Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.Cl.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]([Cl:10])=[O:6])[CH2:18][CH2:17]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CCN(C(=O)Cl)CC1

Procedure:
To a stirred solution of triphosgene (7.4 g, 0.025 mmol) in dichloromethane (200 ml) at ice bath was added dropwise a solution of 4-methoxy-piperidine hydrochloride salt (10 g, 0.066 mmol) and pyridine (10.9 g, 0.139 mmol) in dichloromethane (100 ml). The mixture was stirred over night and filtered through a silica pad, eluting with dichloromethane and evaporated. After trituration with diisopropyl ether, the mixture was used without purification.
Reaction SMILES: COCN[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].[C:20]1([O:28][CH3:29])[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][CH3:23]>>[CH3:23][O:22][C:21]1[C:20]([O:28][CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]1)=[O:6]
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1OC
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC

Procedure:
In Scheme G, step c, 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) is reacted with lithiated veratrole to give 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2.O>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:33]([C:32]([C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:37])([CH3:19])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)=[O:36])=[O:34])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)Cl)ccc21
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.7 g (40 mmol) of methyl 2-hydroxy-4-aminobenzoate, 10 ml (0.12 mol) of pyridine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 10.5 g (40 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxyloyl chloride, prepared in 1(c), in 100 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (30:70). After evaporation of the solvents, 7.3 g (45%) of methyl ester, melting point 146°-7° C., are collected.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=O)(=O)[CH3:2].[C:9]([O:15][CH3:16])(=[O:14])[CH2:10]C(C)=O.CO.ClC(Cl)C>[Fe].O>[CH3:16][O:15][C:9]([C:10]1[CH:6]=[C:5]([CH3:8])[O:4][C:1]=1[CH3:2])=[O:14]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)OC(C)C=O
Agent: [Fe]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C)oc1C

Procedure:
12.2 parts by weight of anhydrous iron-III chloride followed by 44.9 parts by weight of 85.5 percent strength by weight α-acetoxypropionaldehyde are added to a solution of 34.8 parts by weight of methyl acetoacetate in 36 parts by weight of methanol, during which addition the mixture rises to the boil. The mixture is then refluxed for a further 1-6 hours and, when it has cooled, is mixed with 80 parts by weight of water and 37.5 parts by weight of dichloroethane; the water phase is separated off and is extracted twice, each time with 25 parts by weight of dichloroethane. The dichloroethane is distilled off under atmospheric pressure and the product is then distilled under reduced pressure. 39 parts by weight of 2,5-dimethylfuran-3-carboxylic acid methyl ester of boiling point 92° C./26 mbar are obtained.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1)=[O:39]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)CC1CCCNC1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Product: CCOC(=O)CC1CCCN(C(=O)Cc2cccs2)C1
Yield: 51.3 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 3-piperidinylacetate (414.2 mg; 2.4 mmol) and 2-thiopheneacetyl chloride (295 μl; 2.4 mmol). The crude product was purified by chromatography on silica, eluting with 50% ethyl acetate in hexane, giving ethyl 1-(2-thiopheneacetyl)-3-piperidinylacetate (364 mg) as a pale yellow oil. MS m/z (positive ion) 318 (M+Na+; 40), 296 (MH+; 100).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[Br:14]Br>CO>[Br:14][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:8]([O-:10])=[O:9])[N:4]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0° C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: OCCN1CCNC1=Nc1ccccc1N1CCOCC1
Solvent: ClCCl
Product: CC(=O)OCCN1CCNC1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 4-(2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl)morpholine (3 g prepared as described in Example 175) in dichloromethane (20 ml) with acetic anhydride (0.86 g) yielded 4-(2-[1-(2-acetyloxyethyl)-2-imidazolidinylideneamino]phenyl)morpholine (m.p. 89°-91° C.) which was recrystallised from hexane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(O)C>[OH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:10]=1
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)COc1ccc(CO)cc1
Yield: 48.6 %

Procedure:
Mix potassium carbonate (2.764 g, 20 mmol), 4-hydroxy-benzyl alcohol (1.49 g, 12 mmol) in absolute ethanol (100 mL), add 1-bromopinacolone (1.791 g, 10 mmol) dropwise. Heat the mixture under reflux for 12 h. Add water to dissolve the solid, and remove most of the ethanol in vacuo. Extract the mixture with EtOAc three times. Combine the organic layers, wash with brine, dry over Na2SO4, filter and concentrate. Purify the residue by chromatography on silica gel eluting with EtOAc:hexane (1:2) to provide the desired intermediate as a colorless oil (1.08 g, 48%). MS (ES+) m/z: 205 (M+H—H2O)+.
