Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14]([O:16]CCCC)=[CH2:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CC#N.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:16])[CH3:15]
Reactant: C=COCCCC
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(OC)ccc1C(C)=O
Temperature: 99 °C
Reaction time: 16.5 h
Yield: 99.6 %

Procedure:
A mixture of methyl 2-bromo-5-methoxybenzoate (1) (5.0 g, 20.4 mmol), butyl vinyl ether (13.1 mL, 102.0 mmol), Ph3P (802.3 mg, 3.1 mmol), Et3N (3.7 mL, 26.5 mmol), and Pd(OAc)2 (343.0 mg, 1.5 mmol) in MeCN (40 mL) is stirred under argon at 99° C. for 16.5 h and then cooled to room temperature. The residue is diluted with H2O (50 mL), and the resultant suspension is filtered through Celite® (H2O rinse). The filtrate is concentrated to dryness at reduced pressure. To the residue is added tetrahydrofuran (125 mL) and 10% HCl (125 mL). The mixture is stirred for 2 h before the tetrahydrofuran is removed at reduced pressure. This residue is extracted with ethyl acetate (100 mL, 70 mL, and 60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (16.7% to 33.3% ethyl acetate/hexane) to give 4.23 g (99%) of 2 as a yellow liquid. IR 2958, 1730, 1683, 1270 cm−1; 1H NMR (CDCl3) δ 2.55 (s, 3H, CH3CO), 3.90 (s, 3H, CH3O), 3.94 (s, 3H, CO2CH3), 7.04 (dd, J=8.7, 2.7 Hz, 1H, 4-PhH), 7.17 (d, J=2.7 Hz, 1H, 6-PhH), 7.61 ppm (d, J=8.7 Hz, 1H, 3-PhH).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1N
Reactant: Brc1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1nccnc1Nc1cccnc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Aminopyrazine-2-carboxylic acid methyl ester (0.8 g, 5.2 mmol) and 3-bromopyridine (1.2 g, 7.8 mmol) were dissolved in 20 mL dry toluene. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.6 g, 1.04 mmol), sodium tert.-butylate (0.75 g, 7.8 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (0.54 g, 0.52 mmol) were added and the reaction mixture was stirred under microwave irradiation for 60 minutes at 150° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 1:2->0:100 gradient). The desired product was obtained as a brown solid (260 mg, 22%), MS: m/e=231.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]N1C(=O)C2=CC=CC=C2C1=O.ClNC1C=CC(C(F)(F)F)=CN=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: FC(F)(F)c1ccc(NCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5-trifluoromethylpyridine, 20.9 g (0.115 mol) of N-chlorophthalimide and 150 g of toluene were added, and the reaction was carried out at 80° C. for one hour under heating with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 g of a 25% sodium hydroxide aqueous solution was added thereto and stirred. An aqueous layer and an oil layer were separated. A 20% hydrochloric acid aqueous solution was added to the oil layer, and the mixture was stirred. An aqueous layer and an oil layer were separated again. The aqueous layer was neutralized with a 25% sodium hydroxide aqueous solution. Precipitated slightly yellow crystals were collected by filtration and dried to obtain 17.5 g 2-amino-3-chloro-5-trifluoromethylpyridine (purity as measured by liquid chromatography: 97%, yield: 86%).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([OH:20])=O)[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl.O.CN1C(=O)CCC1.CN(C=O)C>[CH2:40]([NH:47][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:23]([Br:24])=[C:15]([CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([CH:11]2[CH2:12][CH2:13]2)=[O:10])[CH:16]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccccc1)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Reaction time: 0.5 h

Procedure:
3-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid (0.1 g, 0.26 mmol) and catalytic DMF (0.01 mL) were combined in CH2Cl2 (4 mL) at room temperature. Oxalyl chloride (0.03 mL, 0.33 mmol) was added, and the reaction was stirred for 30 minutes. The solution was concentrated and dried under vacuum, and then NMP (3 mL) and diisopropylethylamine (0.14 mL, 0.78 mmol) were added. Benzylamine (0.04 mL, 0.39 mmol) was then added, and the reaction was stirred for 5 minutes. The mixture was poured into H2O and partitioned with 1:1 EtOAc:hexanes. The organic layer was washed with saturated aqueous NaHCO3, H2O, and dilute brine, and then dried, filtered, and concentrated to give N-benzyl-3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzamide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[CH:27]/[C:25]#[N:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1sc(COc2ccc(/C=C/C=O)cc2)nc1-c1ccccc1
Product: Cc1sc(COc2ccc(/C=C/C=C/C#N)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2,4-pentadienenitrile. Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.108°-109° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:21])=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:15](=[C:14]([F:20])[C:13]([O:21][CH2:23][CH2:24][CH3:25])=[CH:12][CH:11]=3)[CH2:16][C:17]=2[C:18]=1[F:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCBr
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(OCCC)c1F

