3), 1.50 (m, 1H, CH), 1.65 (m, 1H, CH), 2.32 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.25 Hz, CH2), 2.62 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.94 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.47 (s, 2H, CH2Naphthyl), 480 (s, 1H, OH), 6.86 (d, 1H, J=8.36 Hz), 6.98-7.16 (m, 9H), 7.38 (m, 1H), 7.43-7.48 (m, 2H), 7.73 (dm, 1H, J=8.73 Hz), 7.83 (m, 1H), 8.06 (m, 1H). MS (EI): m/z=552 (30), 551 (65), 446 (21), 419 (21), 178 (19), 155 (15), 149 (24), 142 (18), 141 (100), 128 (28), 97 (23), 85 (26), 83 (25), 71 (39), 69 (30), 57 (74), 55 (35). HR-MS (EI): Calcd. for C40H41NO: 551.318814. Found: 551.318768.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(Br)c1
Reaction time: 3.5 h

Procedure:
0.5 g of 3-bromophenol and 0.33 ml of ethyl bromoacetate were dissolved in 4 ml of dimethylformamide, and 0.4 g of potassium carbonate was added. The mixture was stirred at 65°-70° C. for 3.5 hours. The solvent was evaporated, and the residue was worked up in a customary manner to give 0.6 g of ethyl 3-bromophenoxyacetate as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:9]([NH:11]/[C:12](=[C:18]1/[CH2:19][CH2:20][C@@H:21]2[C@:35]/1([CH3:36])[CH2:34][CH2:33][C@@:32]1([OH:37])[C@H:22]2[CH2:23][CH:24]=[C:25]2[C@:30]1([CH3:31])[CH2:29][CH2:28][C:27]([O:38][CH3:39])=[CH:26]2)/[C:13](OCC)=[O:14])=[O:10].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1.C(O)C>[CH:9]([NH:11]/[C:12](=[C:18]1/[CH2:19][CH2:20][C@@H:21]2[C@:35]/1([CH3:36])[CH2:34][CH2:33][C@@:32]1([OH:37])[C@H:22]2[CH2:23][CH:24]=[C:25]2[C@:30]1([CH3:31])[CH2:29][CH2:28][C:27]([O:38][CH3:39])=[CH:26]2)/[CH2:13][OH:14])=[O:10]
Reactant: CCOC(=O)/C(NC=O)=C1\CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC1=CC2=CC[C@H]3[C@@H]4CC/C(=C(\CO)NC=O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
Under a nitrogen atmosphere sodium borohydride (0.53 g) and lithium aluminium hydride (0.65 g) were added to a stirred solution of ethyl (20Z)-20-formamido-9α-hydroxy-3-methoxypregna-3,5,17(20)-trien-21-oate (4.85 g, prepared according to example 10), in dry tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at 5° C. for 2 hours, after which another 0.54 g of sodium borohydride and 0.65 g of lithium aluminium hydride were added. Stirring was continued at 5° C. for 1.5 hours, then ethanol (50 ml) was added dropwise to decompose excess reducing agent. After adding 60 ml of an aqueous solution of sodium potassium tartrate, the reaction mixture was filtered and extracted with ethyl acetate. The organic phase was washed with an aqueous sodium carbonate solution and with water, dried (MgSO4) and concentrated under reduced pressure. The residue (3.02 g) was purified by column chromatography (toluene/acetone 2/1 containing 0,1% triethylamine) to provide 1.08 g of the title compound.
Reaction SMILES: [CH:1]12[NH:13][CH:5]([CH2:6][CH:7]([CH2:9][C:10]([OH:12])=[O:11])[CH2:8]1)[CH2:4][O:3][CH2:2]2.S(Cl)(Cl)(=O)=O.[CH3:19]O>>[CH3:19][O:11][C:10](=[O:12])[CH2:9][CH:7]1[CH2:6][CH:5]2[NH:13][CH:1]([CH2:2][O:3][CH2:4]2)[CH2:8]1
Reactant: O=C(O)CC1CC2COCC(C1)N2
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)CC1CC2COCC(C1)N2
Yield: 99 %

Procedure:
To a solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (200 mg, 0.9 mmol) in 10 mL of methanol was added dropwise sulfuryl chloride (0.3 mL, 1.8 mmol) under ice cooling. After the mixture was refluxed for 3 hours, it was concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL×2). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL×2), and then dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (Compound AG) as colorless oil (179 mg, 99%) which was used directly in next step without further purification. MS: calc'd (MH+) 200, measured (MH+) 200.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O)([OH:33])=[O:32]>C(O)C>[C:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)([OH:33])=[O:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(O)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (20.3 mg, 0.0377 mM), then 3-carboxy-benzaldehyde (5.7 mg, 0.038 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was washed with methanol to thus give the title compound (14.0 mg, yield: 84%).
