Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[C:9]1/[CH2:10][CH2:11][C:12]2[C:17]/1=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)/C(OCC)=O)#[N:2].[C-:19]#[N:20].[K+]>C(O)C.O>[C:1]([CH2:3][C:9]1([C:19]#[N:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2ccc(F)cc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1(C#N)CCc2ccc(F)cc21
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a solution of (E)-ethyl 2-cyano-2-(6-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep44, 7.5 g, 0.03 mol) in ethanol (100 ml), a solution of KCN (4.65 g, 0.08 mol) in water (30 ml) was added. The mixture was warmed to 65° C., and stirred for 7 h.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:2]=1.[Cl:23]CCl>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([Cl:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (15b) (0.28 g, 0.88 mmol) in dichloromethane (3.5 ml) oxalyl chloride (0.23 ml, 2.64 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.29 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]2[CH:11]=[CH:12][C:3]=1[CH:4](Br)[O:5][CH2:6][O:7]2.[C-:14]#[N:15].[K+].O>C(O)C>[F:1][C:2]1[C:9]([F:10])=[C:8]2[CH:11]=[CH:12][C:3]=1[CH:4]([C:14]#[N:15])[O:5][CH2:6][O:7]2
Reactant: [C-]#N
Reactant: Fc1c2ccc(c1F)C(Br)OCO2
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CC1OCOc2ccc1c(F)c2F
Temperature: 70 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
2,3-Difluoromethylenedioxybenzyl bromide (40.4 g) was dissolved in ethanol and potassium cyanide (11.3 g) was added. The mixture was stirred at 70° C. for 5 hours. Water and a further portion of potassium cyanide (2 g) were added and the mixture was stirred at 70° C. for a further 3 hours. Most of the solvent was removed in vacuo and water was added to the residue, which was extracted with diethyl ether, washed with water, dried and concentrated to yield the title compound as a yellow oil, (30.2 g), NMR (CDCl3): 3.80(s,2H), 7.10(m,3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl>>[F:35][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][NH:9]4)=[CH:4][CH:3]=3)=[O:22])=[C:19]([CH3:18])[N:27]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Reactant: Cc1nc(-c2ccc(F)c(F)c2)ccc1C(=O)O
Agent: Cl
Product: Cc1nc(-c2ccc(F)c(F)c2)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (73 mg, 0.30 mmol) and 2-methyl-6-(3,4-difluorophenyl)nicotinic acid (D108) (82 mg, 0.33 mmol) then converted to the HCl salt as a buff solid. 1H NMR (400 MHz, DMSO) δ (ppm): 8.23 (dd, 1H), 8.04 (m, 3H), 7.87 (d, 1H), 7.63 (d, 1H), 7.57 (m, 1H), 7.29 (d, 1H), 3.34 (m, 2H), 2.80 (m, 2H), 2.67 (s, 3H), 2.02 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[OH:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(CO)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(CO)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-[5-(hydroxymethyl)-2-thienyl]acetate in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1 N aqueous solution of lithium hydroxide (11.83 mL) and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and acidified to pH 1 with 2 N aqueous solution of HCl. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an orange solid (1.02 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[Cl:10][CH2:11][C:12](O)=O>Cl.O.C(=O)(O)[O-].[Na+]>[Cl:10][CH2:11][C:12]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=1
Reactant: O=C(O)CCl
Reactant: CNc1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1c(CCl)nc2ccccc21
Temperature: 55 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
N-methyl-phenylenediamine (1 g, 8.2 mmol) and chloroacetic acid (0.9 g, 9.4 mol) were dissolved in 5 N aqueous hydrochloric acid (10 mL) and stirred at 55° C. overnight. The reaction mixture was then diluted with water and basified with solid sodium bicarbonate to give a precipitate which was filtered, washed with water and dried to provide the desired compound (1.3 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=O)([O-:3])=[O:2].[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cccc(N)c1C
Reactant: O=C(O)COc1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)COc2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Nitrophenoxy)acetic acid S11 (5.28 g) and 2,3-dimethylaniline (3.25 g) were dissolved in dichloromethane (100 ml). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.17g) and 4-dimethylaminopyridine (3.93 g) were added to the solution, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed successively with 1N HCl saturated aqueous sodium hydrogencarbonate solution and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 7.7 g of the compound S12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][C:39]1([NH2:43])[CH2:42][O:41][CH2:40]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:43][C:39]4([CH3:38])[CH2:42][O:41][CH2:40]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: CC1(N)COC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(NC(=O)c2ccc(OCc3c(-c4ccc(F)cc4)noc3CO)nc2)COC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) in DMF (3.3 mL) was added 1,1′-carbonyl-diimidazole (58.2 mg, 0.35 mmol). The reaction mixture was stirred for 1 h at 60° C. 3-Methyl-3-oxetanamine (27.8 mg, 0.32 mmol) was then added at room temperature and the mixture was stirred overnight. Extraction with water/ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (10 mg, 8%) as a white solid. MS: m/e=414.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH:4]([CH:5](OC(=O)C2C=CC=CC=2)[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]=1[CH3:38])=[O:23]>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:39])[CH:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]=1[CH3:38])=[O:23]