Procedure:
The etherification of 9 mmol of 7-butoxy-1,8-difluorofluoren-2-ol with 12 mmol of 1-bromopropane and 27 mmol of potassium carbonate in 50 ml of acetone is effected in a similar manner to the procedure described in Example 1. Purification of the crude product by chromatography on silica gel (dichloromethane/heptane) and recrystallization from heptane provides 2-butoxy-1,8-difluoro-7-propyloxyfluorene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])[CH:2]=1.C(=O)(O)[O-].[Na+].C1COCC1.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:34]([NH:11][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([F:14])[CH:12]=1)([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35]
Reactant: Nc1cc(F)c(-c2cccnc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1

Procedure:
4-(3-Pyridyl)-3,5-difluoroaniline (PREPARATION 2, 625 mg, 3.03 mmol), sodium bicarbonate (382 mg, 4.55 mmol, 1.5 eq) and dry THF (60 ml) are combined. The resulting mixture is placed under an atmosphere of nitrogen and benzylchloroformate (394 μl, 4.55 mmol, 1.5 eq) is added. The reaction is allowed to stir at 20°-25°. After this time, the reaction is added to methylene chloride (150 ml) and washed with saturated sodium bicarbonate then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to a solid which is puffed by silica gel chromatography (200 g of silica gel, eluted with acetonitrile/chloroform (3/97-1 l, 5/95-2 l), the title compound is recovered as a solid, mp 188°-190°; FTIR (neat) cm-1 3030, 1737, 1642, 1478, 1408, 1231, 1029, 723; MS (EI, m/z) 340, 296, 232, 205, 91, 79; NMR (CD3CL3) δ 8.59, 8.53-8.51, 7.95-7.92, 7.56-7.51, 7.44-7.31, 7.28 and 5.21.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: SC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(SC2CCCCC2)nc1-c1ccc(Cl)cc1
Yield: 52 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), cyclohexylmercaptan (0.6 g) and N,N-dimethylformamide (20 mL) was stirred at 100° C. for 1.5 hrs. The reaction mixture was diluted with water, and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-(4-chlorophenyl)-2-(cyclohexylsulfanyl)-5-oxazolyl]propionic acid (0.95 g, yield 52%) as crystals. Recrystallization from ethanol gave colorless prism crystals. melting point: 136–137° C.
Reaction SMILES: Cl.C([O:6][C:7](=[O:34])[CH2:8][N:9]([S:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:33])=[CH:24][N:25]=[C:26]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C>O1CCOCC1>[ClH:33].[Cl:33][C:23]1[C:22]2[C:27](=[CH:28][C:19]([S:16]([N:9]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:8][C:7]([OH:34])=[O:6])(=[O:17])=[O:18])=[CH:20][CH:21]=2)[C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)CN(CC1CCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)CC3CCCC3)cc12
Temperature: 60 °C
Yield: 160 %

Procedure:
A solution of HCl (2 mL, 2 M, 4 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(cyclopentylmethyl)glycine t-butyl ester (50 mg, 0.10 mmol) in dioxane (4.0 mL) and the mixture was heated at 60° C. for 24 h. The solvents were evaporated in vacuo, and the residue triturated with dichloromethane to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(cyclopentylmethyl)glycine hydrochloride (40 mg, 0.080 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])=[O:5])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCCC1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (10 g, 64.0 mmol) in ethanol (106.7 mL) cooled to 0° C. was treated with 98% sodium borohydride (686 mg, 17.78 mmol). The reaction was stirred at 0° C. for 30 min. At this time, the reaction mixture was poured into water (53 mL) and was extracted into diethyl ether 3×100 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-hydroxy-cyclopentanecarboxylic acid ethyl ester (8.5 g, 83.9%) as a clear liquid.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH:17]=[O:18])=[CH:12][CH:11]=1)[CH3:9].C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCc1ccc(C(=O)C=O)cc1
Reactant: CNN=CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 7.7 %

Procedure:
2-Oxopropanal methylhydrazone (13.7 mmol, 1.37 g) and (4-ethylphenyl)(oxo)acetaldehyde (13.5 mmol, 2.19 g) synthesized in Reference Synthetic Example 11 were dissolved in acetic acid (30 mL) and stirred at 100° C. for 6 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1), then by silica gel thin layer chromatography (chloroform) and by silica gel thin layer chromatography (n-hexane/ethyl acetate=7/2) to give the desired product as a brown solid (255 mg, yield 8%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:7])[C:3]1([CH3:18])[CH3:17].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](Cl)=[C:26]([C:29]([NH2:31])=[O:30])[CH:25]=[N:24][N:23]2[CH:32]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:27]([NH:1][C@@H:2]3[CH2:6][CH2:5][C@@:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:7])[C:3]3([CH3:18])[CH3:17])=[C:26]([C:29](=[O:30])[NH2:31])[CH:25]=[N:24][N:23]2[CH:32]=1
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](N)C1(C)C
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Temperature: 90 °C
Yield: 72.1 %

