Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2cnccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cnccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A mixture of hydroxylammonium chloride (2.1 g), sodium hydrogen carbonate (3.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(pyrazin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.87 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.38 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 38%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 7.9 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine from Example 10 (270 mg, 1.13 mmol), 6-chloro-9H-purine (250 mg, 1.59 mmol) and DIPEA (0.36 mL, 2.04 mmol) in n-butanol (1.5 mL) was stirred in a sealed tube for 48 h at 120° C. After cooling to RT, the crude reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM), then triturated with diethyl ether and then submitted to preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) affording 114 as an off-white solid (32 mg, 8%). LCMS: RT 2.64 min [M+H]+ 357.0. 1H NMR (DMSO, 400 MHz): δ 8.23 (1H, dd, J=4.76, 1.48 Hz), 8.18-7.97 (4H, m), 7.67-7.41 (5H, m), 7.29 (1H, dd, J=7.99, 4.76 Hz), 1.57 (3H, d, J=6.83 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:14])[CH2:12]Br)[CH:5]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:12][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:15])=[O:14])=[CH:21][C:20]=1[CH3:26])([CH3:18])[CH3:17]
Reactant: Cc1cc(O)ccc1C(C)C
Reactant: COC(=O)c1cccc(NC(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cccc(NC(=O)COc2ccc(C(C)C)c(C)c2)c1
Reaction time: 12 h

Procedure:
A solution of 3-(2-bromo-acetylamino)-benzoic acid methyl ester (1.80 g, 6.61 mmol), 4-isopropyl-3-methylphenol (1.00 g, 6.61 mmol) and potassium carbonate (1.00 g, 7.23 mmol) in 2-butanone (15 mL) was heated to reflux under inert atmosphere with stirring for 12 h. After cooling, the mixture was partitioned between water and ethyl acetate (50 mL each). The aqueous phase was extracted with ethyl acetate, and the extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The residual material was separated on a column (silica gel) with 20:80 ethyl acetate-hexane, and the eluant containing the product was evaporated to afford pure methyl 3-[2-(4-isopropyl-3-methyl-phenoxy)acetylamino]benzoate, as a glassy solid (1.64 g, 4.80 mmol, 73%). TLC RF 0.41 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): δ 8.39 (1H, br s), 8.05 (1H, t, J=1.8 Hz), 7.99 (1H, ddd, J=8.0, 2.2, 1.1 Hz), 7.80 (1H, dt, J=7.7, 1.3 Hz), 7.42 (1H, t, J=7.9 Hz), 7.18 (1H, d, J=8.8 Hz), 6.81-6.77 (2H, m), 4.57 (2H, s), 3.90 (3H, s), 3.07 (1H, heptet, J=7.0 Hz), 2.32 (3H, s), 1.18 (6H, d, J=7.0 Hz). MS (ESI): m/e 344 (3), 343 (22), 342 (100).
Reaction SMILES: C([N:8]1[C@H:17](CO)[CH2:16][C:15]2[C:10](=[C:11]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:12]3=[C:13]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:14]3=2)[CH2:9]1)(OC(C)(C)C)=O.CCN([CH2:39][CH3:40])CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[C:61]([O-:64])(C)C.[K+]>C(Cl)Cl.CS(C)=O.C(Cl)(Cl)Cl>[CH3:27][O:26][C:21]1[C:22]([O:24][CH3:25])=[CH:23][C:13]2[C:14]([CH:20]=1)=[C:15]1[C:10](=[C:11]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:12]=23)[CH2:9][NH:8][C@H:17](/[CH:40]=[CH:39]/[O:64][CH3:61])[CH2:16]1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c3c(c4cc(OC)c(OC)cc4c2c1)C[C@@H](CO)N(C(=O)OC(C)(C)C)C3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CO/C=C/[C@@H]1Cc2c(c3ccc(OC)cc3c3cc(OC)c(OC)cc23)CN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
N-Boc-alcohol 2 (1.812 g, 4 mmol) was dissolved in CH2Cl2 (50 ml) and Et3N (1.95 ml, 14 mmol) at 0° C., to which Py.SO3 (2.23 g, 14 mmol) in 10 ml of DMSO was added dropwise. The ice bath was then removed and the mixture was stirred at r.t. until alcohol disappeared by TLC. HCl (1N) was added, and the organic layer was then separated and washed with sat. NaHCO3, brine, and dried over MgSO4. In another flask, Ph3P+CH2OMeCl− (2.74 g, 8 mmol) was added to KOtBu (875 mg, 7.8 mmol) at 0° C. under N2, which was stirred for 0.5 h. The aldehyde in 20 ml of CH2Cl2 was added dropwise, followed by removal of ice bath. The reaction was kept for 2-3 h before sat. NH4Cl was poured into the mixture. CH2Cl2 was used for extraction and the organic layers were washed with sat. NaHCO3 and brine, dried over MgSO4. Chromatography afforded 1.5 g of light yellow solid. Yield: 78% for two steps. mp 150-152° C.; [α]23D=108.1° (c 0.59, CHCl3); 1H NMR (400 MHz, CDCl3, E/Z=2.5:1): δ 7.94-7.91 (m, 2H), 7.88 (d, J=9.2 Hz, 1H), 7.29 (s, 1H), 7.26-7.22 (m, 1H), 6.30 (d, J=12.8 Hz, 0.68H, E isomer), 5.86 (dd, J=6.4 Hz, J=1.6 Hz, 0.28 Hz, Z isomer), 5.72 (m, 0.31H, Z isomer), 5.30-5.25 (d, J=16.8 Hz, 1H+0.67H, E isomer), 4.80 (dd, J=12.8 Hz, J=8.4 Hz, 0.71H, E isomer), 4.59 (d, J=17.2 Hz, 1H), 4.42 (dd, J=8.0 Hz, J=6.4 Hz, 0.29H, Z isomer), 4.12-4.11 (m, 3H), 4.05-4.04 (m, 3H), 4.03-4.02 (m, 3H), 3.62 (s, 0.7111, Z isomer), 3.44-3.32 (m, 1H), 3.36 (s, 211, E isomer), 3.13 (d, J=16.0 Hz, 1H), 1.55 (s, 9H); ESI MS m/z 480.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.Cl[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)C2=O.FC1C=C2C(=CC=1)NC(=O)C2=O>>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]1[C:19](=[N:20][C:21]3[C:22]([C:10]1=[O:12])=[CH:23][CH:15]=[CH:16][CH:17]=3)[C:7]2=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(Cl)ccc2-n2c1nc1ccccc1c2=O