Reaction SMILES: [CH3:1][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([OH:33])=O)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:81]([CH2:83][NH2:84])[OH:82]>C(Cl)Cl.C(OCC)(=O)C>[OH:82][CH2:81][CH2:83][NH:84][C:31]([C:26]1[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:9]3[C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[CH2:12][CH2:13][C@@H:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])([CH3:35])[CH3:1])[C:8]3=[O:34])=[CH:20][CH:21]=2)=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:33]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)O)cc2)C1=O)NC(=O)OCc1ccccc1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)NCCO)cc2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a solution of 70 mg (0.11 mmol) of 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[(benzyloxycarbonyl)amino]butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) in 2 mL of dry methylene chloride under nitrogen at 0° C. was added 0.023 mL (0.17 mmol) of triethylamine followed by 55 mg (0.12 mmol) of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate. After 5 minutes, 0.010 mL (0.33 mmol) of ethanolamine was added to the reaction by syringe. The reaction mixture was slowly warmed to room temperature. After 2 hours, the reaction was diluted with 75 mL of ethyl acetate, washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/methanol (97:3) to afford 58 mg (78%) of the product as a white foam. 1H NMR (200 MHz,CDCl3): 1.30 (s,3H), 1.35 (s,3H), 1.80 (m,1H), 2.20-2.75 (m,7H), 3.10-3.40 (m,4H), 4.51 (m,1H), 4.92 (d, 14 Hz, 1H), 5.00 (s,2H), 5.10 (d,14 Hz, 1H), 5.68 (s, 1H), 6.53 (d,6 Hz, 1H), 7.12-7.48 (m,16H), 7.65 (d;1.6 Hz;1H). FAB-MS: calculated for C39H42N4O6 662; found 686 (M+Na).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH:5]=[O:6].[BH4-].[Na+]>>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=CCC(F)(Cl)C(F)(F)Br
Agent: [BH4-]
Agent: [Na+]
Product: OCCC(F)(Cl)C(F)(F)Br

Procedure:
Alternatively, the intermediate VII can be reduced with sodium borohydride without isolation to give 4-bromo-3-chloro-3,4,4-trifluorobutanol ((IX) in high yield; or by hydrolysis of 1,4-dibromo-2-chloro-1,1,2-trifluorobutane (XVI) to give IX. Oxidation of IX with Jones reagent to give VIII in 85% yield.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH:45]#[C:46][CH2:47][CH2:48][CH2:49][CH3:50]>CN(C=O)C.[Cu](I)I>[C:1]([C:5]1[N:10]=[C:9]([C:45]#[C:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: C#CCCCC
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC#Cc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (300 mg), dichloro[bis(triphenylphosphine)]palladium (412 mg), copper iodide (112 mg) and N,N-diisopropylethylamine (0.51 μL) were dissolved in DMF (8 ml), and the mixture was stirred at room temperature for 15 min. 1-Hexyne (0.08 ml) was added and the mixture was stirred at room temperature 2 hr, and further at 70° C. for 8 hr. The mixture was cooled to room temperature, adsorbed to silica gel (10 g), and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with hexane-ethyl acetate (95:5-30:70) was concentrated under reduced pressure to give the object product (218 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:30][C:31]2[CH:32]=[C:33]([CH3:41])[C:34]3[O:38][N:37]=[C:36]([CH3:39])[C:35]=3[CH:40]=2)[C:9]2[C:10]([C:27]([OH:29])=O)=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[C:13]=3[CH:14]([CH3:16])[CH3:15])[C:27](=[O:29])[N:30]2[C:31]2[CH:32]=[C:33]([CH3:41])[C:34]3[O:38][N:37]=[C:36]([CH3:39])[C:35]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(C)c4onc(C)c4c3)c3ccc(Cl)cc3)c2C(C)C)c(OC)n1
Solvent: CCOC(C)=O
Product: COc1ncc(-n2nc3c(c2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(C)c4onc(C)c4c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((3,7-dimethylbenzo[d]isoxazol-5-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylic acid (Step 46.13). tR: 1.25 min (LC-MS 2); ESI-MS: 559 [M+H]+ (LC-MS 2); Rf=0.50 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.48 (d, J=6.8 Hz, 3H) 1.17 (d, J=6.7 Hz, 3H) 2.45 (s, 3H) 2.52 (s, 3H) 2.61-2.71 (m, 1H) 3.96 (s, 3H) 4.01 (s, 3H) 6.69 (s, 1H) 7.33-7.42 (m, 4H) 7.67 (s, 1H) 7.84 (d, J=1.5 Hz, 1H) 8.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(=O)(O)[O-:22].[Na+].C(OO)(C)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][C:17](=[O:22])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=C([O-])O
Reactant: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Agent: CC(C)(C)OO
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.4 %

Procedure:
To a solution of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindine (76.0 mg, 0.27 mmol) and dirhodium(II, III) tetrakis caprolactamate (1.8 mg, 0.0027 mmol; synthesis described in M. P. Doyle et al., J. Am. Chem. Soc. 1993, 115, 958-964) in dichloromethane (0.5 mL) was added sodium bicarbonate (22.7 mg, 0.27 mmol) and tert-butyl hydroperoxide (0.25 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 48 h. During this time period additional equivalents of tert-butyl hydroperoxide (1.25 mL, 6.75 mmol) were added in small portions. The solvent was removed under reduced pressure and the crude reaction mixture purified by flash chromatography (20 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc-heptane gradient to provide 15.5 mg (19%) of 4-(3-fluoro-4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one (intermediate A-14 [C1]) as slightly yellow solid; MS: 296.1 (M+H)+; and 17.4 mg (22%) of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-[2]pyrindin-5-one (intermediate A-14 [C2]) as slightly yellow solid. MS: 296.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:25])[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)[C:16]=2[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)Cc1ccc(OC)c(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methoxy-phenyl]-acetic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[N:27]=[C:26]([CH:39]([CH3:41])[CH3:40])[C:25]=2/[CH:42]=[CH:43]/[CH:44]=[O:45])=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[N:27]=[C:26]([CH:39]([CH3:41])[CH3:40])[C:25]=2/[CH:42]=[CH:43]/[CH:44]([OH:45])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2ccc3ccccc3n2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred suspension of hexane washed NaH (0.77 g, 19.1 mmoles) in 30 mL THF at 0° C. under a nitrogen atmosphere, was added dropwise a solution of ethyl acetoacetate (2.27 mL, 17.9 mmoles) in 30 mL THF. The mixture was stirred for 15 minutes before a 2.2 M solution of n-BuLi (8.2 mL, 17.9 mmoles) in THF was added dropwise via syringe. The resulting orange solution was stirred at 0° C. for 15 minutes and then cooled to -7S° C. A solution of trans-3-[5-(4-fluorophenyl)-3-(l-methylethyl)-1-(2-quinolinyl)-1H-pyrazol-4-yl]-2-propenal (4.61 g, 12.0 mmoles) in 50 mL THF was added dropwise and after 2 hours at -78° C. the reaction was quenched by adding 6 mL glacial HOAc and removing the cooling bath. The reaction was partitioned between 5% K2CO3 and Et2O. The organic layer was dried over MgSO4, filtered, and evaporated to give an orange oil. Chromatography (SiO2, 20% EtOAc/hexanes) gave 5.57 g (90%) of the title compound as a yellow solid, mp 47°-53° C.
Reaction SMILES: C(OC(C[NH:9][C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:46][C:47]([Cl:74])([Cl:73])[CH2:48][O:49][C:50](=[O:72])[NH:51][CH2:52][CH2:53][CH2:54][CH2:55][C@@H:56]([C:69](=[O:71])[NH2:70])[NH:57][C:58](=[O:68])[C@H:59]([NH:66][CH3:67])[CH2:60][C:61]1[S:62][CH:63]=[CH:64][CH:65]=1>C(Cl)Cl>[Cl:74][C:47]([Cl:46])([Cl:73])[CH2:48][O:49][C:50](=[O:72])[NH:51][CH2:52][CH2:53][CH2:54][CH2:55][C@H:56]([NH:57][C:58](=[O:68])[C@H:59]([NH:66][CH2:67][C:11](=[O:13])[C@H:10]([NH2:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH2:60][C:61]1[S:62][CH:63]=[CH:64][CH:65]=1)[C:69](=[O:71])[NH2:70]
Reactant: CN[C@H](Cc1cccs1)C(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(N)=O
Reactant: CC(C)(C)OC(=O)CN[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: NC(=O)[C@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)NC(=O)[C@@H](Cc1cccs1)NCC(=O)[C@H](N)Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
(2R)-2-(tert-Butoxycarbonylmethylamino)-3-(2-napthyl)propionic acid (5.00 g; 15.8 mmole), HOAt (2.35 g; 17 mmole) and EDAC (3.03 g; 15.8 mmole) were added to methylene chloride (200 ml) and stirred for 15 min. [(5S)-5-carbamoyl-5-((2R)-2-methylamino-3-(2-thienyl)propionylamino)pentyl]carbamic acid 2,2,2-trichloroethyl ester (7.01 g; 14.5 mmole) was added and the mixture was stirred overnight. Methylene chloride (200 ml) was added and the organic phase was washed with water (200 ml), an aqueous solution of sodium hydrogensulphate (200 ml), an aqueous solution of sodium hydrogencarbonate (200 ml) and water (200 ml). The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was dissolved in a mixture of trifluoroacetic acid (30 ml) and methylene chloride (70 ml) and stirred for 15 min. Water (150 ml) and sodium hydrogencarbonate were added to neutral pH, the phases were separated and the aqueous phase was extracted with methylene chloride (2×100 ml) and the phases were separated. The combined organic phase were dried (magnesium sulphate) and the solvent was removed in vacuo and the residue was chromatographed on silica using a mixture of aqueous ammonia in water (25%), ethanol and methylene chloride (0.7:9.3:90) as eluent to afford 6.3 g of ((5S)-5-{(2R)-2-[((2R)-2-amino-3-(2-naphthyl)propionyl)methylamino]-3-(2-thienyl)propionylamino}-5-carbamoylpentyl)carbamic acid 2,2,2-trichloroethyl ester.