Reactant: Cc1c(COC(=O)C2C(C(OC(=O)c3ccccc3)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1c(COC(=O)C2C(C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 97.5 %

Procedure:
To a solution of 56 mg (0.097 mmol) of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-benzoyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 12 and dissolved in 0.1 ml of DMF, 8 mg (0.12 mmol) of zinc powder was added, and the mixture was stirred at 60° C. for 6 hours. The subsequent operation was carried out in the same manner as in Reference Example 9, whereby 40 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)cyclopropanecarboxylate was obtained. Yield: 98%. (Z):(E)=86:14.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=O)[C:12]=2[CH3:19])=[CH:7][CH2:6]1)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[C:46](=[O:58])[N:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:48]([CH3:51])[C:49]=1[CH3:50].C(N(CC)CC)C>CN1C(=O)CCC1>[CH:52]1([N:47]2[C:46](=[O:58])[C:45]([NH:44][C:16]([C:13]3[C:12]([CH3:19])=[C:11]([C:8]4[CH2:9][CH2:10][CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH2:6][CH:7]=4)[O:15][N:14]=3)=[O:18])=[C:49]([CH3:50])[N:48]2[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C1=CCC(OC(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-(4-isopropoxycyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid (174 mg, 0.656 mmol) in dry NMP (3 mL), HATU (274 mg, 0.721 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (151 mg, 0.721 mmol) and triethylamine (0.201 mL, 1.443 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (20 mL) and 1M NaOH (aq) (20 mL) and the organic phase was washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DMSO and purified using a UV-directed reverse phase chromatography with a gradient of 40-80% MeCN in water (0.1% formic acid) over 9.5 minutes. The product fraction was added to EtOAc (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][CH2:22][N:21]([CH3:30])[C:20]1=[O:31]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][N:21]([CH3:30])[C:20]2=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1CCc2ccccc2C(N)C1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)CCc2ccccc21

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.15 in ethyl acetate) and purification was by flash chromatography using ethyl acetate as the eluant.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:28][CH:27]=1)[CH3:25]
Reactant: CCc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 37.5 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-ethylaniline (40.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.7 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
To 4-fluoro-1-nitrobenzene (1 eq) in N,N-dimethylformamide was added Ethyl piperazine (2 eq) and N,N-diisopropylethyl amine (2 eq) and heated at 80° C. for 16 h. Concentrated the resultant mixture and partitioned between ethyl acetate and water. The organic layer was then washed with brine and dried with sodium sulfate and concentrated. Passed through a plug of silica to yield 4-Ethyl-1-(4-nitrophenyl)piperazine. MS: MH+=235.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CO/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26](OC)=[O:27]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]([C:30]([O:32][CH3:33])=[O:31])=[CH:22]1
Reactant: Nc1c(F)cccc1F
Reactant: CO/C=C(/C=C/C(=O)OC)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of (2,6-difluorophenyl)amine (15.5 g) in THF (140 mL) was added dropwise an 1 M THF solution of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (120 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To the solution was added a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (20 g) in THF (60 mL) at 0° C., and the resulting mixture was stirred at the same temperature for 2 hr. The reaction was quenched with a mixture of EtOAc (200 mL) and 0.5 M HCl (200 mL). The aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was diluted with MeOH (100 mL), and to the resulting solution was added 28% sodium methoxide in MeOH (38.6 mL). The resulted mixture was heated to reflux for 6 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (200 mL) and 1 M HCl (300 mL). The aqueous layer was separated and extracted with EtOAc (200 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (300 mL) and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with IPE, and the precipitates produced were collected by filtration to give methyl 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (5.34 g).
