Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([O:16][C@H:17]1[CH2:55][N:20]3[C:21](=[O:54])[C@@H:22]([NH:46]C(=O)OC(C)(C)C)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]4[CH2:35][C@@:31]4([C:36](=[O:45])[NH:37][S:38]([C:41]4([CH3:44])[CH2:43][CH2:42]4)(=[O:40])=[O:39])[NH:32][C:33](=[O:34])[C@@H:19]3[CH2:18]1)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1>ClCCl.Cl.O1CCOCC1>[NH2:46][C@@H:22]1[C:21](=[O:54])[N:20]2[CH2:55][C@H:17]([O:16][C:12]3[N:13]=[C:14]4[C:5](=[C:6]5[C:11]=3[CH:10]=[CH:9][CH:8]=[CH:7]5)[CH:4]=[CH:3][C:2]([F:1])=[CH:15]4)[CH2:18][C@H:19]2[C:33](=[O:34])[NH:32][C@:31]2([C:36]([NH:37][S:38]([C:41]3([CH3:44])[CH2:42][CH2:43]3)(=[O:39])=[O:40])=[O:45])[CH2:35][C@H:30]2[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4cc(F)ccc4c4ccccc34)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4cc(F)ccc4c4ccccc34)CN2C1=O
Agent: CC1(S(=O)(=O)NC(=O)[C@@]23C[C@H]2/C=C\CCCCC[C@H](N)C(=O)N2C[C@H](Oc4nc5cc(F)ccc5c5ccccc45)C[C@H]2C(=O)N3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(S(=O)(=O)NC(=O)[C@@]23C[C@H]2C=CCCCCC[C@H](N)C(=O)N2C[C@H](Oc4nc5cc(F)ccc5c5ccccc45)C[C@H]2C(=O)N3)CC1

Procedure:
A solution of the product of Example 1h (tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(3-fluorophenanthridin-6-yloxy)-14a-(1-methylcyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate, 16.0 g, 20.6 mmol) in dichloromethane (100 mL) and 4 N HCl in dioxane (100 mL) was stirred at room temperature for 90 min and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL) and the resulting solid isolated by filtration of the mixture through a medium porosity sintered glass funnel. The isolated solid was washed with water (2×150 mL) and dried under reduced pressure to provide the title compound (12.2 g, 88% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=3)[C:19](=[O:27])[N:18]([CH3:28])[CH:17]=2)[CH2:3][CH2:2]1.C[O-].[Na+].C[C:33](=O)[O:34]CC>CN(C)C(=O)C.CO.CCCCCC>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:34][CH3:33])[CH:24]=3)[C:19](=[O:27])[N:18]([CH3:28])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2cc(F)ccc2c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1ccc2c(=O)n(C)cc(-c3cc(S(C)(=O)=O)ccc3OCC3CC3)c2c1
Temperature: 85 °C
Yield: 74 %

Procedure:
The title compound of Example 90, step 2 (30 mg, 0.075 mmol) in N,N-dimethylacetamide was treated with excess 25% sodium methoxide in methanol and heated at 85° C. until complete. Silica gel chromatography (40-80% EA in hexane over 8 min, then isocratic) gave the title compound 23 mg, 0.056 mmol, 74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.06-0.20 (m, 2H) 0.27-0.43 (m, 2H) 0.83-1.05 (m, 1H) 3.22 (s, 3H) 3.53 (s, 3H) 3.73 (s, 3H) 3.83-4.16 (m, 2H) 6.47 (s, 1H) 7.04-7.20 (m, 1H) 7.36 (d, J=8.59 Hz, 1H) 7.50 (s, 1H) 7.81 (s, 1H) 7.96 (d, J=6.82 Hz, 1H) 8.23 (d, J=8.59 Hz, 1H). LCMS: 414 (M+H)+
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[Cl-].[Ca+2].[Cl-].[CH3:29]I>CC(C)=O>[CH3:29][O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CI
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: COc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Yield: 79.7 %

