Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C([Cl:15])=NC=CC=1)C1C=CC=CC=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][NH:27][C:26](=O)[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:15])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Clc1ncccc1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(OCc2ccccc2)ccn1
Temperature: 90 °C
Yield: 47.1 %

Procedure:
Preparation of 4-(benzyloxy-2-chloropyridine: A 250 mL round-bottomed flask was charged with 4-(benzyloxy)pyridin-2(1H)-one (10.0 g, 49.7 mmol) and phosphorus oxychloride (55.6 mL, 596 mmol). The reaction mixture was heated at 90° C. overnight, then cooled and carefully quenched with sodium carbonate and sodium hydroxide to pH 7. The aqueous layer was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with dichloromethane as eluent to afford 4-(benzyloxy)-2-chloropyridine (5.14 g, 47.1% yield) as white solid. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.34-7.44 (m, 5H), 6.91 (d, 1H), 6.81 (dd, 1H), 5.10 (s, 2H). LC/MS: (5 to 95) Rt=2.64 min (ESI) m/z=220 (M+H) (40%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[N:38]=[C:37]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:35][C:34]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52]>ClCCl>[CH3:32][C:33]1[N:38]=[C:37]([CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:44][CH2:45]2)[CH:36]=[CH:35][C:34]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1-c1ccc(CN2CCNCC2)nc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.5 %

Procedure:
A 40 mL vial was charged with a solution of triphosgene (83.0 mg, 0.280 mmol, 0.39 equiv) in dichloromethane (20 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (141 mg, 0.840 mmol, 1.18 equiv). N,N-Diisopropylethylamine (542 mg, 4.19 mmol, 5.90 equiv) was added dropwise at 0° C. The mixture was stirred for 2 hours at room temperature. 1-[[6-Methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine (200 mg, 0.710 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The residue was chromatographed on a C18 column with acetonitrile/water (40/60) to provide 219 mg (65% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.43 (d, J=7.5 Hz, 1H), 7.28-7.34 (m, 4H), 7.09 (d, J=6.9 Hz, 1H), 5.72-5.80 (m, 1H), 3.77 (s, 2H), 3.65 (br, 4H), 2.63 (br, 4H), 2.31 (s, 3H), 2.07 (s, 3H). LCMS (ESI, m/z): 476 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:32])([CH3:31])[CH2:12][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:14](O)[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:31])([CH3:32])[CH2:12][C@@H:13]([C@H:14]1[O:18][C:17](=[O:19])[CH2:16][CH2:15]1)[NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCC(=O)O1

Procedure:
5.52 g of the ethyl 9-benzyloxy-5(S)-tert-butoxycarbonylamino-4(R,S)-hydroxy-7,7-dimethyl-nonanoate obtained as the crude product are refluxed in 100 ml of toluene and 4 ml of glacial acetic acid at 110° C. under argon for 4.5 h. After the reaction mixture has cooled, it is diluted with ethyl acetate and worked up in the customary manner. The crude product is purified by chromatography over silica gel (mobile phase B), the two 5(S) and 5(R) stereoisomers being separated. This gives the pure title compound (diastereomer I) as a yellowish oil: Rf (B)=0.26; FAB-MS: (M+H)+ =406; and diastereomer II: Rf (B)=0.22.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 72 h
Yield: 83.1 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.277 g, 1.14 mmol) and 3,5-dichlorophenyl isothiocyanate (0.238 g, 1.17 mmol) in ethyl acetate (30 mL) was warmed until a solution was obtained, then allowed to stand at room temperature for 3 days. The reaction was concentrated until a crystalline precipitate was obtained then allowed to stand overnight at room temperature. The solid was collected by filtration, rinsed with ethyl acetate/hexane, and dried to afford the product (0.423 g); m.p. 195-197° C.
Reaction SMILES: [C-]#[N:2].[Na+].Br[CH2:5][CH2:6][C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[C:8]=1[CH3:19].[C:20]1([CH3:26])C=CC=CC=1>O>[C:20]([CH2:26][CH2:5][CH2:6][C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[C:8]=1[CH3:19])#[N:2]
Reactant: Cc1c(CCBr)c2cccc3c2n1CCC3
Reactant: [C-]#N
Reactant: Cc1ccccc1
Agent: [Na+]
Solvent: O
Product: Cc1c(CCCC#N)c2cccc3c2n1CCC3

