Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:19]3=[C:20]([CH:27]([CH3:29])[CH3:28])[C:21]([C:23]([NH:25][CH3:26])=[O:24])=[CH:22][N:18]3[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[N:30]1([CH2:35]CN)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][NH:3][C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:19]3=[C:20]([CH:27]([CH3:29])[CH3:28])[C:21]([C:23]([NH:25][CH2:26][CH2:35][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:24])=[CH:22][N:18]3[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: NCCN1CCCC1
Reactant: CNC(=O)c1cn2ncnc(Nc3ccc(C)c(C(=O)NOC)c3)c2c1C(C)C
Product: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)NCCN4CCCC4)c(C(C)C)c23)ccc1C

Procedure:
Example 19 was prepared from compound A of Example 18 and 2-pyrrolidin-1-yl-ethylamine by a method analogous to the preparation of Example 18 in similar yields LC/MS; (M+H)+=480.4.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22](O)=[O:23])=[C:20]([CH3:29])[CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22]([NH:1][CH:2]([C:3]2([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:23])=[C:20]([CH3:29])[CH:19]=1
Reactant: CSc1cc(Cl)cc(C)c1C(=O)O
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CSc1cc(Cl)cc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (203 mg; 0.93 mmol), 4-chloro-2-methyl-6-(methylthio)benzoic acid (obtainable as described in F. P. Doyle, J. H. C. Nayler, H. R. J. Waddington, J. C. Hanson and G. R. Thomas. J. Chem. Soc. 1963, 497) (202 mg; 0.93 mmol), EDC (178 mg; 0.93 mmol) and HOBt (143 mg; 0.93 mmol) in DCM (20 ml) was stirred at room temperature for 4 h and then stood at room temperature for 90 h. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate (50 ml) and the organic layer separated by passage through a phase separation cartridge. The organic layer was evaporated, the residue dissolved in a minimum of DCM and chromatographed on silica gel, eluting with 0-100% ethyl acetate-pentane. The fractions were combined and evaporated under reduced pressure to afford the title compound (200 mg; 52%). 1H NMR (CDCl3) δ: 0.90-1.10 (1H, m), 1.38-1.55 (3H, m), 1.60-1.76 (2H, m), 1.80-1.90 (2H, m), 2.21 (6H, s), 2.26 (3H, s), 2.47 (3H, s), 5.11 (1H, d, J=6 Hz), 6.94 (1H, d, J=5.2 Hz), 7.00 (1H, m), 7.09 (1H, m), 7.20-7.35 (3H, m), 7.40-7.50 (2H, m). Mass spectrum (Electrospray LC/MS), ES+: Found 417 (MH+). C23H2935ClN2OS requires 416. Ret. time 2.03 min. The title product was converted to its corresponding hydrochloride salt (210 mg).
Reaction SMILES: O[C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:29][C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)O
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of ethyl 4-hydroxy-9-iodo-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (350 mg, 0.85 mmol, 1.00 equiv) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (271 mg, 1.68 mmol, 2.00 equiv) at 0° C. After being stirred overnight at room temperature the resulting mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:20) to give 200 mg (57%) of the titled compound as a white solid; LC-MS (ES, m/z) 417 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[H-].[Na+].Cl[C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)cc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3,5-difluoro-4-(4-fluorophenoxy)phenyl)methanol, NaH and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1 (5H)-carboxylate.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:27][CH:28]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoate (273 mg, 0.71 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 2 h. The solution was evaporated to dryness to yield 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoic acid as an off-white powder that was carried on without further purification. MS (ESI) calcd [M+H]+ 327.1, found 327.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]([C:18](=[NH:21])[NH:19][OH:20])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)[CH3:24].C(Cl)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]([CH3:17])([C:18]1[N:21]=[C:23]([CH3:24])[O:20][N:19]=1)[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(CS(C)(=O)=O)(NC(=O)OCc1ccccc1)C(=N)NO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of [1-(N-Hydroxycarbamimidoyl)-2-methanesulfonyl-1-methyl-ethyl]-carbamic acid benzyl ester (Example 109b, 2.04 g, 6.19 mmol) in dry DMF (30 mL) were added triethylamine (1.73 mL, 12.4 mmol) and acetyl chloride (572 μL, 8.05 mmol). the reaction was stirred 30 minutes at room temperature. Reaction was then stirred at 130° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.21 g, 55%) as yellow oil. MS (ESI, m/z): 354.5 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([NH:20][C:21](=[O:24])[CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH2:13]([NH:20][C:21](=[O:24])[CH2:22][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-benzyl-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.58 (m, 4H), 3.05 (s, 2H), 3.52 (m, 4H), 4.35 (d, J=5 Hz, 2H), 6.63 (t, J=5 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 7.28 (m, 5H), 7.55 (t, J=6 Hz, 1H), 8.12 (t, J=5 Hz, 1H), 8.35 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH:13]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[C:6]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)[CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 75.6 %

