Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCCO
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: OCCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 4-aminobutan-1-ol according to general procedure 1 providing the intermediate (150 mg, 82%) as a yellow solid: Rf=0.45 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.7 Hz, 1H), 7.38 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.77-1.72 (m, 2H), 1.69-1.64 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C[Si](C)(C)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].[F-].[K+]>CN(C)C=O.[Cu](I)I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: Brc1ccc(I)cc1
Agent: I[Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Under argon in a microwave vial 2 g 1-bromo-4-iodobenzene, 3.3 g trimethyl(perfluoroethyl)silane, 493 mg potassium fluoride and 2 g copper iodide are suspended in 10 ml N,N-dimethylformamide. The mixture is heated for 12 hours at 80° C. Further 3.3 g trimethyl(perfluoroethyl)silane are added and heating is continued for 48 hours. Then the mixture is partitioned between 2 M ammonia and diethylether. The aqueous phase is twice extracted with diethylether. The combined organic phases are washed three times with water and dried with magnesium sulphate. The solvent is evaporated in vacuo (300 mbar, temperature of water bath 50° C.). The residue is chromatographed on silica gel (dichloromethane).
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1.IC.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:1])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Procedure R′: A 15 m-1L DMF mixture of 4-bromo-N-tert-butyl-benzenesulfonamide (1022 mg, 3.5 mmol), iodomethane (0.44 mL, 7 mmol), and K2CO3 (987 mg, 7 mmol) is stirred at room temperature overnight. Water and ethyl acetate are added to the mixture. The aqueous layer is extracted several times with ethyl acetate. The combined organic layers are washed with H2O and brine, then dried over Na2SO4 and evaporated. The crude product is purified by silica-gel column chromatography (gradient: 100% CH2Cl2 to 20% EtOAc/CH2Cl2) give the intermediate 4-bromo-N-tert-butyl-N-methyl-benzenesulfonamide (1040 mg, 97% yield). MS (ES+) 251.9 (M-tBu)+, NMR (CDCl3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14](Br)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>C(O)C.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14]([C:7]4[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-n2c(-c3cccnc3N)nc3cc(Br)cnc32)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-n2c(-c3cccnc3N)nc3cc(-c4cccnc4)cnc32)cc1
Temperature: 100 °C
Yield: 197.5 %

Procedure:
tert-butyl 4-(2-(2-aminopyridin-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)benzylcarbamate (4 g, 8 mmol) was suspended in a mixture of ethanol and toluene, 160 ml respectively and a solution of NaHCO3sat. was added (27 ml). The reaction mixture was degassed with nitrogen for 30 min. Subsequently it was heated to 100° C. overnight under nitrogen. After cooling down to room temperature it was diluted with 300 ml dichloromethane and 200 ml of water were added. The organic phase was separated and washed with brine (200 ml) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (2-20% methanol in ethyl acetate). The solvent was removed under reduced pressure, yielding 3.9 g tert-butyl 4-(2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzylcarbamate (7.9 mmol, 99% yield). 400 M Hz 1H NMR (DMSO-d6) δ: 8.98 (d, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.59 (dd, J=1.6 Hz and 4.7 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.20 (m, 1H), 7.98 (m, 1H), 7.52 (m, 2H), 7.48-7.34 (m, 4H), 7.23 (m, 1H), 7.01 (s, br, 2H), 6.38 (m, 1H), 4.19 (m, 2H), 1.38 (s, 9H), MS 438.22, 494.00, [M-(t-Bu)+H, M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:44])[C:34]3[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][CH:35]=3)[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[SiH3]CC(N)=O.CN1CCOCC1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>O>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:44])[C:34]3[CH:35]=[CH:36][C:37]([C:40]([OH:42])=[O:41])=[CH:38][CH:39]=3)[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](CNC(=O)[C@@H]2CCCN(C(=O)CCC3CCN(C(=O)OC(C)(C)C)CC3)C2)C(=O)O)cc1
Agent: NC(=O)C[SiH3]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(C(=O)N[C@@H](CNC(=O)[C@@H]2CCCN(C(=O)CCC3CCNCC3)C2)C(=O)O)cc1
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
The mixture of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-methoxycarbonylbenzoyl)amino-β-alanine (55 mg, 0.106 mmol) in water (0.5 mL), monosilylacetamide (1.0 g) and N-methylmorpholine (61 mL, 0.55 mmol) was added 1N LiOH solution (0.37 mL) at 5° C. After stirring for 40 minutes, the mixture was neutralized with 20% aqueous KHSO4 solution, then purified by an ODS column chromatography using Daisogel-120sp (10% CH3CN/water) and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-carboxybenzoyl)amino-β-alanine (40 mg, 75.1%) as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][C@@H:23]([NH2:32])[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][C@@H:23]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:24][S:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (685 mg, 2.3 mmol), (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine (500 mg, 2.3 mmol), and DIPEA (0.78 mL, 4.5 mmol) in DMA (18.8 mL) was heated to 100° C. for 6 hours. The reaction was cooled to room temperature and diluted with EtOAc/heptanes (1:1, 50 mL). This solution was washed with water, the layers were separated, and the aqueous layer was extracted with EtOAc/heptanes (1:1) (50 mL×3). The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to afford the title compound as a yellow solid (965 mg, 82% yield). MS (ESI) m/e (M+H+): 512.2
Reaction SMILES: [OH:1][C:2]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[K+]>[CH3:22][O:1][C:2]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1cccc(Sc2ccccc2Cl)c1O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C=O)cccc1Sc1ccccc1Cl
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A mixture of 2-hydroxy-3-(2-chlorophenylthio)benzaldehyde (19.3 g) and dimethyl sulfate (18.4 g) was stirred at room temperature. To the mixture was added dropwise an aqueous solution (50 ml) of potassium hydroxide (12.5 g) at temperature below 60° C., and then the mixture was stirred for an hour. The reaction mixture was cooled to the ambient temperature and insoluble substance was filtered off. The filtrate was extracted with diethyl ether, and the extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-methoxy-3-(2-chlorophenylthio)benzaldehyde (9.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>>[C:2]1([NH:1][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)c1ccccc1Nc1ccccc1
Reaction time: 0.25 h