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=2)[CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3]1.[CH:33]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]O)=[O:34].[O-]CC.[Na+]>C(O)C>[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:38][C:37]3[CH:36]=[C:35]([CH:42]=[CH:41][CH:40]=3)[CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=2)=[CH:3]1
Reactant: c1ccc([P+](Cc2cccc(-c3ccsc3)c2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(CO)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(C=Cc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
1.21 g of the resulting phosphonium salt was dissolved in 45 ml of ethanol, and 0.35 g of 3-formylbenzyl alcohol and 0.27 g of sodium ethoxide were added. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was distributed between ethyl acetate and water, worked up in a customary manner, and purified by silica gel column chromatography [Wakogel C-300, 100 g; eluting solvent: hexane/ethyl acetate=10/1→5/1] to give 0.34 g (yield 46%) of an E-form of 3-[2-[3-(3-thienyl)-phenyl]ethenyl]benzyl alcohol and 0.34 g of its Z-form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]=[N+:12]=[N-:13])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of 4-methoxybenzyl chloride 1000 (51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solid sodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and the resulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic extracts were washed with H2Od (2×200 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2 g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil, which by HPLC and 1H NMR was found to be essentially pure and was directly used in the subsequent reaction without further purifications. For 4-methoxybenzyl azide 1001: 1H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H, ArOCH3), 4.29 (s, 2H, Ar—CH2), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H, J=7.8 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 36.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (150 mg, 0.52 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (208 mg, 0.63 mmol) using Pd(PPh3)2Cl2 (18 g, 1.56 mol) and sodium carbonate (165 mg, 1.56 mmol) in toluene/ethanol/water (10/10/2 ml) to afford 140 mg (83.6% yield) of the titled compound. MS: m/z=677.2 (M+1) (de t-butyl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[N:10]=[C:11]4[N:15]([CH:16]=3)[N:14]=[C:13]([O:17][CH3:18])[S:12]4)=[CH:6][C:5]2=[C:19]([OH:21])[CH:20]=1.[C:22]1([C:28]2[S:29][CH:30]=[C:31]([CH2:33]O)[N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:33][C:31]2[N:32]=[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:29][CH:30]=2)[C:5]2[CH:6]=[C:7]([C:9]3[N:10]=[C:11]4[N:15]([CH:16]=3)[N:14]=[C:13]([O:17][CH3:18])[S:12]4)[O:8][C:4]=2[CH:3]=1
Reactant: COc1nn2cc(-c3cc4c(O)cc(Cl)cc4o3)nc2s1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cc(Cl)cc4o3)nc2s1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
A flame-dried 100 mL round-bottom flask containing 6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 37I, 25 mgs, 0.078 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 37.2 mgs, 0.194 mmol) in dry THF (4 mL) was added tributylphosphine (0.050 mL, 0.194 mmol). The resulting solution was charged with a solution of ADDP (49.0 mgs, 0.194 mmol) in THF (1 mL) added dropwise over 30 minutes via syringe pump. After stirring for 1.5 hours the reaction mixture was diluted with EtOAc then washed with 1N HCl, sat. NaHCO3, water and brine. The organic phase was dried (MgSO4) then concentrated to dryness. The residue was purified by ISCO using 0 to 10% diethyl ether in DCM. Fractions containing the desired product were concentrated to give the title material as a beige solid (20 mgs, 0.040 mmol, 52.0% yield). LC (Method A): 2.534 min. LCMS (APCI) calcd for C23H16ClN4O3S2 [M+H]+ m/z 495.03, found 495.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.49 (s, 1H), 7.99-7.96 (m, 2H), 7.93 (s, 1H), 7.55-7.50 (m, 3H), 7.40 (dd, J=0.8, 1.6 Hz, 1H), 7.15 (dd, J=0.4, 1.6 Hz, 1H), 7.14 (d, J=0.8 Hz, 1H), 5.43 (s, 2H), 4.21 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C:8]3=[CH:7][C:6]=2[C:5]=1[C:16]([O:18][CH3:19])=[O:17])([O-])=O.[Sn](Cl)Cl>CO.O.C(Cl)Cl>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C:8]3=[CH:7][C:6]=2[C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2c1cc1n2CCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc2c1cc1n2CCC1
