Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.C([N:9]1[CH2:13][CH:12]([CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH2:11][C:10]1=[O:20])C1C=CC=CC=1.[Na]>C1COCC1>[CH3:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH:12]1[CH2:13][NH:9][C:10](=[O:20])[CH2:11]1
Reactant: CCCC(C)CC1CC(=O)N(Cc2ccccc2)C1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CCCC(C)CC1CNC(=O)C1
Temperature: -78 °C
Yield: 92.6 %

Procedure:
A 250 mL 3-neck flask equipped with a dry ice condenser was chilled to −78° C. Ammonia (80 mL) was condensed into the flask and 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 (1.67 g, 0.006 mol) in 15 mL THF was added. Freshly cut sodium beads were added until a deep blue color persisted. The cooling bath was removed and the reaction stirred at reflux (−33° C.) for 1 hour. The reaction was quenched with ammonium chloride and the excess ammonia was allowed to evaporate. The resulting residue was diluted with water, extracted with dichloromethane, and dried over magnesium sulfate. Evaporation of the solvent followed by chromatography on silica eluting with 1:1 acetone/hexane gave 0.94 g, 86% of the 4-(2-Methyl-pentyl)-pyrrolidin-2-one 77. 1H NMR (CDCl3) δ 6.25 (br, 1H), 3.44 (m, 1H), 2.95 (m, 1H), 2.54 (m, 1H), 2.40 (m, 1H), 1.98 (m, 1H), 1.30 (m, 6H), 0.80 (m, 6H). MS, m/z (relative intensity): 212 [M+2H+CH3CN, 100%], 171 [M+2H, 72%], 170 [M+1H, 65%].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([O:16]CC)=[O:15])=[CH:3]1.[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc([C@@H]2C[C@H]2C(=O)O)c2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 141.6 %

Procedure:
A mixture of ethyl trans-2-(1-methyl-1H-indol-3-yl)cyclopropanecarboxylate (20 mg, 0.082 mmol) and 2 mol/L aqueous sodium hydroxide solution (0.20 mL, 0.40 mmol) in methanol (3 mL) was stirred at 60° C. for 3 hours. After cooling to room temperature, 2 mol/L hydrochloric acid (0.20 mL, 0.40 mmol) was added, and the solvent was removed in vacuo. To the residue was added THF (2 mL) and filtered off. The filtrate was concentrated in vacuo to give 25 mg of the title compound as a pale yellow oil. This was used for the next step without purification:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([C:33]2[N:37]3[CH:38]=[C:39]([O:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[C@@H:46]([NH2:53])[CH2:45][CH2:44]4)[CH:40]=[CH:41][C:36]3=[N:35][N:34]=2)[CH2:28]1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@H:29]5[CH2:30][CH2:31][CH2:32][N:27]([CH3:26])[CH2:28]5)=[N:34][N:35]=4)[CH:38]=3)[CH2:44][CH2:45]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CN1CCC[C@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@H]5CCCN(C)C5)n4c3)c3ccccc32)cc1
Yield: 74 %

Procedure:
An orange-brown solution (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 243 mg, 0.600 mmol), Intermediate 88e (151 mg, 0.400 mmol) and DIPEA (0.122 mL, 0.700 mmol) in dry dioxane (5 mL) was stirred at 65° C. for 15 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (30 mL); concentration in vacuo left a brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a pale yellow solid (188 mg, 74%). LCMS (Method 5): Rt 3.63 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.55 (1H, qd, J 11.9, 5.3), 1.68-1.79 (2H, m), 1.83-2.03 (4H, m), 2.06-2.14 (2H, m), 2.22 (1H, t, J 10.9), 2.22 (3H, s), 2.36 (3H, s), 2.83 (1H, br d, J 10.9), 3.01 (1H, ddd, J 11.1, 3.6, 1.6), 3.54 (1H, tt, J 11.1, 3.7), 4.83 (1H, td, J 8.4, 5.5), 5.57 (1H, t, J 4.5), 6.33 (1H, s), 7.09 (1H, d, J 8.5), 7.15 (1H, dd, J 9.8, 2.0), 7.27-7.42 (8H, m), 7.68 (1H, d, J 9.9), 8.03 (1H, s), 8.32 (1H, d, J 2.0).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1>O1CCOCC1>[F:18][C:2]([F:1])([F:17])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1)=[O:16])(=[O:13])=[O:12]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Temperature: 20 °C

