Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1)=[O:5].C(N(CC)CC)C.C[O:22][C:23](=O)[N:24]=[C:25](SC)[C:26]([C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH2:49][CH2:50][F:51])[C:41]=1[F:52])=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[C:37]([CH3:39])[O:36][N:35]=2)=[CH:30][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:23](=[O:22])[NH:24][C:25]([CH:26]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH2:49][CH2:50][F:51])[C:41]=3[F:52])[NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:38]=[C:37]([CH3:39])[O:36][N:35]=4)=[CH:32][CH:33]=3)=[N:13]2)[N:7]=1)=[O:5]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Reactant: COC(=O)c1cccc(NN)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2nc(C(Nc3ccc(-c4noc(C)n4)cc3)c3cc(OC)cc(OCCF)c3F)[nH]c2=O)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
After adding 149 mg of 6-hydrazinopyridine-2-carboxylic acid methyl ester hydrochloride and 92 μl of triethylamine to a solution of 255 mg of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (3e)) in 5 ml of DMF, the mixture was stirred at 85° C. for 24 hours under a nitrogen atmosphere.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:21])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c[nH]c2ccccc12
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Next, a solution of indole-3-carbonyl chloride was prepared. A well-stirred suspension of indole-3-carboxylic acid (67.7 mg, 0.42 mmol) in dry DCM (2 ml) containing a small amount of dimethylformamide (DMF) (20 μL) was treated with oxalyl chloride (0.84 mmol, 107 mg, 72 μL) at 0° C. Following addition to the oxalyl chloride, the mixture was stirred for 20 minutes at 23° C., producing a clear, slightly yellow solution. This solution was evaporated to dryness in vacuo at 0.1 Torr to ensure removal of excess oxalyl chloride, and was subsequently re-dissolved in 2 ml of dry DCM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([CH3:15])[CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[C:4]([CH2:15][Br:16])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1CBr)C(F)(F)F
Yield: 67.5 %

Procedure:
A solution of Example 478A (2.5 g, 8.9 mmol) and N-bromosuccinimide (1.58 g, 8.9 mmol) in carbon tetrachloride (25 mL) was irradiated with a 100-watt incandescent bulb overnight. The solution was filtered and the filtrate was concentrated. The concentrate was purified by flash chromatography on silica gel using 3-4% ethyl acetate/hexanes to give 2.17 g (68% yield) of the desired product. MS (ESI(−)) m/e 360, 362 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[Na+].Cl.[C:10]([NH2:13])(=[NH:12])[CH3:11].C(Cl)Cl>O>[CH2:5]([O:4][C:2]([NH:13][C:10](=[NH:12])[CH3:11])=[O:3])[CH3:6]
Reactant: CC(=N)N
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(C)=N
Yield: 72 %

Procedure:
123 parts of ethyl chloroformate and 170.4 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 94.6 parts of acetamidine hydrochloride in 750 parts of methylene chloride and 250 parts of water, at from 10° to 15° C., in the course of 30 minutes, while stirring. After the mixture has been stirred at 25° C. for 15 minutes, the phases are separated. The aqueous phase is extracted with twice 100 parts of methylene chloride, and the solvent is removed from the organic extract to give 93.4 parts (72% of theory) of N-ethoxycarbonylacetamidine of melting point 111°-114° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)(C)(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>CCOCC.CCO>[C:27]1([CH3:37])[CH:28]=[CH:29][C:30]([S:33]([OH:36])(=[O:34])=[O:35])=[CH:31][CH:32]=1.[NH2:8][CH2:9][CH2:10][N:11]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CN(CCN)C(=O)OCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
A solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)((2-(trimethylsilyl)ethoxy)carbonyl)amino)acetate (intermediate 125, 7.70 g, 19.72 mmol) in Et2O (50 ml) was added to a solution of para-toluene sulphonic acid (3.94 g, 20.70 mmol) in EtOH (50 ml) at room temperature. The rotated solution was then evaporated under a reduced pressure of 270 mbar at room temperature for 40 minutes and then for 1 h at 55° C. To the residue was added EtOH (50 ml), which was again removed by evaporation to give the title compound as a yellow oil. (MS) ESI-MS 291.3 [M+H]+
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(OCC)(=O)C>CCCCCC>[CH3:4][NH:6][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a mixture of 40% aqueous solution of Methylamine hydrochloride (2.175 g, 33.2 mmol) and Triethyl amine (3.75 g, 37.18 mmol) at 0° C., added 4-Nitro-benzoyl chloride (4.6 g, 24.78 mmol) and stirred for 30 mins. The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The solid precipitate so obtained was filtered, washed with ice cold water and dried to afford 4 g (89%) of N-Methyl-4-nitro-benzamide. 1H NMR: (DMSO-d6): δ 8.78 (s, 1H), 8.32 (d, 2H), 8.06 (d, 2H), 2.8 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[CH:17]=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[CH:17]=[S:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N2CCOCC2C=O)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2C=S)cc1OC
Reaction time: 8 h