Procedure:
34 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) was dissolved in 50 ml of acetone and 27.6 g of anhydrous calcium chloride was added to this solution. 15 g of methyl iodide was slowly added dropwise thereto while stirring under reflux. After stirring for 6 hours, the reaction mixture was cooled and solid matter was filtered off. The filtrate was poured into ice-water and the formed crystals were filtered off. The crystals were recrystallized from water-containing methanol to obtain 28.2 g of compound (59).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl [(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (23, 58 mg, 0.059 mmol) and K2CO3 (139 mg, 1.008 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (2 mL), was added thiophenol (61 μL, 0.590 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. The crude product was purified by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 10 min; retention time=7.6 min) to afford 7 (15 mg, 32%) mp 101-104° C.; 1H NMR (500.13 MHz, CDCl3) δ 9.54 (br s, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.42 (br s, 1H), 8.01 (t, J=5.7, 1H), 7.82 (t, J=5.7 Hz, 1H), 6.39 (d, J=6.4 Hz, 1H), 5.36 (d, J=4.7 Hz, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 3.11 (m, 2H), 2.93-2.84 (m, 3H), 2.39-2.28 (m, 2H), 2.22 (t, J=7.0 Hz, 2H), 2.04 (t, J=7.4 Hz, 2H), 1.97-0.94 (m, 36H), 0.92 (s, 3H), 0.86 (d, J=6.5 Hz, 3H), 0.84 (d, J=2.4 Hz, 3H), 0.82 (d, J=2.4 Hz, 3H), 0.61 (s, 3H); 13C NMR (125 MHz, DMSO d6) δ 171.9, 170.9, 145.1, 144.4, 144.1, 138.5, 137.9 122.4, 120.5, 99.0, 56.6, 56.0, 55.5, 49.3, 43.3, 41.8 (×2), 41.6, 40.5, 36.4, 36.1 (×2), 35.6, 35.5 (×2), 35.3, 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.3, 26.0, 24.9, 24.4, 23.8, 23.2, 22.6, 22.4, 20.4, 18.7, 18.5, 11.6; IR (film) νmax 3257, 3093, 2940, 2858, 1636, 1548, 1377 cm−1; CI m/z 790.5605 (MH+, C45H72N7O5 requires 790.5595).
Reaction SMILES: [Na].[CH2:2]1[O:13][C:12]2[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][C:4]=2[O:3]1.CN(C)[C:16]1[CH2:20][CH2:19][CH2:18][N+:17]=1[CH3:21].COS([O-])(=O)=O>C(O)C>[C:8]([C:7](=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])[C:6]1[CH:10]=[CH:11][C:12]2[O:13][CH2:2][O:3][C:4]=2[CH:5]=1)#[N:9]
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: CN(C)C1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CN1CCCC1=C(C#N)c1ccc2c(c1)OCO2

