Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].CN(C)CCNC(=O)N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1.Cl.C([O:93][C:94]([C:96]1([NH2:99])[CH2:98][CH2:97]1)=[O:95])C>>[C:94]([C:96]1([NH:99][C:2](=[O:3])[NH:1][C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:98][CH2:97]1)([OH:95])=[O:93]
Reactant: CCOC(=O)C1(N)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NC3(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride was used instead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 657.3 (M+H)+, 4.18 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3-5.3 (1H, m), 4.8 (1H, br. s.), 4.6 (1H, br. s.), 3.7-3.8 (1H, m), 3.6-3.6 (1H, m), 3.5-3.6 (1H, m), 2.5-2.7 (2H, m), 2.4 (1H, dd, J=12.1, 8.4 Hz), 2.2 (1H, dd, J=17.1, 6.4 Hz), 2.0 (1H, d, J=11.9 Hz), 1.9 (2H, dt, J=6.6, 3.2 Hz), 1.8-1.9 (2H, m), 1.7-1.8 (4H, m), 1.4-1.7 (7H, m), 1.4 (3H, td, J=13.1, 4.0 Hz), 1.3 (3H, t, J=11.7 Hz), 1.2 (3H, s), 1.1-1.1 (3H, m), 1.1 (3H, d, J=2.4 Hz), 1.0 (3H, s), 1.0 (2H, s), 0.9 (1H, m).
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)[CH3:31]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([N:8]([CH3:9])[C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:37]3[CH:38]=[CH:39][C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:41])=[CH:35][CH:36]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(N(C)Cc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg, 0.10 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (65 mg, 0.10 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 86 mg (75%) of the title compound as an oil.
Reaction SMILES: C([O:8][N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:37][CH2:38][CH3:39])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:40])C1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:37][CH2:38][CH3:39])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:10]1=[O:40]
Reactant: CCCN([C@@H]1C[C@H](C(C)C)N(OCc2ccccc2)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CCCN([C@@H]1C[C@H](C(C)C)N(O)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 95.3 %

Procedure:
N-[(3R,5R)-1-(Benzyloxy)-5-isopropyl-2-oxopyrrolidinyl]-N-propyl-4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonamide (0.015 g, 0.026 mmoles, Example 28b) in 5.0 mL methanol was hydrogenated on 5% Pd/BaSO4 (0.005 g) at 1 atm H2 and 22° C. After 6 hours the solution was filtered through Celite and concentrated by rotary evaporation to afford 0.012 g (95% yield) of the title compound as a white solid. LC-MS (APCI) m/z 485 (M+1). 1H NMR (CD3OD) δ 8.07 (d, J=8 Hz, 2H), 7.89 (d, J=6 Hz, 2H), 7.87 (d, J=6 Hz, 2H), 7.79 (d, J=8 Hz, 2H), 4.69 (t, J=10 Hz, 1H), 3.57 (ddd, J1=4 Hz, J2=7 Hz, J3=10 Hz, 1H), 3.10 (t, J=8 Hz, 2H), 2.30–2.18 (m, 2H), 1.81–1.57 (m's, 3H), 0.95 (d, J=7 Hz, 3H), 0.90 (d, J=7 Hz, 3H) and 0.85 (t, J=8 Hz, 3H) ppm.
Reaction SMILES: ClC[C:3]([NH:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[NH:5][C:3](=[O:4])[CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN2CCC[C@@H]2CN1
Temperature: 60 °C

Procedure:
1,1-Dimethylethyl (2R)-2-{[(chloroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (D13; 1.24 g, 4.5 mmol), was dissolved in 20 ml of DCM and treated with TFA (5 ml) at room temperature. After 1 h complete conversion into the desired material was observed and the reaction mixture was loaded onto a SCX cartridge. The product obtained after elution with 2M NH3 in MeOH was then dissolved in acetonitrile (30 ml) and treated with sodium carbonate (1.43 g, 10.34 mmol). The reaction mixture was heated at 60° C. for 6 hours; the crude obtained after removal is purified by flash-chromatography eluting with dichloromethane/MeOH 95/5 affording 250 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]([C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1)=[O:7].CCN(CC)CC>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1)=[O:7]
Reactant: COC(=O)CNC(=O)c1cc(F)cnc1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1cncc(F)c1
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of [(2-chloro-5-fluoropyridine-3-carbonyl)-amino]-acetic acid methyl ester (4.65 g, 18.9 mmol) in methanol (200 mL) in a Parr vessel was added Et3N (3.15 mL, 22.6 mmol) and palladium hydroxide on carbon (1.5 g, 20 wt % Pd, moisture 60%). The vessel was evacuated and then put under an atmosphere of hydrogen (initial pressure 42 psi). After 5 min the hydrogen pressure was 14 psi. The catalyst was removed via suction filtration over Celite® and then the filtrate was concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate/hexanes) afforded a light yellow solid (3.83 g, 95%): mp 80-82° C.; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.62 (d, J=2.7 Hz, 1H), 7.87 (m, 1H), 7.00 (br s, 1H), 4.27 (d, J=5.3 Hz, 2H), 3.82 (s, 3H); ESIMS m/z 213 (M+1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:14][CH:15]=3)[N:10]2COCC[Si](C)(C)C)=[CH:5][CH:4]=1.Cl>CCO>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:14][CH:15]=3)[NH:10]2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c2cc(-c3ncccc3C(F)(F)F)ccc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: O=c1c2ccc(-c3ncccc3C(F)(F)F)cc2[nH]n1-c1ccc(C(F)(F)F)cc1