Reaction SMILES: C([N:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH:9]2[NH:8][CH2:17][CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)=[CH:21][CH:22]=1
Reactant: COc1ccc(CCC2c3cccnc3C=CN2Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CCC2NCCc3ncccc32)cc1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
To a solution of 2.1 g (5.85 mmol) 6-benzyl-5-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-[1,6]naphthyridine in 70 mL methanol and 7 mL acetic acid was added 210 mg Pd/C 10% and hydrogenated at atmospheric pressure for 4 h at 55° C. The apparatus was purged with argon, the catalyst was filtered and the filtrate was concentrated in vacuo. The oil was dissolved in ethyl acetate and the solution was washed once with a sat. NaHCO3 solution. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield 1.47 g (93%) of the title compound was yielded as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8]CC(=N)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:17].C(#[N:20])C>>[ClH:17].[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][NH2:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=N)COc1ccc([N+](=O)[O-])cc1
Reactant: CC#N
Agent: Cl
Product: NOc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 71.2 g of ethyl 4-nitrophenoxyethaneimidoate (0.32 mol) (compound VII) in 925 ml of acetonitrile are added slowly, at 20° C., 35 ml of 37% hydrochloric acid (0.38 mol). The reaction medium is stirred at 20° C. for 2 hours and then filtered, and the O-(4-nitrophenyl)hydroxylamine hydrochloride thus formed is dried at 30° C. in a vacuum oven. With stirring, this hydrochloride is dissolved in a mixture formed from 800 ml of dichloromethane and of a sodium hydroxide solution (16.8 g in 500 ml) and the phases are then allowed to separate by settling. The organic phase is separated out and washed with 500 ml of water. This organic phase is evaporated on a rotary evaporator and the solid obtained is then dried in a vacuum oven.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]12[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][CH2:6][C@@:5]23[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]2)[CH:24]=[N:25][CH:26]=1
Reactant: NC1=N[C@@]2(CCSc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncc(Cl)c1
Product: NC1=N[C@@]2(CCSc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 70 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6′-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (intermediate B6.9) with 5-chloropyridin-3-ylboronic acid yielded the title compound (70% yield) as a white solid. MS (ISP): m/z=382.0 [M+H]+.
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][CH2:7][P:8](=[O:15])([O:12]CC)[O:9]CC)([OH:4])=[O:3]>>[P:8]([CH2:7][NH:6][CH2:5][C:2]([OH:4])=[O:3])([OH:15])([OH:12])=[O:9]
Reactant: CCOP(=O)(CNCC(=O)O)OCC
Agent: Cl
Product: O=C(O)CNCP(=O)(O)O
Yield: 62.7 %

Procedure:
60 ml. of concentrated hydrochloric acid are added to 11.25 g. (0.05 moles) of diethyl N-carboxymethyl-aminomethyl-phosphonate, and the mixture is boiled for 2 hours. The reaction mixture is concentrated to one-fourth volume under a pressure of 80 to 100 mmHg., and the residue is triturated with 60 ml. of ethanol. The solid substance is filtered when cold, dissolved in 15 to 20 ml. of hot water, the solution is decolorized, cooled, and the product is precipitated with 45 ml. of acetone. 5.3-5.7 g. (62.7-67.5%) of N-phosphonomethyl-glycine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.[Br:22]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:12]=2[Br:22])=[CH:4][CH:3]=1
Reactant: N#Cc1[nH]c(-c2ccc(Cl)cc2)cc1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(Br)c1-c1ccc(Cl)cc1
Yield: 44 %

Procedure:
Bromination of 2,4-bis(p-chlorophenyl)-5-cyanopyrrole is accomplished by treatment with 1 equivalent of bromine in acetic acid in the presence of anhydrous sodium acetate yields the desired product (0.47 g, yellow solid, 44% yield, mp 98°-100° C.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])(OCC1C=CC=CC=1)=O>>[NH2:34][C@@H:35]([CH3:36])[C:37]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:38]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: C[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 3 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-alanine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-3.99 (m, 1H), 3.93 (q, 1H), 3.42-3.25 (m, 2H), 1.98-1.85 (m, 2H), 1.83-1.61 (m, 6H), 1.59-1.55 (m, 2H), 1.52 (d, 3H), 1.42-0.98 (m, 5H). 31P NMR (CD3OD, 300 MHz): δ 42.98. LCMS m/z: [M+H]+=307.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]1([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)=[O:17])[CH2:19][CH2:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCC1COCCN1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
3-(4-Phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (3.31 g, 8.16 mmol) was stirred in DCM (30 mL) at 0° C. TFA (6 mL) dissolved in DCM (24 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between DCM (30 mL) and aq NaHCO3 (5 g in 30 mL). The aqueous layer was extracted with DCM (3×30 mL), dried (MgSO4) and the solvents were removed in vacuo to give morpholin-3-ylmethyl 4-phenylpiperazine-1-carboxylate (2.55 g, quant.) as a white solid.