Procedure:
5.6 g of 2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl isocyanate and 2.5 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are stirred in absolute dioxan for 3 hours at 70°-80° C. After it has been cooled to 20° C., the reaction mixture is filtered and the clear solution so obtained is concentrated to a quarter of its volume. Then 50 ml of ether are added and 5.0 g of N-[2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea crystallise from the solution. Melting point: 154°-155° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C1C(=O)N([I:20])C(=O)C1>CN(C=O)C.CCOC(C)=O>[I:20][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
5-nitro-1H-indazole (2 g, 12.26 mmol) was taken up in DMF (40 mL) and NIS (5.52 g, 24.52 mmol) was added. The reaction was stirred at rt for 72 h. The reaction mixture was diluted with EtOAc and washed with sat'd sodium bisulfite solution, water, and then 2× with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give 3-iodo-5-nitro-1H-indazole (3.4 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH3:19])[CH:6](C)[CH2:5]2)[CH:11]=1.C=[O:27]>C(O)(=O)C>[F:1][C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH2:19][OH:27])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: C=O
Reactant: CC1Cc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Solvent: CC(=O)O
Product: O=C(O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2CO
Temperature: 80 °C

Procedure:
200 mg of the compound (160) obtained in Example 38 was added to a mixture solvent of 8 ml of acetic acid and 4 ml of formalin, and the solution was heated at 80° C. for 2 hours. The deposited solid matter was filtered off and washed with ether to obtain 50 mg of the subject compound (179).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[N:25]=[C:24]3[CH2:29][CH2:30][CH2:31][C:23]3=[C:22](Cl)[C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[N:25]=[C:24]3[CH2:29][CH2:30][CH2:31][C:23]3=[C:22]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([N:11]5[CH2:16][CH2:15][O:14][CH2:13][CH2:12]5)[CH:6]=4)[C:2]([CH3:17])([CH3:1])[CH2:3]3)[C:21]=2[CH:20]=1
Reactant: Clc1ccc2nc3c(c(Cl)c2c1)CCC3
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CN(c2c3c(nc4ccc(Cl)cc24)CCC3)c2cc(N3CCOCC3)ccc21
Temperature: 140 °C

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.2 g, 0.86 mmol), 7,9-dichloro-2,3-dihydro-1H-cyclopenta[b]quinoline (0.41 g, 1.72 mmol), cesium carbonate (0.561 g, 1.72 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol) and (±) BINAP (0.084 g, 0.129 mmol) were added 1,4-dioxane (2 mL). The resulting mixture was purged with Argon and subjected to microwave heating at 140° C. for 3 h. The crude residue was purified by HPLC to give 7-chloro-9-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2,3-dihydro-1H-cyclopenta[b]quinoline. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.07 (1H, d, J=2.0 Hz), 8.0 (1H, m), 7.94 (1H, dd, J=8.9, 2.1 Hz), 7.17 (1H, d, J=8.3 Hz), 6.64 (1H, dd, J=8.3, 2.0 Hz), 6.17 (1H, s), 4.33 (1H, d, J=9.3 Hz), 3.98 (1H, m), 3.66 (4H, dd, J=5.6, 3.9 Hz), 3.24 (2H, m), 2.97 (4H, dd, J=5.9, 3.7 Hz), 2.90 (1H, m), 2.61 (1H, m), 2.18 (2H, m), 1.30 (3H, s) 1.29 (3H, s). Mass Spectrum (ESI) m/e=434 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:22]([O:24]CC)=[O:23])=[CH:6][N:7]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].C(O)(=O)C.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)c(Cl)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)c(Cl)c2c1=O
Temperature: 0 °C
Yield: 91.5 %