Procedure:
4-Bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (700 mg, 2.03 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (629 mg, 2.03 mmol), Pd(PPh3)4 (235 mg, 0.20 mmol), and Cs2CO3 (1325 mg, 4.07 mmol) were combined in DMF (10 mL) and heated at 90° C. for 4 h under N2 atmosphere. The reaction was diluted with water and extracted with dichloromethane (3×10 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (596 mg, 77% yield). LC/MS m/z 389.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[OH:15]/[N:14]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)/C(=N/O)c1ccccc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 12.9 %

Procedure:
A mixture of methyl phenylglyoxylate (25.5 g), hydroxylamine hydrochloride (11.3 g), triethylamine (22.8 ml) and methanol (300 ml) was stirred for 17 hours at 60° C. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, (MgSO4), and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain methyl E-2-hydroxyimino-2-phenylacetate (3.58 g, yield 13%) as colorless crystals. m.p. 151-153° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]=1[CH3:16].Cl[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:27]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[C:12]1[O:13][C:9]2[C:8]([CH3:16])=[C:7]([CH3:6])[CH:15]=[CH:14][C:10]=2[CH:11]=1)[CH2:28][CH2:29][CH3:30]
Reactant: Cc1ccc2ccoc2c1C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ccc(C)c(C)c2o1

Procedure:
A solution of 1.5 M hexane (21 ml) of n-butyllithium was added dropwise to a solution of 6,7-dimethyl-benzofuran (4.1 g) in tetrahydrofuran (100 ml) at −78° C. under an argon atmosphere, and the mixture was stirred for half an hour. Then, chloro tri-n-butyltin (8.4 ml) was added to the mixture, and the mixture was stirred for one hour. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane) to obtain tri-n-butyl(6,7-dimethyl-benzofuran-2-yl) tin (10.8 g).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:34]=[CH:33][C:10]([CH2:11][N:12]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH:14]([O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:34]=[CH:33][C:10]([CH2:11][N:12]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH:14]([O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=3)[C:13]2=[O:32])=[CH:9][CH:8]=1
Reactant: COc1ccc(CN2CC(C)(C)C(Oc3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN(Cc2ccc(O)cc2)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Boron tribromide (3 eq.) was added dropwise to a −78° C. solution of 4-[1-(4-methoxy-benzyl)-4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy]-2-trifluoromethyl-benzonitrile (220 mg, 1_eq. in dichloromethane, i.e. the product of example 7). The reaction was allowed to gradually warm to ambient temperature overnight. Water was carefully added to the reaction and the product was extracted into dichloromethane. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography. (Procedure of example 8 will be referred to as a “demethylation reaction hereinafter”) MS (APCl, M+1) 405.0 LCMS: 50-2% H2O, 214 nm, 2.390 min, 100%
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[NH2:25][CH:26]([C:30]1[CH:59]=[CH:58][C:33]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:19]([O:18][P:16]([CH2:21][C:22]([NH:25][CH:26]([C:30]1[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[CH:58][CH:59]=1)[CH2:27][CH2:28][CH3:29])=[O:24])([O:15][CH2:13][CH3:14])=[O:17])[CH3:20]
Reactant: CCCC(N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)CP(=O)(OCC)OCC)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of 4-dimethylaminopyridine (DMAP; 197 mg, 1.61 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl; 309 mg, 1.61 mmol) was added to a stirred solution of diethylphosphonoacetic acid (129 μL, 0.805 mmol) and (2-(2-(2-(4-(1-aminobutyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (45; 400 mg, 0.805 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred under nitrogen for 3 hours at room temperature, and then poured into 100 mL of ethyl acetate. This solution was washed with 1N aqueous HCl (2×) and sat. brine, dried over sodium sulfate, and concentrated to an oil. Purification by flash silica gel column chromatography, eluting with ethyl acetate, afforded 49 (540 mg, quantitative) as a clear oil: MS (ES+) m/z 675.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>C(Cl)CCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][CH:35]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Nc1ccc(F)cc1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: ClCCCl
Product: CSc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 34 %