Procedure:
A solution of 2.96 g of sodium cyanide in 60 ml of water was added to a solution of 14 g of 1-(2-bromoethyl)-5,6-dihydro-2-methyl-4H-pyrrolo[3,2,1-ij]quinoline in 100 ml of toluene, and the reaction mixture was heated under reflux for 4 hours. To work up the reaction mixture it was concentrated to dryness, and the residue was washed with water and extracted with dichloromethane. The dichloromethane phase was separated, dried and evaporated. 10.5 g of crude 1-(3-cyanopropyl)-5,6-dihydro-2-methyl-4H-pyrrolo[3,2,1-ij]-quinoline were obtained as a brownish oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][S:5][C:4](=[O:7])[CH:3]=1.COC1C=C2C(=C(OC)C=1)N(CC1C=CC(Cl)=CC=1)C=C2.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:56]=[CH:55][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50](=[O:54])[C:51](Cl)=[O:52])=[CH:42]2)=[CH:38][CH:37]=1>COCCOC.O>[Cl:35][C:36]1[CH:56]=[CH:55][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50](=[O:54])[C:51]([NH:1][C:2]3[CH2:6][S:5][C:4](=[O:7])[CH:3]=3)=[O:52])=[CH:42]2)=[CH:38][CH:37]=1
Reactant: NC1=CC(=O)SC1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: COc1cc(OC)c2c(ccn2Cc2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-amino-5H-thiophen-2-one of Preparation 5 (103 mg), powdered potassium carbonate (138 mg) and 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride of Example 1 (334 mg) in 1,2-dimethoxyethane (5 ml) is stirred at room temperature for 2 h. After this time the reaction mixture is poured in water (50 ml) and the obtained precipitate is collected by filtration and thoroughly washed with water. The still wet solid is suspended in methanol and stirred for 30′. Filtration followed by drying at 40° C. under vacuum gives 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-thienyl)acetamide (280 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[H-].[Na+].CI.[C:25](OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:25])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C