Procedure:
Add (dropwise at 80°, with stirring) a solution of 3.5 g of sodium in 80 ml of ethanol to a mixture of 16.1 g of 3,4-methylenedioxybenzylcyanide and 36 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate. Continue boiling the resulting reaction mixture for a further 2 hours. Then distil off the solvent under a vacuum and take up the residue with water/diethyl ether. Collect the ethereal layer. Dry it over sodium sulfate and concentrate it to obtain 18 g (67% of theory) of the title compound as oily liquid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=3)[C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=3)[C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)NCCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)NCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of methyl [4-({{4-[(4-butylphenyl)ethynyl]benzyl}[(propylamino)carbonyl]-amino}methyl)phenoxy]acetate (47 mg, 0.089 mmol) in MeOH/THF (2 ml, (1/1)) was added an aqueous solution of NaOH (2 mL, 1N). The reaction mixture was stirred at rt for 2 hrs. Then an aqueous solution of HCl (7 mL, 1N) was added and extracted with Et2O (2×7 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure to give 42 mg (77%) of the title compound as a yellow oil. HPLC, Rt: 5.1 min (purity: 83.9%). LC/MS, M+(ESI): 513.4, M−(ESI): 511.4. 1H NMR (DMSO-d6) Ε: 7.49 (d, J=8.3 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.22 (m, 4H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.53 (t, J=5.3 Hz, 1H), 4.63 (s, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.03 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.58-1.22 (m, 6H), 0.89 (t, J=7.3 Hz, 3H), 0.78 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][C:53]=1[C:65]([F:68])([F:67])[F:66])([O-:51])=[O:50].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:60][CH2:61][N:62]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:8]=[N:9][C:4]([C:3]([F:2])([F:23])[F:22])=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH2:63][CH2:64]2)=[CH:54][C:53]=1[C:65]([F:68])([F:66])[F:67])([O-:51])=[O:50]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)nc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)nc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 148) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (16 mg; 0.028 mmol). The structure was confirmed using Protocol I-D. Calculated mass=588; observed mass=588; HPLC retention time=1.44 min.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[S:18][CH2:19][CH2:20][NH2:21])[N:14]=[C:13]([O:22][CH:23]([CH3:25])[CH3:24])[CH:12]=[C:11]2[C:26]([F:29])([F:28])[F:27]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:23]([O:22][C:13]1[CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[C:10]2[CH:9]=[C:8]3[NH:21][CH2:20][CH2:19][S:18][C:17]3=[CH:16][C:15]=2[N:14]=1)([CH3:25])[CH3:24]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(Br)c(SCCN)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A 10 mL Schlenk flask was charged with palladium acetate (10.7 mg, 0.0476 mmol), R-BINAP (32.6 mg, 0.0524 mmol) and sodium t-butoxide (0.137 g, 1.43 mmol). The flask was placed under vacuum, then bled with nitrogen. This process was repeated twice. The solids were dissolved in 3 mL toluene, and a solution of 2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine (0.390 g, 0.953 mmol) in 3.3 mL toluene was added. The flask was heated to 100° C. for 4 h, whereupon the reaction was quenched with sat'd NH4Cl (30 mL) and water (30 mL). The mixture was extracted with EtOAc (2×60 mL), and the combined organic layers washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. Flash chromatography (4:1 hexanes:EtOAc) afforded 0.242 g (77%) of 2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline, a yellow solid. Data for 2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 6.99 (s, 1H), 6.90 (broad s, 1H), 5.44 (hept, 1H, J=6.2), 4.35 (broad s, 1H), 3.64-3.70 (m, 2H), 3.11-3.16 (m, 2H), 1.37 (d, 6H, J=6.2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=O)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20]1([CH:26]([CH3:35])[CH2:27][S:28][C:29]2[S:33][C:32]([NH2:34])=[N:31][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([CH:26]([CH3:35])[CH2:27][S:28][C:29]2[S:33][C:32]([NH:34][C:14](=[O:16])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:17][CH2:18][CH3:19])=[N:31][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CSc1nnc(N)s1)c1ccccc1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(SCC(C)c2ccccc2)s1
Temperature: 25 °C