Procedure:
A mixture of 25.1 g (0.1 mole) of 4-(3',4'-dimethoxyphenyl)-oxomethylmorpholine, 100 ml of pyridine and 22.3 g (0.1 mole) of diphosphorus pentasulfide is boiled for 8 hours. Then the solvent is removed in vacuo, the residue is poured into 300 g of icy water and the product is crystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.CCCCCC.Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 1,3-bis{[(methyloxy)methyl]oxy}benzene (Reference Intermediate 208, 2.19 g) in dry tetrahydrofuran (10 ml) at room temperature BuLi 1.6M in hexane (8.29 ml, 13.26 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chloro(oxo)acetate (2.263 g, 16.57 mmol) in dry tetrahydrofuran (10 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml) and extracted with ethyl acetate (2×30 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound as a light yellow oil (1.75 g).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C1COCC1>[C:29]([O:28][C:26]([CH2:25][C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:23])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the resultant compound from Example 65 (12.9 g, 41.7 mmol) in dry THF (100 ml) under nitrogen was added at -78° C. a solution of sodium hexamethyldisilylamide 45.9 ml (1M in THF). After 30 min, t-butyl bromoacetate (13.6 ml, 83.4 mmol) was added as a solution in THF. The resulting reaction mixture was stirred for 1 h at -78° C., quenched with sat. NH4Cl solution (50 ml) and the entire reaction mixture partitioned between diethyl ether and water. The organic layer was separated and the aqueous layer extracted once with ether. The combined organic solutions were washed with 10% HCl, sat. NaHC3O, brine, dried (Na2SO4). filtered, and concentrated. The resulting yellow oil was submitted to silica gel chromatography (flash): yield 12.4 g (70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.080 g, 0.20 mmol) and beta-alanine ethyl ester hydrochloride, according to Reference S and the general procedure for amide formation afforded ethyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)propanoate. MS (ESI) m/z: Calculated: 489.2; Observed: 490.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 1-neck round-bottom flask under an atmosphere of nitrogen was dissolved 2-chloronicotinoyl chloride (2.12 g, 0.0120 mol) in methylene chloride (25 mL) and the reaction cooled to 0° C. N-ethylethanamine (2.7 mL, 0.026 mol) was added to the mixture and stirred at 0° C. for 2 hours and then at 20° C. for 16 hours. The reaction was extracted with dichloromethane and the organic extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 8.42-8.44 (m, 1H), 7.64-7.65 (m, 1H), 7.29-7.63 (m, 1H), 3.75-3.79 (m, 1H), 3.35-3.40 (m, 1H), 3.13-3.22 (m, 2H), 1.82 (t, 3H), 1.088 (t, 3H). MS: [M+1]=213.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])=[C:15]([O:26][CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH3:27][O:26][C:15]1[CH:14]=[C:13]([O:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:3]([O:28][CH3:29])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]=1[NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccncc4)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A starting compound (N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (48 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 65 mg (yield 67%) of the title compound.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:32]([O:34]C(C)(C)C)=[O:33])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C@@H:13]([OH:24])[C@@H:12]2[C@H:10]1[C@H:11]2[C:25]([O:27]C(C)(C)C)=[O:26])=O)(C)(C)C.O.C(O)(=O)C>>[NH2:8][C@@:9]1([C:32]([OH:34])=[O:33])[C@H:14]([CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C@@H:13]([OH:24])[C@@H:12]2[C@H:10]1[C@H:11]2[C:25]([OH:27])=[O:26]
Reactant: Cc1ccc(SC[C@@H]2[C@@H](O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(SC[C@@H]2[C@@H](O)[C@H]3[C@H](C(=O)O)[C@H]3[C@]2(N)C(=O)O)cc1
Temperature: 140 °C
Yield: 89.6 %

