Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20](S(N)(=O)=O)=[CH:19][C:18]=1[N+]([O-])=O>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:11](=[O:12])[CH2:10][C:22]12[CH2:21][CH:20]3[CH2:1][CH:2]([CH2:7][CH:18]([CH2:19]3)[CH2:17]1)[CH2:3]2)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCNCc1ccccc1
Product: CCOC(=O)CCN(Cc1ccccc1)C(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared by substituting 1-adamantaneacetic acid for EXAMPLE 1A and ethyl 3-(benzylamino)propanoate for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:22]([C:25]1[S:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[CH3:23].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:22]([C:25]1[S:29][C:28]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CC(=O)N(CCCNc1ccc2ncc(Br)n2n1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCCN(C(C)=O)C(C)C)nn23)s1
Temperature: 85 °C

Procedure:
To a mixture of N-(3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propyl)-N-isopropylacetamide (219.2 mg, 0.6 mmol), (5-acetylthiophen-2-yl)boronic acid [206551-43-1] (128.4 mg, 0.8 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (266.5 mg, 1.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane [95464-05-4] (53.6 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (13 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to yield a dark brown solid. Product was purified by preparative RP-HPLC. Purified chromatography fractions were combined and partitioned between aqueous saturated sodium bicarbonate and ethyl acetate. The organic extract dried (CaSO4) and evaporated to provide N-(3-((3-(5-acetylthiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)propyl)-N-isopropylacetamide as 45.7 mg of yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.20 (m, 4H) 1.24 (br. s., 1H) 1.86-2.03 (m, 4H) 2.49-2.56 (m, 6H) 3.24-3.48 (m, 5H) 6.76 (dd, J=9.73, 1.14 Hz, 1H) 7.33-7.43 (m, 1H) 7.79-7.84 (m, 1H) 7.97 (d, J=4.04 Hz, 1H) 8.14 (d, J=5.05 Hz, 1H). LRMS (ESI) m/z 400.2 [(M+H)]+, calc'd for C20H25N5O2S: 399.52.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:30]1([CH2:36][C:37]([OH:39])=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:15])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH:25]([N:28]([CH3:29])[C:37](=[O:39])[CH2:36][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)[CH2:24]4)=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CN1CCCCC1
Reactant: CNC1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1
Product: CN(C(=O)CN1CCCCC1)C1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1

Procedure:
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with piperidin-1-ylacetic acid by method E. This resulted in the product with the molecular weight of 519.69 (C30H41N5O3); MS (ESI): 520 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1ccccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccccc1Cl)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(2-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 105.2) in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(2-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=388.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>CN(C)C=O.CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c2nc(Cl)ccc21
Reactant: Brc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cn1c(=O)n(-c2cccnc2)c2nc(Cl)ccc21
Temperature: 30 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
7.36 g of 1-methyl-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one were dissolved in 160 ml of hot dimethylformamide and after cooling the solution to 30° C., 4.64 g of a 50% sodium hydride-oil suspension were slowly added thereto. The mixture was stirred at 40°-50° C. for 2 hours and then 80 ml or 128.8 g of 3-bromo-pyridine and 1.5 g of cuprous chloride were added thereto. The mixture was refluxed for 9 hours and was then cooled and evaporated to dryness. The residue was taken up in ammonium hydroxide solution and was filtered. The product was washed with water to obtain 8 g of raw product which was dissolved in acetone. The solution was chromatographed over silica gel and was eluted with acetone. The product was crystallized from 95% ethanol to obtain 5 g of 1-methyl-3-(3-pyridyl)-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of white needles melting at 206°-208° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[C:21]([O:26][CH3:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:9]1([CH:15]([Br:1])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[C:21]([O:26][CH3:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1COCCCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccccc1COCCC(Br)c1ccccc1

Procedure:
Using a similar procedure to that above, a reaction mixture was prepared containing 48 g. of N-bromosuccinimide, 65 g. of 1-phenyl-3-(o-anisyloxy)propane and 300 ml. of carbon tetrachloride. 500 mg. of benzoyl peroxide were added and the resulting mixture heated at reflux for about 2 hours at which point thin-layer chromatography indicated that no starting material remained in the reaction mixture. The reaction mixture was cooled, the succinimide separated by filtration and the solvent removed from the filtrate by evaporation in vacuo. A residual oil weighing about 88 g. comprising 1-phenyl-3-(o-anisyloxy)propylbromide formed in the above reaction was obtained.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1O)(=[O:3])[CH3:2].[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH2:28])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCN
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: CC(=O)N[C@H]1C(CCCCCCCCCCCCN)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
15 g of N-acetylglucosamine and 19 g of dodecylamine are heated at 80° C. for 3 hours in 50 ml of ethanol, with stirring. The undissolved material is then filtered off hot, the filtrate is cooled and the precipitated product is filtered off with suction and rinsed with ethanol and ether. The residue on the filter is dried in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:18]1[CH:17]=[N:16][C:15]([CH3:14])=[CH:20][CH:19]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cn1