Procedure:
Redistilled aniline (310 g, 3.32 mol), pure 2-chlorobenzoic acid (82 g, 0.52 mol), fresh dried potassium carbonate (82 g, 0.6 mol) and cupric oxide (2.0 g) are refluxed for two hours in an oil bath (air cooler). Excess aniline is initially removed by distillation in vacuum and later by water vapor. The remaining solution (500 ml) is boiled for 15 min. with 40 g of activated carbon and filtrated. The filtrate is poured into a mixture of concentrated hydrochloric acid (60 ml) and water (120 ml) during agitation. After cooling the deposit is separated by filtration, washed in water and dried at 120° C. This blue-grey product is cleaned out by dissolving 50 g in 1000 ml of water containing 25 g of sodium carbonate and boiling for 5 minutes with 25 g activated carbon. This is followed by filtration and precipitation with concentrated hydrochloric acid (vigorous foaming). The deposit is separated by filtration, washed in water and dried at 120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH2:11])[C@@H:4]2[O:3]1.[CH3:13][C:14]1([CH3:39])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]4)[CH:29]=[CH:28][CH:27]=3)[CH:17]=[CH:16][C:15]1=2>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][CH:35]3[CH2:34][CH2:33][N:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:18]5[CH:17]=[CH:16][C:15]6[C:14]([CH3:39])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=6[CH:19]=5)[N:31]=4)[CH2:37][CH2:36]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Reactant: CC1(C)O[C@H]2[C@H](N)CCC[C@H]2O1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](NC3CCN(c4cccc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)n4)CC3)CCC[C@H]2O1

Procedure:
The preparation is carried out analogously to FS1008 in THF starting from 34 mg (0.199 mmol) of (3aS,4R,7aR)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-yl-amine and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The purification is carried out by means of flash chromatography on silica gel.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[CH:3][N:4]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1nccc2c1c(I)cn2C1CCOCC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2C1CCOCC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridine (50.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (59.0 mg), tetrakis(triphenylphosphine)palladium(0) (16.0 mg) and potassium carbonate (39.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica, gel column chromatography (hexane/ethyl acetate) to give the title compound (22.9 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N[OH:45]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH:43][OH:45])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Reactant: NO
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)NO)cc1
Reaction time: 3 h
Yield: 18 %