Procedure:
Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-3-(p-tolylsulfanylmethyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (300 mg, 545.73 μmol) is placed in a microwave vial. To the vial is added water (2 mL, 110 mmol), and acetic acid (2 mL, 34.9 mmol). The mixture is heated in the microwave to 140° C. for 20 minutes. The solvent is removed under reduced pressure to give the title compound (165 mg, 489.04 μmol, 89.6%). MS (m/z): 338.0 (M+H).
Reaction SMILES: C([Li])CCCCC.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([CH:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[CH:27]([CH3:29])[CH3:28].[P:30](Cl)([O:34]CC)[O:31][CH2:32][CH3:33].Cl>C1COCC1>[CH:21]([C:20]1[CH:19]=[C:18]([CH:24]([CH3:25])[CH3:26])[CH:17]=[C:16]([CH:27]([CH3:29])[CH3:28])[C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[PH:30](=[O:34])[O:31][CH2:32][CH3:33])([CH3:22])[CH3:23]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2I)c(C(C)C)c1
Reactant: CCOP(Cl)OCC
Agent: Cl
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Product: CCO[PH](=O)c1ccccc1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: -60 °C
Reaction time: 0.42 h
Yield: 94 %

Procedure:
A 1-L 3-neck round-bottom flask was fitted with an addition funnel and the atmosphere was purged with nitrogen. Anhydrous, degassed THF (170 mL) was added to the 1-L flask and cooled to −60° C. (internal temperature). The addition funnel was charged with hexyllithium (2.38 M in hexanes, 57 mL, 135 mmol, 2.0 equiv). The hexyllithium was transferred into the cold THF over 20 min, maintaining the temperature below −40° C. The solution was re-cooled to −60° C. (internal temperature). A solution of 2′-iodo-2,4,6-triisopropylbiphenyl (27.5 g, 67.7 mmol, 1.0 equiv) in 170 mL of anhydrous, degassed THF was transferred, via cannula, drop wise to the n-hexyllithium solution. This was done over 25 min while maintaining the temperature below −40° C. After addition, the reaction mixture was allowed to stir at −60° C. for 30 min. Diethyl chlorophosphite (19.62 mL, 135 mmol, 2.0 equiv) was added to the reaction mixture, over 10 min while maintaining the temperature below −40° C. After addition of diethyl chlorophosphite, the reaction was allowed to proceed at −60° C. for an additional 30 min. Aqueous hydrochloric acid (1 M, 338 mL, 338 mmol) was added at −60° C. The flask was removed from the cold bath and the reaction was allowed to warm to 22° C. The resultant solution was diluted with heptane (340 mL) and transferred to a separatory funnel. The layers were separated and the organic layer was assayed for product by quantitative HPLC (94% yield). The organic layer was concentrated under reduced pressure to give an oil which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH2:15]Br)=[CH:4][N:3]=1.ClC1C=CC([Mg]Br)=CC=1.ClC1C=CC(C=[O:34])=CN=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH2:15][OH:34])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Clc1ccc(CBr)c(-c2ccc(Cl)nc2)c1
Agent: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1-c1ccc(Cl)nc1

