Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:15])[CH3:5].[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([N:6]([C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:15])[C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:19]
Reactant: CCc1cccc(C)c1N[C@@H](C)COC
Reactant: O=C(Cl)CCl
Product: CCc1cccc(C)c1N(C(=O)CCl)[C@@H](C)COC

Procedure:
(S)-N-(1-Methoxyprop-2-yl)-2-methyl-6-ethylphenylamine is acylated with chloroacetyl chloride in a manner known per se to yield the known (S)-N-chloroacetyl-N-(1-methoxyprop-2-yl)-2-methyl-6-ethylphenylamine (also known as S-metolachor).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([O:23][CH3:24])[C:12]=1[C:13]#[N:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)C>[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([O:23][CH3:24])[C:12]=1[C:13]([NH2:14])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(N)=O
Temperature: 90 °C

Procedure:
To a solution of 254 mg (6.350 mmol) sodium hydroxide in 2 ml water and 2 ml ethanol at room temperature under nitrogen, was added 195 mg (0.635 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzonitrile. The reaction mixture was heated in a 90° C. oil bath overnight. The reaction mixture was cooled to room temperature and 7 ml water was added. The product was collect by filtration and dried to provide 192 mg (y: 93%) of the title compound as a white solid. MS (m/e): 326.3 (MH+).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[C:20]2=[N:21][N:22]([CH2:32][CH3:33])[C:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:10][C:11]1[C:20]2=[N:21][N:22]([CH2:32][CH3:33])[C:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:27][CH2:26]3)=[C:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCNCC1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCN(S(C)(=O)=O)CC1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
Methanesulfonic anhydride (0.160 g, 0.922 mmol) was added to a slurry of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol (0.300 g, 0.922 mmol) in chloroform (10 mL). After 16 hours, 2M aqueous sodium carbonate was added and the biphasic mixture was stirred for 30 minutes resulting in a white precipitate. The mixture was extracted with 10% methanol in dichloromethane. The solution was concentrated. The residue was purified via automated flash chromatography and recrystallized from acetonitrile to provide 0.165 g of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol as a white solid, mp 268-270° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1

Procedure:
Stage 3.05 g (3.23 mmol) of 4-chloroacetophenone are stirred in 3.6 ml of dimethylformamide diethylacetal for 17.5 h at 110°. After cooling, precipitation is effected with hexane and the precipitate is isolated by filtration and dried. 3-dimethylamino-1(4-chloro-phenyl)-2-propen-1-one is obtained; 1H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 5.8 (1H,d), 7.5 (2H,m), 7.75 (1H,d), 7.95 (2H,m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].Cl[CH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: Cc1nc(CCl)cs1
Reactant: OCc1c(F)cc(O)cc1F
Product: Cc1nc(COc2cc(F)c(CO)c(F)c2)cs1
Yield: 73 %

Procedure:
This compound was prepared from 3,5-difluoro-4-hydroxymethyl-phenol and 4-chlormethyl-2-methylthiazol according to the procedure described in Example 179 to give the product as a colorless oil (369 mg, 73%); MS (ISP): 272.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30](I)[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].[C:40]([Cu])#[N:41].N>CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:40]#[N:41])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26]
Reactant: N#C[Cu]
Reactant: COC(=O)N(Cc1cc(I)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: N
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cc(C#N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 100 °C
Reaction time: 30 h

Procedure:
To a solution of methyl[3-iodo-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 119, 508 mg, 0.76 mmol) in DMF (40 mL) was added CuCN (1.7 g, 19.0 mmol). The reaction was stirred at 100° C. for 30 hours. The reaction was poured into aq. NH3 (40 mL) and extracted with EtOAc (3×40 mL). All the collected organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl[3-cyano-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.55 (20% EtOAc/hexanes). LCMS=565.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.63 (s, 1H), 7.43-7.38 (m, 3H), 7.17-7.13 (m, 3H), 6.86 (s, 1H), 6.74 (d, J=8.5 Hz, 1H), 4.37 (broad singlet, 2H), 4.08 (broad singlet, 2H), 3.45 (s, 3H), 3.40 (s, 3H), 2.80 (m, 1H), 1.18 (d, J=7.0 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[NH2:24])[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:24][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=3)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I