Procedure:
41.6 g of ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux with 250 ml of acetic acid, 200 ml of water and 28.5 ml of concentrated sulphuric acid for 3 hours. After cooling, the mixture is poured into 2 liter of ice-water and the precipitate is filtered off with suction, washed with water and dried. 35.5 g of 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3quinolinecarboxylic acid are obtained.
Reaction SMILES: [C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([O:17]C)=O)[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH3:19].ClCCl.CO>CO>[C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([NH2:19])=[O:17])[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 8 h

Procedure:
A solution of 168 g (521 mmol) of the methyl ester, VI, in 2.0 l of methanol was cooled to approximately 10° and treated with anhydrous ammonia gas for eight hours. The solution was allowed to stand at room temperature overnight. The TLC (SiO2, dichloromethane-methanol, 5:1) indicated complete conversion to the desired product. A very small amount of a red solid was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was recrystallized from 2-propanol and dried at 40° under 0.5 atmospheres to give 136 g (84.9%) of the product, mp 128-130 (lit. (see below) mp 131°-133°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].CC(O)=[O:13].O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:13])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CC(=O)O
Reactant: COc1cc(C)ccc1Cl
Solvent: O
Product: COc1cc(C=O)ccc1Cl
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Ceric ammonium nitrate (43.3 g, 79.0 mmol, 4.00 equiv) was dissolved in 1:1 HOAc/H2O (200 mL). This solution was added dropwise over one hour to a stirred solution of the product from Step 1 (3.09 g, 19.7 mmol, 1.00 equiv) in 1:1 HOAc/H2O (100 mL) at 100° C. After the addition was complete, the reaction was stirred for an additional 15 minutes. The reaction was cooled, diluted with H2O and extracted twice with Et2O. The combined organic extracts were washed three times with H2O, three times with satd. NaHCO3, and once with brine. The organic phase was dried over MgSO4 and concentrated en vacuo to afford the title compound (3.00 g, 89%) as an amber oil. 1H NMR (400 MHz, CDCL3) 9.97 (s, 1H), 7.57 (d, 1H), 7.46 (s, 1H), 7.43 (d, 1H), 4.00 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@:12]2([CH3:23])[O:16][C:15]3=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]3[CH2:13]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C@:12]3([CH3:23])[O:16][C:15]4=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]4[CH2:13]3)[CH2:7][CH2:6]2)=[O:4])=[CH:27][CH:26]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@]1(CN2CCN(C(=O)CCl)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(C(=O)COc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A mixture of (S)-2-chloro-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazin-1-yl]ethanone prepared in Example 420 (300 mg, 0.87 mmol), 4-chlorophenol (170 mg, 1.32 mmol), potassium carbonate (180 mg, 1.3 mmol) and DMF (5 ml) was stirred at 60° C. for 3 hours. The reaction mixture was allowed to return to room temperature, then diluted with water. The solution was extracted with ethyl acetate twice. The organic phases were combined, washed with a sodium hydroxide solution, water and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to afford (S)-2-(4-chlorophenoxy)-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone (260 mg, yield 68%) as a light brown powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([O:42]CC4C=CC=CC=4)=[C:37]([CH3:50])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([OH:42])=[C:37]([CH3:50])[CH:36]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(Cc3ccccc3)CC2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCNCC2)cc(C)c1O

Procedure:
1.62 g (2.22 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL MeOH were combined with 150 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac. The residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 85:13.5:1.5).
Reaction SMILES: [C:1]([NH:9][CH:10]([S:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[C:1]([NH:9][CH:10]([S:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([NH:13][CH2:14][C:16]([OH:18])=[O:17])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)C(NC(=O)c1ccccc1)SC(=O)c1ccccc1)C(=O)O
Solvent: CCOCC
Product: O=C(O)CNC(=O)C(NC(=O)c1ccccc1)SC(=O)c1ccccc1