Procedure:
A 3.74 g (20 mmol) sample of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 3.27 g (30 mmol) of 2-methyl-5hydroxypyridine were reacted with triphenylphosphine and DEAD (30 mmol each) in 100 mL of THF according to the procedure of Example 14a, to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Reactant: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C(=O)CCC2CCC(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 55 °C

Procedure:
A solution of 13 g of 5-oxo-2-pyrrolidinepropanoic acid benzyl ester in 250 ml of tetrahydrofuran is treated with 14.0 g of 3-benzyloxy-4-methoxybenzoyl chloride. The mixture is heated to 55° C. and a solution of 5.5 g of triethylamine in 400 ml of tetrahydrofuran is added dropwise over a two hour period. The mixture is stirred and heated at 55° C. for 16 hours. The warm mixture is filtered through filter aid to remove triethylamine hydrochloride and concentrated at reduced pressure. Chromatography over silica using a Waters Prep 500 HPLC apparatus yields 1-(3-benzyloxy-4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid benzyl ester with mp 92°-95° C. after concentration and crystallization.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCc1cccc(O)c1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCC(=O)c2ccccc2)c1

Procedure:
The title compound was prepared as described in General Method 5 using 4.11 g (18.2 mmol) of 3-(3-hydroxy-phenyl)-1-phenyl-propan-1-one from Example M, 1.5 g (22 mmol) of imidazole, 3.0 g (20 mmol) of t-butyldimethylsilyl chloride and 75 mL of CH2Cl2. The product was carried on crude to the next step (see Example UU).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][F:22])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(C(C)C)CC)(C)C.[F:32][CH:33]([F:37])[C:34](Cl)=[O:35].O>CN(C)C=O>[F:32][CH:33]([F:37])[C:34]([NH:1][C@H:2]([CH2:21][F:22])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:12]=2)=[CH:7][CH:6]=1)=[O:35]
Reactant: CS(=O)(=O)Cc1cc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)on1
Reactant: O=C(Cl)C(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)Cc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
(1R,2S)-2-amino-3-fluoro-1-(4-(3-(methylsulfonylmethyl)isoxazol-5-yl)phenyl)propan-1-ol (75 mg, 0.21 mmol) in dimethylformamide (2 mL) at 5° C. is treated with diisopropylethylamine (0.055 mL, 0.62 mmol) and then difluoroacetylchloride (0.026 mL, 0.25 mmol) is added and the mixture stirred at room temperature for 1 hour. Water is added (10 mL) and extracted with ethyl acetate (10 mL) and the organics washed with brine (10 mL), dried over MgSO4, filtered, concentrated and purified by reverse phase preparative HPLC to give the title compound (35 mg). 1H NMR (400 MHz, DMSO-d6) δ: 3.10 (s, 3H), 4.33 (m, 1H), 4.40-4.60 (m, 1H), 4.65-4.80 (m, 3H including 2H singlet at 4.75), 4.92 (bs, 1H), 6.17 (t, 1H), 7.08 (s, 1H), 7.51 (d, 2H), 7.86 (d, 2H), 8.80 (d, 1H); m/z (Cl) 407 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:14]([SnH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[C:10](=[CH:9]/[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)/[C:11]([NH2:13])=[O:12])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: NC(=O)CCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(Cl)c(Cl)c1)C(N)=O
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
3-(3,4-dichlorophenyl)propionic acid amide (21 mg, 0.1 mmol) prepared in the same manner as in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, and under cooling with ice, tetrakistriphenylphosphine palladium(0) (5 mg, 0.004 mmol) was added, and then a tetrahydrofuran solution (0.5 ml) of tri-n-butyltin hydride (35 μl, 0.13 mmol) was dropwise added. After stirring for 30 minutes, the solution was concentrated under reduced pressure, and the residue was purified by tin-layer silica gel column chromatography (hexane:ethyl acetate=3:1) to give (E)-2-(tributylstannyl)-3-(3,4-dichlorophenyl)acrylamide (12.3 mg, 24%) as a pale yellow oily substance.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1COCC1.BrC(Br)C>[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)=[O:13]
Reactant: CN1CCC(Cl)CC1
Reactant: O=C(Cl)c1cc(I)ccc1F
Agent: CC(Br)Br
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cc(I)ccc2F)CC1
Temperature: 70 °C
Yield: 52.6 %