Procedure:
3-Iodo-4-methylbenzoyl chloride (2.2 g, 7.88 mmol), dissolved in anhydrous THF (13 mL), was added dropwise to a solution of 3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.5 g, 5.5 mmol), DIPEA (2.1 mL, 11.8 mmol) in THF (30 mL) at ˜5° C. The resultant solution was stirred at ambient temperature overnight. The solvent was removed in vacuo and the crude residue was redissolved in CH2Cl2 and washed with 1N NaOH. The organic layer was then washed with water, and brine then dried over NaSO4 before being concentrated in vacuo. The brown colored residue was then triturated in a mixture of hexanes/DCM to precipitate 1.4 g of the desired product as an off-white powder: 529 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=O)=[CH:4][CH:3]=1.[CH2:12]([Mg]Br)[CH3:13]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:10])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: OC1(c2ccc(Cl)nc2)CC1
Reaction time: 16 h
Yield: 18.2 %

Procedure:
To a suspension of methyl 6-chloropyridine-3-carboxylate (1 g, 5.83 mmol) in 17 mL anhydrous ether was charged with 3 M ethyl magnesium bromide (8.5 mL, 26 mmol) in ether and stirred for 1 h before the addition of titanium isopropoxide (1.73 mL, 5.84 mmol) to the reaction mixture. The mixture was stirred for 16 h under nitrogen atmosphere. The mixture was quenched with saturated ammonium chloride aqueous solution and aqueous phase was adjusted to pH 3 with 1 N HCl. The mixture was partitioned between DCM and brine. The organic layer was dried over Na2SO4 and concentrated to afford the crude material. The resulting solid was purified by flash chromatography on silica gel, eluting with 10-80% EtOAc:heptane. Fractions containing the desired product were combined and concentrated to afford a brown greasy solid (180 mg, yield: 18.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[SH:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1S
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1S
Yield: 85 %

Procedure:
2- {[(Phenylamino)carbonyl]amino }thiophenol was prepared from 2-aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85%). mp: 194.5° C.; 1H NMR (CD3 OD/CDCl3): d 7.48-7.26 (m, 4H), 7.25-7.10 (m, 3H), 7.04-6.79 (m, 2H); El-MS m/z 244 (M+H)+ ; Anal. (C13H12N2OS) C, H, N.
Reaction SMILES: [CH:1]1([CH2:7][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[CH:1]1([CH2:7][C:11]2([OH:10])[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: Br[Mg]CC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(O)(CC3CCCCC3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of cyclohexylmethylmagnesium bromide (1.90 mL of a 2M solution in THF) at −78° C. was treated with ethyl 4-(4-oxo-1-piperidinyl)benzoate (prepared according to the procedure described in Synthesis 1981, 606-608, 0.30 g), and was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 20% ethyl acetate to give the product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:31]#[N:32].O>CS(C)=O>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:32]
Reactant: [C-]#N
Reactant: BrCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
1-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6 g) in dry dimethyisulphoxide (70 ml) was added over 10 minutes to a mixture of sodi-m cyanide (3.68 g) in dimethyl-sulphoxide (50 ml) and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The extracts were combined, washed with water, dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5-triphenylimidazole (24.19 g, 99%) as a white solid, m.p. 104°-6°.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:14]I.[H-].[Na+]>C(COC)OC>[CH3:14][N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH2:13]1
Reactant: CI
Reactant: c1ccc2c(c1)NCc1nnnn1-2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1Cc2nnnn2-c2ccccc21