Procedure:
To a solution of tert-butyl (((1S,3R)-3-amino-1,2,2-trimethylcyclopentyl)methyl)carbamate (417 mg, 1.626 mmol) and 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (446 mg, 1.626 mmol, from preparation 5) in DMF (4.07 ml) was added DIEA (625 μl, 3.58 mmol). The reaction mixture was heated at 90° C. for 2 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml). The ethyl acetate solution was washed with water (3×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a light yellow oil. The solid was dissolved in 50% EtOAc/hexanes (5 ml) and loaded directly on a pre-packed silica gel column. The crude product was purified via medium pressure chromatography (10-60% EtOAc-hexanes solvent system over 30 minutes) to afford tert-butyl (((1S,3R)-3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)methyl)carbamate (580 mg, 1.173 mmol, 72.1% yield) as a yellow solid. ESI-MS m/z 496.1 ([M+H]+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.O.CN([CH:21]=[O:22])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[O:16][CH2:15][O:14][C:11]2=[CH:12][C:13]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)OCO2
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1C=O)OCO2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of phosphorous oxychloride (3.0 ml. 0.033 mol) in DMF (10 ml) was added a solution of 1-methoxy-3,4-methylenedioxybenzene (2.0 g, 0.013 mol) in DMF (2 ml) at 0° C. After stirring at 60° C. for 18 h the mixture was cooled to 0° C. and then poured into water (500 ml). The precipitate was filtered and dried. The tide compound was collected as a yellow solid (2.20 g. 92%).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11](I)[C:10]([CH3:14])=[C:9]([F:15])[CH:8]=1)[CH3:4].C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1.O>[CH2:3]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([F:15])[C:10]([CH3:14])=[C:11]([B:26]([OH:27])[OH:25])[CH:12]=1)=[O:16])[CH3:4]
Reactant: CCNC(=O)c1cc(F)c(C)c(I)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1cc(F)c(C)c(B(O)O)c1
Temperature: -75 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% in mineral oil, 1.23 g) was added in portions to a solution of N-ethyl-3-fluoro-5-iodo-4-methylbenzamide (Intermediate 4, 4.81 g) in anhydrous THF (75 ml). The resulting mixture was cooled to −75° C. and n-butyllithium (1.6M in hexanes, 20 ml) was added dropwise over 20 min. Triisopropylborate (8 ml) was added over 5 min and the reaction mixture was stirred at −75° C. for 6 h. Water (20 ml) was added and the mixture was warmed to 15° C. overnight and the mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with aqueous ammonium chloride and brine, dried (MgSO4) and concentrated under vacuum. The residue was dissolved in dichloromethane and applied to a silica column (10 g) eluting with an ethyl acetate/dichloromethane gradient (0-100% ethyl acetate) followed by methanol. The methanol fractions were concentrated under vacuum to give the title compound as an off-white foam (550 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][NH:44][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([CH:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:31][CH:30]=1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of 4-[1-(4′-tert-butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoic acid (310 mg, 0.75 mmol) in methylene chloride (7 mL) are added triethyl amine (0.31 mL, 2.24 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (156 mg, 1.12 mmol) and EDCI (431 mg, 2.24 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, and eluted with hexanes using a gradient from 0-100% ethyl acetate to provide 230 mg of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]=O)[CH:19]=[N:20][C:21]=1[CH3:22].[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[N:20][C:21]=1[CH3:22]
Reactant: Cc1ncc(C=O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: Cc1ncc(CNC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (11.19 g, 55.9 mmol), 5-chloro-6-methyl-3-pyridinecarbaldehyde (for a synthesis see WO2006/137485 A1 Example 256) (7.82 g, 50.3 mmol) and Na2SO4 (8.73 g, 61.5 mmol) in DCE (200 ml) was stirred at 90° C. for 4.5 h and at room temperature overnight. NaBH(OAc)3 (35.5 g, 168 mmol) was added portionwise for 7 h until imine was not detected by LCMS analysis. 10% NaHCO3 was added and the organic phase was extracted twice with DCM, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 1,1-dimethylethyl 4-{[(5-chloro-6-methyl-3-pyridinyl)methyl]amino}-1-piperidinecarboxylate (18.7 g, 94%) as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)#[N:2].C[Si]([N:23]=[N+:24]=[N-:25])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>CO>[N:2]1[NH:23][N:24]=[N:25][C:1]=1[CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of trans-benzoic acid 4-cyanomethyl-cyclohexyl ester (3.42 g) obtained in Example (44a), trimethylsilyl azide (3.7 mL), di-n-butyltin oxide (348 mg), and toluene (30 mL) was heated at 110° C. for 48 hours. The progress of the reaction was stopped using methanol, and the reaction mixture was concentrated. The residue was diluted with ethyl acetate, followed by extraction with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was acidified (pH=2) by the addition of 1 N hydrochloric acid, followed by extraction with ethyl acetate (×2). The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated to obtain the title compound (2.57 g, 64%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1NCc1ccccc1)C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using benzylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 71%).