Procedure:
2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol 68 (175 mg) was cooled in DMF to 0° C. and then NaH was added at once. The reaction was allowed to warm to room temperature and stirred several minutes before addition of methyl iodide. Reaction was stirred several hours and monitored by LC-MS until complete. Ethyl acetate was added and the solution was extracted with saturated bicarbonate solution. Organic was collected and dried, filtered and concentrated to get crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5](O)[C:6]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8][C:7]=2[N:23]=1.C(OC(C1C(=O)CCN([C:38]2[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][N:39]=2)CC1)=O)C.[CH3:48]C[O-].[Na+].NC(N)=S.CI>CCO>[CH3:1][S:2][C:3]1[N:4]=[C:5]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([C:44]([F:45])([F:46])[F:47])=[CH:38][CH:48]=2)[C:6]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8][C:7]=2[N:23]=1
Reactant: CCOC(=O)C1CCN(c2ncccc2C(F)(F)F)CCC1=O
Reactant: CC[O-]
Reactant: CSc1nc(O)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: NC(N)=S
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol. To solution of 5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethyl ester (3.0 g, 9.09 mmol) in EtOH (40 mL) was added NaOEt (1.97 g, 29.1 mmol) and thiourea (1.1 g, 13.6 mmol). The mixture was heated at reflux for 12 h. The mixture was cooled, treated with MeI (0.74 mL, 11.8 mmol) drop-wise, and stirred at rt for 1 h. The mixture was concentrated and the residue was dissolved in water and acidified to pH=7 with HOAc (a precipitate formed). The solid was filtered to give the title compound (3.3 g, >99%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:64][P-](F)(F)(F)(F)F.FC1C=C(C=CC=1)CNC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>CN(C=O)C>[F:64][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][NH:37][C:27]([C:26]1[C:20]2[NH:19][C:18]([C:12]3[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:22][C:21]=2[CH:23]=[CH:24][CH:25]=1)=[O:28]
Reactant: NCc1ccccc1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1F)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid 2-fluoro-benzylamide was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid 2-fluoro-benzylamide. LC/MS calcd for C28H23ClFN5O2 (m/e) 515.0, obsd 516 (M+H). 1H NMR (tautomers, DMSO-d6): 13.33-13.49 (m, 1H), 11.14-11.45 (m, 1H), 10.05-10.92 (m, 1H), 9.08-9.32 (m, 1H), 7.70-7.98 (m, 2H), 7.02-7.61 (m, 11H), 6.16-6.32 (m, 1H), 4.53-4.80 (m, 2H), 3.43-3.84 (m, 2H), 2.75-3.12 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[O:22]1CCO[CH2:24][CH2:23]1>>[C:1]([O:12][CH2:11][CH2:10][C:9]1[CH:13]=[CH:14][C:6]([NH:5][C:23](=[O:22])[CH3:24])=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of acetyl chloride (35.6 ml) in dioxan (110 ml) was added dropwise at 0° C. to a stirred mixture of p-aminophenethyl alcohol (34.3 g, Aldrich) and triethylamine (37.5 g) in dioxan (110 ml). When addition was complete, the mixture was stirred at room temperature for 17 hours, then poured into 2N aqu. HCl, saturated with NaCl, and extracted with ethyl acetate (×3). The combined extracts were washed with water and brine, dried over MgSO4 and evaporated in vacuo to give the desired product as a brown solid (55.3 g).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].CC(C)([O-])C.[K+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1COCC1.CCOCC>[CH3:1][C:2]([O:6][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH3:3])[C:4]#[CH:5]
Reactant: CCOC(=O)CBr
Reactant: C#CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(C)(C)OCC(=O)OCC
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A solution of 0.87 g (10.32 mmol) of 2-methylbut-3-yn-2-ol in 20 ml of anhydrous THF is cooled to 0-5° C. with an ice bath and then 10.32 ml (10.32 mmol) of 1.0M potassium t-butoxide in THF (Aldrich) are added. Stirring is carried out under cold conditions for 10 minutes and then 1.89 g (11.35 mmol) of ethyl bromoacetate are added. The reaction mixture is stirred at ambient temperature for 45 minutes and then 0.1 N aqueous HCl and ether are added. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 1.45 g of the expected product are obtained in the form of a yellow oil which is used without subsequent purification. Yield=83%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:30])[CH:28]=[CH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1cccc(I)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-{4′-[4-(1-hydroxy-allyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-3-trifluoromethyl-benzene. The crude material was purified on silica gel (0-60% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[CH:26]([C:28]1[N:29]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)[OH:27])([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[C:26]([C:28]1[N:29]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:42])=[O:43])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([C:37]([F:39])([F:40])[F:38])[CH:31]=2)=[O:27])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1C(O)c1cc2ccc(C(F)(F)F)cc2n1S(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(N2CCCCC2)ccc1[N+](=O)[O-])c1cc2ccc(C(F)(F)F)cc2n1S(=O)(=O)c1ccccc1
Temperature: -80 °C
Yield: 99.6 %