Procedure:
A solution of 1 g. of 4,5-dihydrotetrazolo[1,5-a]quinoxaline and 2 g. of methyl iodide in 50 ml. of dimethoxyethane was stirred with 1.5 g. of sodium hydride, as a 50 percent suspension in mineral oil, overnight at room temperature. The reaction mixture was then filtered and evaporated under vacuum. The residue was dissolved in ethyl acetate and extracted twice with water. The brown residue which resulted on evaporation of the dried organic layer was washed with cyclohexane, leaving 0.87 g. of crude product. Two recrystallizations from ethanol produced pure 4,5-dihydro-5-methyltetrazolo[1,5-a]quinoxaline, m.p. 107°-10°C., which was identified by NMR analysis and elemental micro-analysis with the following results.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:23][CH2:24]2)=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 23.9 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide (343 mg, 0.95 mmol), 4-chloropyridine hydrochloride (709 mg, 4.73 mmol), triethylamine (479 mg, 4.73 mmol), and ethanol (3 mL) yielded 100 mg (24%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:27]=3)[N:18]=[C:17]([NH:37][C:38]3[CH:42]=[C:41]([CH3:43])[NH:40][N:39]=3)[CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:27]=3)[N:18]=[C:17]([NH:37][C:38]3[CH:42]=[C:41]([CH3:43])[NH:40][N:39]=3)[CH:16]=2)[CH2:13][CH2:14]1
Reactant: Cc1cc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(N3CCC(N)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
6-(4-(N-tert-Butoxycarbonylamino)piperidin-1-yl)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 124) (120 mg, 0.20 mmol) was stirred in DCM (10 ml) and trifluoroacetic acid (2 ml) was added and the mixture stirred at room temperature for 3 hours. The mixture was concentrated by evaporation and the residue dissolved in methanol (10 ml) and passed down a 20 g SCX-2 ion exchange column, eluting with methanol to elute impurities and then 2M methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (79 mg, 81%) as a cream powder.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH:33]2[CH2:35][CH2:34]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:39]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:39])=[O:32])[C:20]([CH:33]2[CH2:34][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C2CC2)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-cyclopropyl-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 240, 2.35 g, 4.61 mmol) following the procedure described for Intermediate 19. The desired product was obtained as an orange foam (2.28 g, 94%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][NH:12][C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:17])=[O:15].[F:21][C:22]([F:30])([F:29])[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].Cl>C(Cl)Cl>[F:21][C:22]([F:30])([F:29])[CH2:23][CH2:24][S:25]([N:12]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:17])=[O:15])[CH3:11])(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: C=CC[C@H](NC)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@H](C(=O)OC)N(C)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
Step I (1): DIEA (436 μL, 3.2 mmol) was added to a solution of (S)-methyl 2-(methylamino)pent-4-enoate hydrochloride (229 mg, 1.28 mmol) and 3,3,3-trifluoropropane-1-sulfonyl chloride (250 mg, 1.28 mmol) in DCM. The reaction mixture was stirred for 24 h at rt. The resulting solution was poured into 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (1-50% EtOAc/hexanes, linear gradient) to afford 288 mg (74% yield) of (S)-methyl 2-(3,3,3-trifluoro-N-methylpropylsulfonamido)pent-4-enoate as a viscous oil. LC-MS (M+H)+=303.9; 1H NMR (500 MHz, CDCl3) δ ppm 2.42-2.51 (m, 1H) 2.58-2.69 (m, 2H) 2.73-2.81 (m, 1H) 2.87 (s, 3H) 3.17-3.29 (m, 2H) 3.77 (s, 3H) 4.63 (dd, J=10.53, 5.34 Hz, 1H) 5.13-5.23 (m, 2H) 5.70-5.83 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:21]=[C:20]([I:22])[C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.O>ClCCl>[CH3:23][N:17]1[CH2:16][CH2:15][C:14]2[C:20]([I:22])=[CH:21][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:12][C:13]=2[CH2:19][CH2:18]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(I)c2c(c1)CCNCC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(I)c2CC1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 7-(4-fluorophenylsulfonyl)-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (2.4 g, 5.5 mmol) in dichloromethane (20 ml) were added sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and formalin (1 ml, 37%, 12 mmol). The mixture was stirred for 2 h without cooling then poured into water (100 ml) and extracted with more dichloromethane (100 ml). The resulting organic layer was washed with brine (100 ml), dried (MgSO4), and evaporated to give the subtitle compound as a white foam (2.4 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]>C(O)C.[C].[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: CNC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C1(c2ccc(N)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
To a solution of N-methyl-4-(4-nitrophenyl)tetrahydro-2H-pyran-4-carboxamide (380 mg) obtained in Step C of Example 151 in ethanol (20 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature for 10 hr under hydrogen atmosphere (at normal pressures). The palladium-carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (330 mg).
Reaction SMILES: C(O)(=O)C.C(O)CCC.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:21])(O)=[O:11].P(Cl)(Cl)(Cl)(Cl)Cl>CO.[Pd].C1COCC1.O.N1C=CC=CC=1>[NH2:26][CH2:25][CH2:24][CH2:23][O:22][C:20]1[O:21][C:10]([C:13]2[C:14]([CH:19]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11]
Reactant: NCCCOC(=O)Cc1ccccc1C(=O)O
Agent: [Pd]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCO
Product: NCCCOc1cc2ccccc2c(=O)o1
Yield: 10.8 %