Procedure:
A stirred suspension of Mg turnings (3.82 g, 157 mmol) in dry THF, under N2, was treated with 2-3 drops of dibromoethane, followed by slow addition of freshly-distilled 4-chloro-N-methylpiperidine (7.00 g, 52.4 mmol) in THF. The reaction mixture was heated at 70° C. for 3 h, cooled to room temperature, added to 2-fluoro-5-iodobenzoyl chloride (10.1 g, 35.6 mmol) in THF at −78° C., warmed to room temperature over 1 h and concentrated in vacuo. The resultant residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 concentrated in vacuo. This residue was purified by chromatography (0-10% CH2Cl2 in CH3OH as eluent) to provide the title compound (6.50 g, 53%), characterized by HNMR and mass spectral analyses.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 405.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([O:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccc(Cl)cc1
Solvent: CO
Product: CN(CCOc1ccc(CC(Oc2ccc(Cl)cc2)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
The title compound, mp 164-5° C. (methanol), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(4-chlorophenoxy)propanoate by a procedure analogous to that described for Example 2.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[C:7]([F:19])[CH:6]=1)([CH3:3])[CH3:2].[H-].[Na+].I[CH3:23].Cl>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[N:15]([CH3:23])[C:14](=[O:18])[CH:13]=[N:12]2)=[C:7]([F:19])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)Oc1ccc(-n2ncc(=O)[nH]c2=O)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-n2ncc(=O)n(C)c2=O)c(F)c1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of 3.25 g (0.0123 mole) of 2-(4-isopropoxy-2-fluorophenyl)-1,2,4-triazine-3,5-dione in 30 mL of N,N-dimethylformamide was added to a suspension of 0.50 g (0.0125 mole) of sodium hydride in 30 mL of N,N-dimethylformamide at ambient temperature. When gas evolution had ceased, 3.55 g (0.025 mole) of iodomethane was added in one portion. This mixture was stirred for one hour without heating and was then poured into 300 mL of dilute hydrochloric acid. The resulting mixture was extracted several times with diethyl ether, and the extracts were combined. The ether extract was washed in succession with water and a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate and filtered through a short column of silica gel. The solvent was evaporated under reduced pressure, leaving 2.80 g of 2-(4-isopropoxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione as a syrup. The NMR was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[O:10][CH3:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:11][O:10][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cccnc1OC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ncccc1CO
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 80.5 %

Procedure:
A solution of 2-methoxy-nicotinic acid methyl ester (4.42 g, 26.5 mmol) in tetrahydrofuran (7 mL) was added via an addition funnel over a period of 15-20 min to a cooled (0° C.) mixture of lithium aluminum hydride (1.22 g, 32.1 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0° C. for 40 min and then at room temperature for 3 h. The reaction mixture was poured into a solution of potassium sodium tartrate (10% w/v) and the resulting mixture was stirred at room temperature for 25 min. The mixture was filtered through a pad of Celite, washing with ethyl acetate (400 mL). The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (magnesium sulfate), filtered and purified using a Biotage 40M system, eluting with 30% ethyl acetate/hexanes, to give (2-methoxy-pyridin-3-yl)-methanol (2.97 g, 81%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[OH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2[C:31]2[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(O)cc2)c1OCC1CC1
Yield: 58.4 %

Procedure:
A solution of Intermediate 2 (500 mg, 1.040 mmol), 4-hydroxyphenylboronic acid (172 mg, 1.249 mmol), Pd[(C6H5)3P]4 (120 mg, 0.104 mmol) and cesium fluoride (506 mg, 3.331 mmol) in dry THF was heated to reflux for 4.0 h. After completion of reaction, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4 to afford a crude residue which was purified using 1% CH3OH in CHCl3 to afford 271 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.48-0.54 (m, 2H), 1.03-1.07 (m, 1H), 3.67-3.70 (m, 2H), 3.76 (s, 3H), 6.81-6.92 (m, 3H), 6.97-7.03 (m, 3H), 7.10-7.13 (m, 2H), 7.47 (d, J=4.5 Hz, 1H), 7.95 (d, J=5.1 Hz, 1H), 8.10 (d, J=15.6 Hz, 1H), 9.57 (s, 1H); ESI-MS (m/z) 447.20 (M+H)+.
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.Cl.OC([C@@H]1CCCN1C(=O)[C@@H]1CCCN1)COC1C=CC(OC)=CC=1.C([O:48][C:49]([N:51]1[CH2:74][CH2:73][CH2:72][C@H:52]1[C:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[CH:60]([OH:71])[CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1)=[O:54])=O)(C)(C)C.Cl.O1CCOCC1>C(N(CC)CC)C>[OH:71][CH:60]([C@@H:56]1[CH2:57][CH2:58][CH2:59][N:55]1[C:53](=[O:54])[C@@H:52]1[CH2:72][CH2:73][CH2:74][N:51]1[C:49]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:48])[CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: COc1ccc(CN)cc1
Agent: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2)cc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(O)COc2ccc(OC)cc2)cc1

Procedure:
By the same procedure as in Example 24-A) using trichloromethyl chloroformate (0.20 ml), 4-methoxybenzylamine (449 mg), triethylamine (0.45 ml+0.89 ml) and (2S)-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]-l-(L-prolyl)pyrrolidine hydrochloride (1.18 g) as obtained by treating (2S)-1-[N-(t-butoxycarbonyl)-L-prolyl]-2-[1-hydroxy-2-(4-methoxyphenoxy) ethyl]pyrrolidine obtained in Example 22-A) with 4N hydrochloric acid/1,4-dioxane, there was obtained 661 mg of the title compound.