Procedure:
N-[N-Benzoyl-α-(benzoylthio)-glycyl]-alanine, in the form of a diastereomer mixture, melting point 162°-164° C. (diethyl ether), Rf=0.47 and 0.40 in system I.
Reaction SMILES: [BH4-].[Na+].C(COC)OC.[C:9]1([Sn:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>COCCOCCOC>[C:22]1([SnH:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: COCCOCCOC
Product: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3.9 g of sodium borohydride (0.1 mol) and 70 ml of monoglyme were mixed together in a 200 ml eggplant type flask and cooled to -10° C. 70 ml of a diglyme solution containing 10.0 g of triphenyltin chloride (0.026 mol) was added to this mixture dropwise for 30 minutes. Subsequently, the mixture was stirred for another 30 minutes at -10° C. Then diglyme was removed under a reduced pressure of greater than 1 mmHg at below 0° C. Then, the resultant residue was extracted with diethylether followed by concentration under reduced pressure to yield 9.1 g of the final product of triphenyltin hydride (yield=100%).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C(N1CCCCC1=O)(OC(C)(C)C)=O.C1(N)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C.[N:63]1([C:69](Cl)=[O:70])[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:69]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:70])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:28])=[CH:8][N:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCNCC2)s1
Reactant: O=C(Cl)N1CCOCC1
Agent: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CCOC(=O)CSc1cnc(N)s1
Solvent: NC1CCCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(=O)N3CCOCC3)CC2)s1

Procedure:
{2-[3-Cyclohexyl-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was pre-pared in a similar manner to the synthesis of example 12 from N-Boc piperidone, cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester, Boc deprotection, reaction with 4-morpholine carbonyl chloride and hydrolysis of the ester moiety as described in general procedure (I) gave the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28]CC)=[O:27])=[O:5])C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[Cl:38]>>[C:4]([CH2:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[CH:18][CH:17]=2)[C:9]2[C:10]([C:25]=1[C:26]([OH:28])=[O:27])=[CH:11][C:12]([O:15][C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[C:37]([Cl:38])[CH:36]=1)=[CH:13][CH:14]=2)([OH:3])=[O:5]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(C)c1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(Cl)c(Cl)c4)ccc32)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 3,4-dichlorophenylboronic acid (140 mg, 0.74 mmol). Yield 110 mg (55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
To a solution of 3′-bromo-4′-fluoroacetophenone (6.80 g, 31.3 mmol) in 31 mL TFA, was added triethylsilane (15 mL). The mixture was stirred at rt for 20 h, then concentrated. The crude product was purified by flash chromatography (100% hexanes, 2×) to afford 4.33 g of Intermediate 228.1 as a colorless oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:30]=[CH:31][CH:32]=[CH:33][N:34]=2)=[C:24]([C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:26])[CH:28]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and Intermediate 13. MS (ESI): mass calculated for C25H21FN6O, 440.48; m/z found 441.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.71 (d, J=4.9, 2H), 8.37-8.30 (m, 2H), 7.92-7.88 (m, 1H), 7.72-7.69 (m, 1H), 7.63-7.57 (m, 1H), 7.43-7.37 (m, 1H), 7.23-7.17 (m, 1H), 7.11-7.05 (m, 2H), 4.03-3.93 (m, 2H), 3.87-3.70 (m, 3H), 3.67-3.56 (m, 2H), 3.26-3.03 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[N:21]1([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH:25]=[CH:24][N:23]=[N:22]1.[I-].[K+].C[O-].[Na+]>CO>[F:18][C:17]([S:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:31][CH:32]=3)[N:4]=2)=[CH:11][CH:12]=1)([F:20])[F:19]
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)Sc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1

Procedure:
0.32 g (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole, 0.217 g (1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol, 0.166 g (1.00 mmol) potassium iodide and 0.191 ml (1.00 mmol) of sodium methylate (30% in methanol) were added to 50.0 ml methanol and heated to reflux for 16 h. After removal of solvent and partitioning of the residue between 50 ml ethyl acetate and 15 ml water, the organic phase was washed with 10 ml water, 10 ml 0.1 N NaOH and twice 15 ml water, and dried over sodium sulfate. The solution was concentrated until crystallisation of the product started. After leaving for 1 h at room temperature the precipitate was isolated, washed with ether and dried at 40° C. in vacuo. Yield 0.11 g (18%) 1-[4-(4-{2-[2-(4-Trifluoromethylsulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole, m.p. 144–145° C.