Yield: 45.8 %

Procedure:
The product of Step 6 (0.2 g), in a mixture of concentrated HCl (2 mL) and EtOH (3 mL), was heated at reflux for 1 h. The mixture was concentrated and the residue crystallized from EtOH/H2O to give 70 mg of product as a colourless solid. 1H NMR (360 MHz, CDCl3): 7.33 (1H, s), 7.39 (1H, d, J 8.0 Hz), 7.43 (1H, s), 7.5-7.55 (1H, m), 7.73 (2H, d, J 8.0 Hz), 7.99 (1H, d, J 8.0 Hz), 8.09 (2H, d, J 8.0 Hz), 8.14 (1H, d, J 8.0 Hz), 8.9 (1H, d, J 8.0 Hz).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:38])[N:17]([CH3:37])[C:18]([C:22]3[CH:36]=[CH:35][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)=[N:19]2)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:37][N:17]1[C:16](=[O:38])[C:15]2[C:20](=[CH:21][C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:13][CH:14]=2)[N:19]=[C:18]1[C:22]1[CH:23]=[CH:24][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3cc(N)ccc3c(=O)n2C)cc1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(-c2nc3cc(NS(=O)(=O)c4ccccc4)ccc3c(=O)n2C)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Benzenesulfonyl chloride (0.57 ml) was slowly added dropwise at 0° C. to 10 ml of pyridine containing 1.5 g of the compound obtained in Example 66. The mixture was stirred at room temperature for 12 hours. After adding a saturated sodium bicarbonate solution, the reaction mixture was extracted with dichloromethane. The organic layer was washed with diluted hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 1.75 g of the desired compound as colorless crystals. Table 3 shows the chemical structure and physical property (melting point) of the compound obtained.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:24][CH:25]1[CH2:29][CH2:28][O:27][CH2:26]1>>[O:27]1[CH2:28][CH2:29][CH:25]([NH:24][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:26]1
Reactant: NC1CCOC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOC2)[nH]n1
Yield: 33 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using rac-3-aminotetrahydrofuran instead of morpholine, to the title compound (39 mg, 33%), which was obtained as a white solid. MS: m/e=369.2 [M+H]+.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH2:40]([O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH2:55])[CH:52]=[N:51]2)[O:47][CH:48]=1)[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:40]([O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH:55][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:52]=[N:51]2)[O:47][CH:48]=1)[CH3:41]
Reactant: CCOCc1coc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1coc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (36 mg, 0.19 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (5.8 mg, 0.05 mmol), HOBt (31 mg, 0.23 mmol), EDC (91 mg, 0.48 mmol) and DIPEA (0.13 mL, 0.76 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(ethoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (43 mg, 0.19 mmol) in CH2Cl2 (0.9 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10 mL) and the org. phase was washed with water (10 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.34. LC-MS-conditions 07: tR=0.84 min, [M+H]+=395.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[BH4-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7]([OH:15])[C:6]=2[CH:16]=1
Reactant: O=C1Cn2cccc2Sc2ccc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1Cn2cccc2Sc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 9c (0.037 g 0.16 mmol) in dry tetrahydrofuran (0.5 ml) and dry methanol (0.7 ml), cooled to 0° C. under argon atmosphere, was added in portions sodium borohydride (0.09 g, 0.16 mmol). After stirring for 1 hour at 0° C. the reaction was quenched with a saturated solution of ammonium chloride (1 ml), the solvent was removed and the mixture was extracted with ethyl acetate (3×2 ml). The organic layers were dried and evaporated, the crude product was chromatographed (30% petroleum ether 40-60° in dichloromethane) to give 24c 0.036 g (96% yield). 1H NMR (CDCl3) δ7.40-7.33 (m, 1H); 7.24-7.18 (m, 1H); 6.93-6.84 (m, 2H); 6.33-6.31 (m, 1H); 6.11-6.08 (m, 1H); 5.12-5.04 (m, 1H); 4.91-4.83 (dd, 1H, J=14.22, 2.25 Hz); 4.34-4.24 (dd, 1H, J=14.02, 6.51 Hz); 2.09-2.04 (d, 1H, J=9.83 Hz).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[CH3:13].Br[C:16]1[CH:21]=[C:20]([CH2:22][O:23][CH2:24][CH3:25])[CH:19]=[C:18]([Br:26])[CH:17]=1.C([Li])CCC>>[Br:26][C:18]1[CH:17]=[C:16]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:14])=[C:5]([CH3:13])[CH:6]=2)([OH:12])[CH3:11])[CH:21]=[C:20]([CH2:22][O:23][CH2:24][CH3:25])[CH:19]=1