Procedure:
2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromomethane may be prepared in the following manner: 0.153 cm3 of thionyl bromide is added to a solution of 100 mg of (2-chloropyrid-5-yl)-(4-chlorophenyl)methanol in 2 cm3 of carbontetrachloride, under an inert argon atmosphere, at a temperature in the region of 0° C. After 3.5 hours at a temperature in the region of 0° C., the reaction medium is concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 1.3 g of a brown liquid are thus obtained, which liquid is taken up in dichloromethane and supplemented with water and sodium dithionite. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.33 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)bromomethane is thus obtained in the form of a brown oil. 2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromomethane may be prepared by carrying out the procedure in a manner similar to Example 84, starting with 22.5 cm3 of 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 30 cm3 of tetrahydrofuran, under an inert argon atmosphere, and 2.9 g of 2-chloropyridine-5-carboxaldehyde in 30 cm3 of tetrahydrofuran. 3.42 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)methanol are thus obtained in the form of a pale green powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]([C:44](=[O:48])[NH:45][CH2:46][CH3:47])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][O:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:13]([OH:36])[CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:57](Cl)([O:59]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[CH2:46]([NH:45][C:44]([C:6]([C:4](=[O:5])[NH:3][CH2:1][CH3:2])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:7][O:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[N:17]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[C:57](=[O:59])[O:36][C:13]=2[CH:12]=1)=[O:48])[CH3:47]
Reactant: CCNC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)NCC)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)C(COC(=O)Cc1ccc2c(c1)oc(=O)n2C(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1)(C(=O)NCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 213.3 %

Procedure:
The {3-Hydroxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetic acid 2,2-bisethylcarbamoyl-2-phenylethyl ester (195 mg) obtained in Example 3-2was dissolved in chloroform (5 mL), and to this solution was added triethylamine (72 mg). The solution was cooled to 0° C. and triphosgene (35 mg) was added thereto. After stirring for one hour, the reaction solution was washed with water, dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=1:1 to give the title compound (173 mg) (see Table 59).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH:9]1[C:18](=[O:35])[NH:19][CH:20]([CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1)[CH:21]([CH3:23])[CH3:22])=O)(C)(C)C.[CH2:36]([S-:38])[CH3:37].[Na+]>>[CH3:22][CH:21]([CH3:23])[CH:20]([NH:19][C:18]([CH:9]1[CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][S:38][CH2:36][CH3:37])[CH2:12][CH2:13][NH:8]1)=[O:35])[CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1
Reactant: CSC1OC(C(NC(=O)C2CC(CCCO)CCN2C(=O)OC(C)(C)C)C(C)C)C(O)C(O)C1O
Reactant: CC[S-]
Agent: [Na+]
Product: CCSCCCC1CCNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1

Procedure:
The title compound of example 22 was prepared from protected tosylate intermediate prepared in example 19, according to the procedure used in examples 19-21, using sodium ethanethiolate in the displacement step; MS (ESPOS): 465.3 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[C:9]1=[O:14]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1C(=O)N1CCCC1
Product: CN(C)C=C1CCCC(C(=O)N2CCCC2)C1=O

Procedure:
2-(Pyrrolidine-1-carbonyl)-cyclohexanone (56 mg, 0.29 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (58 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 251.3 (100) [(M+H)+].
Reaction SMILES: [K].[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])=[CH:8][CH:7]=1)([CH3:4])[CH3:3]
Reactant: BrCCCCCCBr
Reactant: CC(C)Oc1ccc(O)cc1
Agent: [K]
Product: CC(C)Oc1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-isopropoxyphenoxy)hexyl bromide was prepared from the potassium salt of 4-isopropoxyphenol and 1,6-dibromohexane.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH:13]=[C:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1.[ClH:32]>ClCCl>[ClH:32].[NH:17]1[CH2:18][CH2:19][C:14](=[CH:13][C:12]2[CH:11]=[C:10]([CH:29]=[CH:28][CH:27]=2)[O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:30])=[N:8][CH:7]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)nc3)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cn1
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of tert-butyl 4-(3-(6-(trifluoromethyl)pyridin-3-yloxy)benzylidene)piperidine-1-carboxylate (0.140 g) in dichloromethane (5 mL, 0.06 M) was treated with hydrogen chloride gas for 2 min. The reaction was allowed to stir for 2 h and then was concentrated to give the title compound as a white foam (0.100 g, 84% yield) which was used without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (2H, t, J=5.8 Hz), 2.59 (2H, t, J=5.8 Hz), 3.04 (2H, t, J=6.0 Hz), 3.10 (2H, t, J=6.0 Hz), 6.44 (1H, s), 7.01-7.09 (2H, m), 7.13 (1H, d, J=7.8 Hz), 7.43 (1H, t, J=7.8 Hz), 7.52 (1H, dd, J=8.6, 2.7 Hz), 7.88 (1H, d, J=8.6 Hz), 8.52 (1H, d, J=2.7 Hz), 8.98 (2H, br. s.).