Temperature: 60 °C
Yield: 70.6 %

Procedure:
A mixture of methyl 7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 19, 0.160 g) and tin (II) chloride (0.520 g) in methanol (6 mL) and water (0.06 mL) was heated at 60° C. for 8 hours. The resultant mixture was cooled and diluted with DCM and filtered through Celite. The filtrate was washed with 1M aqueous sodium hydroxide solution and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.100 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:41]=[C:42]([N:46]=[C:47]=[O:48])[CH:43]=[CH:44][CH:45]=1>O1CCOCC1>[Cl:39][C:40]1[CH:41]=[C:42]([NH:46][C:47]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[C:16]4[CH2:15][N:14]([CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)[C:13](=[O:26])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[C:4]([F:29])[CH:3]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)Nc5cccc(Cl)c5)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (20 mg, 0.05 mmol), DIEA (304, 0.15 mmol), and 3-chlorophenyl isocyanate (9.4 mg, 0.06 mmol) were suspended in dioxane (2 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=548, obsd.=548).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.Cl[CH2:11][C:12]([NH2:14])=[NH:13]>C1COCC1>[O:6]1[CH2:7][CH2:8][N:3]([CH2:11][C:12]([NH2:14])=[NH:13])[CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: N=C(N)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g, 60 mmol, 60%) was added to a solution of morpholine (5.2 g, 60 mmol) in THF (40 mL, anhydrous) and stirred for 30 min at room temperature under nitrogen. Chloroacetamidine hydrochloride (2.58 g, 20 mmol) was added to this solution in one portion and stirred at 50° C. overnight. Solvent was removed under reduced pressure and the dark brown oily residue was directly used in the next step.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.O>C(#N)C.CCOC(C)=O>[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1
Reactant: COc1ccc(CN[C@H]2CC[C@@H](NS(=O)(=O)c3ccc(-c4ccc(F)cc4F)cc3)CC2)c(OC)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N[C@H]1CC[C@@H](NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
N-(cis-4-(2,4-Dimethoxybenzylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide (see ABD787a) (52 mg, 0.10 mmol) was stirred in acetonitrile (3 mL) and water (1 mL) and ceric ammonium nitrate (144 mg, 0.26 mmol) was added. The mixture was stirred at 50° C. overnight and then diluted with EtOAc (15 mL) and washed with water (2×5 mL). The washings were extracted with EtOAc (5 mL) and the combined organics were dried over MgSO4. After evaporation of the solvents, the residue was loaded onto a 1 g SCX column and eluted with MeOH and then 20% 2 M NH3/MeOH in DCM. The resulting material was further purified by chromatography (2 g Isolute II cartridge), eluting with 0-10% 2 M NH3/MeOH in DCM to afford the title compound as an off-white powder (9 mg, 25%). 1H NMR (300 MHz, DMSO-d6): δ 0.86-0.98 (2H, m), 1.09-1.26 (2H, m), 1.55-1.68 (4H, m), 2.40 (1H, br s), 2.87 (1H, br s), 4.12 (1H, br s), 7.22 (1H, td, J=8 Hz, 2 Hz), 7.40 (1H, td, J=10 Hz, 2.5Hz), 7.65 (1H, q, J=7 Hz), 7.71 (2H, d, J=9 Hz) and 7.85 (2H, d, J=9 Hz). LCMS: (MH)+=367.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16]O.N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[Br:2][CH2:16][CH2:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: BrCCc1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
A solution of phosphorus tribromide (3.52 g, 0.013 mol) in chloroform (6.25 ml) was added dropwise at -10° to a stirred solution of 2-naphthalene-ethanol (4.3 g, 0.025 mol) in chloroform (20 ml), containing dry pyridine (0.13 ml, 0.0016 mol). Following the addition, the mixture was stirred at -10° for 2 h, and was then stood at ambient temperature overnight. Next day, the reaction mixture was poured into water (62.5 ml) and the organic layer was separated. The aqueous solution was then extracted with chloroform (3×6.25 ml), and the organic layer and chloroform extracts were combined and washed with sodium hydroxide solution (62.5 ml., 2M), and with water (62.5 ml). The chloroform solution was dried (MgSO4), and the chloroform was then evaporated under reduced pressure to afford 2-(2-bromoethyl)naphthalene which was used without further purification.