Reactant: CC(=O)c1ccc(OC(F)F)c(C)c1
Reactant: CCOCc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Product: CCOCc1cc(Br)cc(C(C)(O)c2ccc(OC(F)F)c(C)c2)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the treatment of 1-(4-difluoromethoxy-3-methyl-phenyl)-ethanone with 1,3-dibromo-5-ethoxymethyl-benzene beforehand reacted with n-butyllithium, yielded the (RS)-1-(3-bromo-5-ethoxymethyl-phenyl)-1-(4-difluoromethoxy-3-methyl-phenyl)-ethanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the title compound (yield: 47% of theory) as a light yellow oil. Mass (calculated) C19H19BrF2O2 [396]; (found) [M]+=396, 398.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH:36]2[CH2:38][CH2:39][O:40][CH2:41][CH:35]2[CH2:34]1.C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH:36]5[CH2:38][CH2:39][O:40][CH2:41][CH:35]5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCCCN1CC2CCOCC2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCOCC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (60 mg) in DMF (6 mL) was added K2CO3 (66 mg) and tetrabutylammonium iodide (5 mg). The mixture was stirred for 10 min at room temperature, to this, a solution of 2-(3-chloropropyl)octahydropyrano[3,4-c]-pyrrole (38 mg) in DMF (1 mL) was added. The reaction mixture was heated at 90° C. for 12 h under N2 and CH2Cl2 (100 mL) was added. Then the mixture was washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (40 mg, 43.95%), HPLC: 98.50%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 488.0 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.26-1.29 (m, 2H), 1.37 (s, 3H), 2.33-2.37 (m, 3H), 2.59 (s, 1H), 3.03 (s, 1H), 3.44-3.47 (m, 1H), 3.50 (s, 1H), 3.72 (d, J=3.28 Hz, 1H), 3.78 (d, J=1.76 Hz, 1H), 3.81 (s, 1H), 3.87-3.89 (m, 1H), 3.99 (s, 3H), 4.50-4.55 (m, 2H), 7.11 (t, J=17.68 Hz, 1H), 7.25 (d, J=15.28 Hz, 1H), 7.35 (m, 1H), 7.82-7.86 (m, 1H), 8.13 (s, 1H), 8.22-8.25 (m, 1H), 8.63 (s, 1H), 8.92 (s, 1H) ppm.
Reaction SMILES: C1C2C(COC([N:18]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[N+:58]([C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[CH:64]=[CH:65][C:66]([OH:68])=O)([O-:60])=[O:59]>>[N+:58]([C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[CH:64]=[CH:65][C:66]([N:18]([C:39]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:68])([O-:60])=[O:59]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)C=Cc1cccc([N+](=O)[O-])c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
This compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]dopamine (628 mg, 0.8 mmol, example 48, step A) as described for example 48 (step B) using 3-nitrocinnamic acid (240 mg, 1.2 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 15%, 20% and 35% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a yellow powder (247 mg, 42%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C:15]2[S:19][C:18]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29]C(=O)OC(C)(C)C)=[O:21])=[CH:17][CH:16]=2)[N:8]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20]([C:18]1[S:19][C:15]([CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:12]=[CH:11][N:10]=2)=[CH:16][CH:17]=1)=[O:21].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccccn3)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccccn3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 381 (35 mg, 0.07 mmol) in 1:1 mixture of DCM and TFA (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to produce a solid which was triturated with ether to afford the title compound as a TFA salt (26 mg, 75% yield). 1H NMR (MeOH-d4) 9.31 (s, 1H), 8.68 (s, 1H), 8.66 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 7.77 (d, J=3.9 Hz, 1H), 7.68 (m, 1H), 7.1-7.5 (m, 6H). LRMS: (calc) 402.2; (found) 403.3 (M+H1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)c1

Procedure:
The title compound was prepared from 2′-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.27) (0.403 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.334 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.375 g, 65%). MS (ISP) 580.3 [(M+H)+]; mp 196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][OH:29])=[O:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(C=Cc2ccccc2OCc2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 4-[2-(2-benzyloxyphenyl)ethenyl]-benzenecarbonyl chloride (0.98 g) in dichloromethane (5 ml) was added dropwise to a solution of 2-aminoethanol (0.51 ml) in dichloromethane (15 ml) maintained at 0° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was washed with water (20 ml) and saturated aqueous sodium bicarbonate (20 ml) and dried. Evaporation of the solvent left a solid residue which was crystallised twice from methanol to give (E)-4-[2-(2-benzyloxyphenyl)ethenyl]-N-(2-hydroxyethyl)benzenecarboxamide (m.p. 149°-151° C.; yield 19%) containing about 4% of the related Z-isomer.