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid and 4-fluoroaniline by following the General Procedure for EDC couplings as disclosed in the general experimental section above. Crude reaction mixture was purified via flash chromatography (EtOAc:Hexanes, 2:1) to afford the title compound (0.125 g, 34%).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[O:11][CH2:10]2)[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH2:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:12][C:1]1[CH:2]=[C:3]([O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(OCC2CO2)c1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNCC(O)COc2cccc(C)c2)cc1OC

Procedure:
When 3-(m-tolyloxy)-1,2-epoxypropane (hereinafter referred to as TOEP) represented by the following formula (2): ##STR2## reacts with β-(3,4 -dimethoxyphenyl) ethylamine (hereinafter referred to as HVA) represented by the following formula (3): ##STR3## to give bevantolol of the above formula (1), the resultant bevantolol further reacts with TOEP of the starting material to produce a by-product represented by the following formula (4): ##STR4## Such consumption of the produced bevantolol causes its low yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added morpholine (17 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, ethyl acetate) yielding the Compound 48 as a solid (20 mg).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH:24](OS(C)(=O)=O)[CH3:25])=[N:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:32])[CH3:31])=[O:4].C(N(C(C)C)CC)(C)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(#N)C>[F:33][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[N:22][C:21]([CH:24]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH3:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:32])[CH3:31])=[O:4]
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)N1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a stirred solution of Methanesulfonic acid 1-(5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-ethyl ester (0.150 g, 0.309 mmol) in acetonitrile (2 mL) is added diisopropylethylamine (0.161 mL, 0.926 mmol) and morphline (0.054 mL, 0.617 mmol). Reaction mixture is stirred at 60° C. for 16 h. The solvent is evaporated in vacuo and the crude material is purified by combiflash using 1% methanol:CH2Cl2 as an eluent to afford the title compound (0.101 g). 1H NMR (400 MHz, CDCl3) δ 1.33 (d, J=6.48 Hz, 3H), 1.53 (s, 3H), 1.60 (s, 3H), 2.32-2.33 (m, 2H), 2.45-2.50 (m, 2H), 3.53-3.58 (m, 4H), 3.60-3.63 (m, 1H), 4.54-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H) 5.26 (d, J=4 Hz, 1H), 6.64 (t, J=52.32, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.12 Hz, 2H), 7.78 (d, J=8.24 Hz, 2H), 8.06-8.10 (dd, J1=8.8 Hz, J2=6.48 Hz, 1H), 8.83 (d, J=2.24 Hz, 1H). LCMS-not ionized.
Reaction SMILES: [H][H].[C:3]([CH2:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])#[N:4]>N.CO.[Rh]>[CH:18]1[N:17]=[CH:16][NH:15][C:14]=1[CH2:13][C@H:9]([NH:8][C:6]([CH2:5][CH2:3][NH2:4])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Agent: N
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 90 °C

Procedure:
A 1-liter pressure autoclave was initially charged with 1.76 g of Rh/C (0.4 mol % pure Rh, based on reactant used) in a mixture of 94.2 g of ammonia solution (25% in H2O) and 62.8 g of methanol. The autoclave was closed, and the contents were heated to 90° C. and the autoclave was pressurized with 40 bar of hydrogen. A solution of 20.0 g (0.09 mol) of (S)-2-(cyanoacetylamino)-3-(1H-imidazol-4-yl)propionic acid (prepared according to Example 3) in a mixture of 94.2 g of ammonia solution (25% in H2O) and 62.8 g of methanol was then metered in over the course of one hour. After further reaction at 90° C. for one hour, the reaction mixture was cooled to room temperature. The autoclave was depressurized and the catalyst was filtered off via activated carbon. An in-process HPLC analysis showed that the clear greenish reaction solution (326.2 g) contained 5.74% (m/m) carnosine, corresponding to a selectivity of 92% for complete conversion. The reaction mixture was then concentrated to approx. 60 g in a rotary evaporator. Dropwise addition of 174 g of ethanol caused precipitation of a white solid which was filtered off and dried at 50° C./20 mbar.