Procedure:
Homophthalic acid (18 g, 0.1 mole) and 3-(benzyloxycarbonylamino)-1-propanol (41 g, 0.2 mole) were heated in 150 ml of benzene at 120°-130° C. for 2 hrs in the presence of a few drops of conc. H2SO4. Benzene was evaporated, and 200 ml of ethylacetate was added. The organic solution was washed with 4% NaHCO3 twice (150 ml×2). The aqueous layer which contained the monoester salt was acidified with 5N HCl and extracted with ethylacetate. 33 g of 3-(benzyloxycarbonylamino)propyl 2-carboxyphenylacetate (yield, 89%) was obtained after the solvent was evaporated. Hydrogenation of this monoester (1.86 g, 5 mmole) was performed in methanol containing 0.3 ml of acetic acid and 10% palladium on carbon to give 1 g of 3-aminopropyl 2-carboxphenylacetate.HAc (yield, 67%). This compound was identified by its NMR spectrum and TLC (Butanol:acetic acid:pyridine:water=4:1:1:2). 2 g of 3-aminopropyl 2-carboxyphenylacetate.HAc (3 mmole) was heated with 1.6 g of PCl5 (7.5 mmole) in 50 ml of anhydrous THF at 70°-80° for 2 hrs, a white precipitate formed. This white solid was purified by column chromatography (methylene chloride:methanol=5:1) and crystalline from MeOH-ether to give 0.2 g of 3-(3-aminopropoxy)isocoumarin.HCl (yield, 26%), m.p. 173°-174° C.; mass spectrum, m/e=220 (M + -Cl). Anal. Calc. for C12H14N1O3Cl1 : C, 56.37; H, 5.52; N, 5.48; Cl, 13.87. Found: C, 56.15; H, 5.49; N, 5.44; Cl 13.95.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[N+:9]([C:4]1[CH:3]=[CH:2][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Nc1cc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a mixture of 4-bromo-2-nitroaniline (217 mg, 1.0 mmol), phenylboronic acid (122 mg, 1.0 mmol), tetrakis-(triphenylphosphine)palladium (55 mg, 0.05 mmol) and cesium carbonate (650 mg, 2.0 mmol) was added 3 mL of ethyleneglycol dimethyl ether (DME). The reaction was heated to 80° C. and stirred under nitrogen atmosphere overnight. The mixture was filtered through a celite pad. The filtrate was concentrated and purified by biotage column chromatography to give 4-nitrobiphenyl-3-amine (207 mg)