Reaction SMILES: [CH2:1]([C@H:3]1[O:8][C@@H:7]([CH2:9][CH3:10])[CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=O)[CH2:4]1)[CH3:2].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CO>[CH2:9]([C@H:7]1[O:8][C@@H:3]([CH2:1][CH3:2])[C@@H:4]2[C:28]3([CH2:13][C:12]4[C:11]([N:5]2[CH2:6]1)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=4)[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]3=[O:30])[CH3:10]
Reactant: CC[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](CC)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: CC[C@@H]1CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](CC)O1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
2-(cis-2,6-Diethylmorpholin-4-yl)-5-nitrobenzaldehyde (1.58 g, 5.39 mmol) is combined with barbituric acid (767 mg, 5.39 mmol, Aldrich) in a flask with MeOH (17 mL). The sealed reaction is stirred with heating at 80° C. overnight. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 40M+ using a 10% MTBE in CH2Cl2 as eluent. The product is dried under vacuum and re-crystallized from CH3OH/heptane. The large crystals are crushed and dried under vacuum @100° C. yielding 1.04 g (48%) of bright yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.86, 0.97, 1.08, 1.24, 1.45, 1.58, 2.84, 3.03, 3.34, 3.60, 3.97, 4.26, 7.01, 7.84, 7.98, 11.56, 11.87.
Reaction SMILES: N1CCC(C2C3C(=CC=CC=3)NC=2)CC1.C(OC(C1OC(C[Br:27])=CC=1)=O)C.[F:28][C:29]1[CH:59]=[CH:58][C:32]([CH2:33]N2C3C(=CC=CC=3)C(C3CCN(CC4OC(C(O)=O)=CC=4)CC3)=C2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:59]=[CH:58][C:32]([CH2:33][Br:27])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: O=C(O)c1ccc(CN2CCC(c3cn(Cc4ccc(F)cc4)c4ccccc34)CC2)o1
Agent: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: Fc1ccc(CBr)cc1
Yield: 32 %

Procedure:
The procedure described in Example 1 was performed using 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.19 g (1.1 mmol) of 5-bromomethyl-furan-2-carboxylic acid ethyl ester. 0.08 g (0.22 mmol) of the crude, obtained as in step D, were then alkylated with 0.04 mL (0.33 mmol) of 4-fluorobenzyl bromide affording 0.031 g (32% yield) of 5-{4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-furan-2-carboxylic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[C:15]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[N:14][CH:13]=[N:12]1.[NH2:25][C@@H:26]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([F:49])([F:48])[F:47])[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:37]=[C:36]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:38])[N:28]1[CH2:27][C@@H:26]([NH:25][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:15]2[N:11]([CH3:10])[N:12]=[CH:13][N:14]=2)=[CH:24][CH:23]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([F:48])([F:47])[F:49]
Reactant: Cn1ncnc1-c1ccc(C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncnc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Hunig's base (0.084 ml, 0.48 mmol) was added to a suspension of 4-(1-methyl-1H-1,2,4-triazol-5-yl)benzoic acid (39.3 mg, 0.19 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (62 mg, 0.16 mmol), and PyBroP (75 mg, 0.16 mmol) in DCM (1 ml). The reaction mixture became clear and was stirred at RT overnight. The reaction mixture was loaded directly on a 25S Biotage column, which was eluted with 50-100% EA/DCM to give 67.3 mg of product. LC-MS (ES) m/z=534 (M+H)+.