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid (25.4 mg, 0.2 mmol), 5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-ylamine (50 mg, 0.2 mmol), HBOT (29 mg, 0.21 mmol), EDC HCl (46 mg, 0.24 mmol.) and triethylamine (0.12 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a light yellow solid (26 mg), LC-MS M+1=505.0
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1.[CH3:18][N:19]1[C:23]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[SH:32])=[CH:22][C:21]([CH3:34])=[N:20]1>[Cu]I>[CH3:18][N:19]1[C:23]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:22][C:21]([CH3:34])=[N:20]1
Reactant: Cc1cc(NC(=O)c2ccccc2S)n(C)n1
Reactant: O=C1Cc2ccc(I)cc2N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)C3)n(C)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
CuI (40 mg, 0.05 mmol), potassium carbonate (1.66 g, 12 mmol), 6-iodooxindole (as prepared in Preparation 1; 0.5 g, 1.93 mmol) and N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-mercapto-benzamide (as prepared in step 3 above; 0.477 g, 1.93 mmol) were added to a dry schlenk tube. The tube was evacuated and refilled with Ar(g) (3 times). Isopropanol (3.0 mL) and ethylene glycol (0.250 mL) were injected into the schlenk tube. The schlenk tube was sealed with a teflon valve and was heated to 80° C. and stirred for over 24 hours. Subsequently the reaction mixture was allowed to reach room temperature then diluted with EtOAc (˜20 mL) and water (˜10 mL). The mixture was acidified with 1 M HCl(aq) and the organics were separated and set aside. The aqueous phase was washed with EtOAc (2×20 mL). The organic layers were combined, dried over silica gel, filtered and concentrated in vacuo affording a yellow solid. The solid was then purified via flash silica gel chromatography (gradient eluant 10 to 40% EtOAc in Hexanes) affording the title compound as a pale yellow solid (0.379 g, 1.01 mmol, 52% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 184-188° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH:8]2[CH2:16][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]2[CH2:16][N:11]3[CH2:12][CH2:13][N:14]([C:23]4[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=4)[CH2:15][C@@H:10]3[CH2:9]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4ccc(Cl)nn4)CCN3C2)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 0.500 g (2.00 mmol) of (7SR,8aSR)-7-(4-fluoro-phenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 3), 1.49 g (10.0 mmol) of 3,6-dichloropyridazine, and 0.508 g (4.79 mmol) of sodium carbonate in 50 mL of isoamyl alcohol was heated to reflux for 48 h. The reaction was cooled to ambient temperature, the solvent removed in vacuo, the residue taken up in ethyl acetate and water, the pH was adjusted to 11 with sodium carbonate and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 ethyl acetate:hexane gave 0.478 g (66%) of the title compound. mp (.HCl) 229° C. (dec). HRMS calcd for C18 H21ClFN4O (MH+): 363.1388, found: 363.1404.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]2>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]3)[C:10]([OH:17])([C:13]([F:16])([F:14])[F:15])[CH2:9][C:8]2([CH3:18])[CH3:19]
Reactant: Cc1ccc2[nH]c(=O)ccc2c1N
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1c(C)ccc2[nH]c(=O)ccc12
Yield: 1.4 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 300 mg of 5-amino-6-methylquinolin-2(1H)-one. 10 mg of the title compound is obtained by reaction of 80 mg of the imine with 2.5 ml of titanium tetrachloride solution (1 M in dichloromethane) in 4.3 ml of dichloromethane.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Oc1ccccc1)C1CCCN1
Reaction time: 1 h

Procedure:
Compound 22 (500 mg, 1.71 mmol) was dissolved in dry DCM (6 mL). Trifluoroacetic acid (0.66 mL, 8.58 mmol) was then added to the solution at 0° C. and stirred under nitrogen for 1 h. The reaction mixture was then concentrated under vacuum and used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([CH:23]3[CH2:24][CH2:25][O:21][CH2:22]3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCOC1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: CO
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)C1CCOC1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and tetrahydro-3-furancarboxylic acid, (CAN 89364-31-8) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (+) enantiomer isolated; LC-MS (UV peak area/ESI) 98.1%, 401.0869 (M+H)+; αD20 (MeOH)=+10.1°
Reaction SMILES: CC1(C)OC(=O)CC(=O)O1.C1(N=C=O)C=CC=CC=1.Cl.[NH:21]([C:28]([OH:39])=[C:29]1[C:34](=[O:35])OC(C)(C)OC1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH2:44]>CN(C=O)C>[CH3:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH:44][C:34](=[O:35])[CH2:29][C:28]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: CC1(C)OC(=O)C(=C(O)Nc2ccccc2)C(=O)O1
Reactant: COc1ccccc1N
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C=Nc1ccccc1
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccccc1
Reaction time: 0.08 h

Procedure:
Meldrum's Acid (5.0 g, 34.7 mmol) was added to a flask along with DMF (40 ml) and TEA (10 ml, 70 mmol). The mixture was allowed to stir for 5 minutes and phenyl isocyanate (4.13 g, 34.7 mmol) was added. The contents of the flask were allowed to stir for 30 minutes. The mixture was poured into a flask containing HCl (200 ml) and ice. The solid was filtered and dried in vacuo overnight to afford product as a white solid. 5-[anilino(hydroxy)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (100 mg, 0.380 mmol) was added to a microwave vial along with o-methoxyaniline (51 mg, 0.418 mmol) and 1 ml of DMF. The vial was capped and microwaved at 165° C. for 10 minutes. The contents of the vial were concentrated and purified by trituration with DCM to afford the product, N-(2-methoxyphenyl)-N′-phenylmalonamide as an off-white solid. ESIMS calcd 285.2 (M++H), found 285.3 (M++H)