Procedure:
A portion of the crude intermediate of example 58 above, (25 mg, 0.03 mmol) was added to a solution of hydroxylamine in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 4.0 mg, 18% of the desired material.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:21])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2CCCCC
Reaction time: 18 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.9 g, 13.3 mmol) in DMF (35 ml) was added cesium carbonate and the mixture stirred for 10 min whereupon iodomethane (0.91 ml, 14.6 mmol) was added and the mixture stirred for 18 h. The reaction was partitioned between ethyl acetate and 2N HCl solution and the organics isolated, dried (MgSO4) and concentrated. Chromatography on silica SPE eluting with cyclohexane/ethyl acetate (5%-20%) provided the product as an oil, 2.78 g, 68%. m/z 311[MH+].
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N([CH2:20][CH3:21])CC)C>CCC(O)CC>[CH2:11]([CH:12]([O:13][CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14])[CH2:20][CH3:21])[CH3:10]
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: CCN(CC)CC
Solvent: CCC(O)CC
Product: CCC(CC)OCc1c(O)ccc2c1CCCC2=O
Yield: 189.1 %

Procedure:
According to step (a) in the method of example 19a, 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0 mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in pentan-3-ol (3 ml, Aldrich Chemical) to produce 248 mg of desired product as an orange-red oil. Low resolution mass spectrum (APCI) m/z 263 [M+H]+.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:40]=[O:41])C.[NH4+].[Cl-]>C(OCC)C.[Li]CCCC.O>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:40]=[O:41])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1OCc1ccccc1)C(C)C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
n-BuLi (2.5 M in hexane, 19 mL, 47.5 nmol) was added to a solution of to (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (prepared as described in WO 94/11337, Example 1) (8.9 g, 18.52 mmol) in dry diethyl ether (100 mL) kept at −40° C. under nitrogen atmosphere. After 1.5 hour of stirring, additional n-BuLi (10 mL, 25 mmol) was added and after 2 hours another n-BuLi (5 mL, 12.5 mmol) was added. The reaction was then stirred for 15 minutes and DMF (6 mL, 77.8 mmol) was added followed by additional DMF (5 mL, 64.8 mmol) after 20 minutes of stirring. The temperature was allowed to rise to room temperature and after 35 minutes of stirring, NH4Cl (sat.) was added followed by water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica (toluene-triethylamine 90:10) to afford 8 g (100%) of a yellowish oil; 1H NMR (CDCl3) δ0.90 (m, 12H), 2.12-2.40 (m, 4H), 2.95 (m, 2H), 4.44 (t, 1H), 5.10 (s, 2H), 6.95 (d, 1H), 7.15-7.36 (m, 10H), 7.70 (dd, 1H), 7.91 (s, 1H), 9.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5].[O-]S(C(F)(F)[F:41])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([C:31]=1[F:41])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2[nH]c3ccccc3c2F)s1

Procedure:
N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-indole-2-carboxamide is dissolved in dichloroethane, and reacted with 1-fluoro-2,6-dichloropyridinium triflate to give N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-fluoroindole-2-carboxamide.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:29]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967)(1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester in THF (5 mL) is added 4M HCl in dioxane (3 mL) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8](C=O)[CH:9]=[CH:10][C:2]1=2.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:21])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Solvent: ClCCl
Product: Oc1ccc2c(c1)OCCO2
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a stirred solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (1 g, 6.09 mmol) in CH2Cl2 (16 mL) was added m-CPBA (4.204 g, 24.36 mmol). The suspension was heated at 50° C. for 2 days, was cooled to rt, was quenched with saturated NaHCO3 soln. and was extracted with CH2Cl2 (3×10 mL). The combined extract was concentrated under reduced pressure, and then was dissolved in MeOH containing NaOH. The solution was stirred at rt for 2 h, was acidified with HCl and was extracted with ethyl acetate (3×10 mL). The combined extract was washed with saturated NaHCO3 solution and brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and was filtered. The DCM solution was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (0.591 g, 63%) as a reddish brown oily liquid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC#N>[CH2:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:17])=[CH:11][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 70 °C

Procedure:
Anhydrous K2CO3 (18.43 g, 0.13 mol) was added to 300 mL of CH3CN, and the solution was degassed with N2 for 20 minutes. Methyl-4-hydroxybenzoate (6.27 g, 41.2 mmol) was added to the reaction flask, which was heated to 70° C., following which 1-bromodecane (8.8 mL, 42.5 mmol) was added. The above solution was refluxed for 12 hours, and upon cooling the solvent was removed under reduced pressure. The residue was taken in CH2Cl2 (200 mL) and washed with 1 M HCl (100 mL). The organic layer was washed with distilled H2O (100 mL), and the solvent was removed under reduced pressure. Yield 12.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 0.90 (3