Procedure:
Into a 50 mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of dimethlysulfoxide (156 mg, 2.00 mmol, 3.73 equiv) in dichloromethane (5 mL). This was followed by the addition of oxalyl dichloride (127 mg, 1.00 mmol, 1.87 equiv) dropwise with stirring at −80° C. The resulting solution was stirred for 10 min at −80° C. in a liquid nitrogen bath. To this was added a solution of (2-nitro-5-(piperidin-1-yl)phenyl)(1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indol-2-yl)methanol (300 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at −80° C. The resulting solution was stirred for an additional 60 min at −80° C. To the mixture was added triethylamine (400 mg, 3.96 mmol, 7.39 equiv) dropwise with stirring at −80° C. The resulting solution allowed to warm to −20° C. over 60 minutes. The solution was diluted with 50 mL of DCM. The mixture was washed with 1×30 mL of water and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg of intermediate if as orange oil.
Reaction SMILES: CO[C:3](=[O:8])[C:4]([NH2:7])([CH3:6])[CH3:5].C(N(CC)C(C)C)(C)C.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([NH:26][C:27](=O)[O:28]C)=[CH:21][C:20]=1[CH3:31].O>CC(N(C)C)=O>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N:26]2[C:3](=[O:8])[C:4]([CH3:5])([CH3:6])[NH:7][C:27]2=[O:28])=[CH:21][C:20]=1[CH3:31]
Reactant: COC(=O)C(C)(C)N
Reactant: COC(=O)Nc1cc(C)c(Br)c(C)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)cc(C)c1Br
Yield: 28.1 %

Procedure:
α-Aminoisobutyric acid methyl ester (3.2 g, 20.92 mmol) and N,N-diisopropylethylamine (6.1 ml, 34.86 mmol) were added to a solution of methyl (4-bromo-3,5-dimethylphenyl)carbamate (900 mg, 3.48 mmol) in anhydrous DMA (17.5 ml, 0.2 M). After irradiation with microwaves at 170° C. for 30 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (304 mg, 28%)
Reaction SMILES: C[C:2]1C(C)=CC=[CH:4][C:3]=1[NH:9]CC(C)=C.[C:14]([O-])(=O)C.[Na+].[C:19]1([CH3:26])[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23][CH:24]=1>O.[Cl-].[Zn+2].[Cl-]>[CH3:2][C:3]1([CH3:14])[CH2:4][C:23]2[C:24](=[C:19]([CH3:26])[C:20]([CH3:25])=[CH:21][CH:22]=2)[NH:9]1
Reactant: Cc1ccccc1C
Reactant: C=C(C)CNc1cccc(C)c1C
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: Cc1ccc2c(c1C)NC(C)(C)C2
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 77 %

Procedure:
To a solution of 2,3-dimethyl-N-(2-methyl-2-propenyl)benzeneamine (3.77 g, 21.5 mmol) in xylene (35 mL) was added zinc chloride (8.80 g, 64.6 mmol), and the mixture was stirred at 150° C. for 3.5 hours. Heating was stopped, and a solution of sodium acetate (10.6 g, 0.129 mol) in water (30 mL) was carefully added dropwise to the resulting hot mixture. The resulting solution was cooled, the organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 20:1) to obtain 2.91 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]([OH:5])=[O:4])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NC(CCCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (±)-2-amino-5-phenyl-pentanoic acid (0.188 g, 0.000973 mol), 4-fluoro-benzenesulfonyl chloride (0.189 g, 0.000971 mol), and sodium carbonate (0.208 g, 0.00196 mol) in water (4 mL) was stirred at room temperature for 4 days. The mixture was heated briefly on a steam bath to give a cloudy solution. The solution was gravity filtered hot, and the filtrate allowed to cool. The resulting solid that crystallized was filtered off, washed with water, and dried in vacuo; yield 0.131 g, (38%). 1H-NMR (DMSO-d6): δ7.81 (m, 2H), 7.37 (t, 2H), 7.25 (t, 2H), 7.14 (m, 4H), 3.34 (br s, H2), 3.04 (t, 1H), 2.46 (m, 2H), 1.6-1.4 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20](F)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.C(OC(=O)C1C=C(OCC)C([Cl:49])=C(OCC)C=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([Cl:49])=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 505.2 (MH+).