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-chloroisatin for 5-fluoroisatin gave the title compound in 39% crude yield: mp 295°-296° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46-8.53 (m, 1H), 8.33 (d, 1H), 7.96 (d, 2H), 7.69-7.84 (m, 3H); MS (M+H)+ 283.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][OH:34])[NH:17][CH:16]2[C:37](O)=[O:38])[CH:12]=[CH:13][CH:14]=1.[NH2:41][C:42]1[CH:47]=[CH:46][N:45]([CH3:48])[C:44](=[O:49])[CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:48][N:45]1[CH:46]=[CH:47][C:42]([NH:41][C:37]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:40])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][OH:34])[NH:17]2)=[O:38])=[CH:43][C:44]1=[O:49]
Reactant: CC(C)(CCO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Cn1ccc(N)cc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(NC(=O)C2NC(CC(C)(C)CCO)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1=O
Yield: 5.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 116c (0.5 g, 0.8 mmol) was reacted with 4-amino-1-methyl-1H-pyridin-2-one (Molbridge) (0.18 g, 1.5 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.71 mL, 4.1 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (25 mg, 5.1%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](S([O-])(=O)=O)=[CH:13][CH:12]=1.C1C=C[NH+]=CC=1.COC(OC)C1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:7][O:8][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@H:3]1[CH2:4][OH:5]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(CO)[C@@H](O)CO
Agent: COC(OC)c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)COC(c2ccccc2)O[C@H]1CO
Yield: 220.4 %

Procedure:
Following the general procedure for the transacetalization reaction of Description 6, 6.6 g (49.2 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 120 mL of dichloromethane (DCM) in the presence of 2.51 g (10.0 mmol) of PPTS with 11.3 mL (11.4 g, 75.0 mmol) of benzaldehyde dimethyl acetal. Purification by silica gel column chromatography using diethylether (Et2O) and hexane (Hxn) mixtures as eluent (Et2O/Hxn=2:3→Et2O/Hxn=1:1→Et2O/Hxn=3:2) provided 4.9 g (45% yield) of the title compound (7a) as a colorless liquid. Rf=0.44 (Et2O/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.02-2.06 (m, 1H), 3.60-3.64 (m, 1H), 3.68-3.72 (m, 4H), 5.52 (s, 1H), 7.33-7.41 (m, 3H), 7.49-7.53 (m, 2H) ppm. MS (ESI) m/z: 223.0 (M+H)+, 245.0 (M+Na)+. The analytical data for the compound was consistent with that given in the literature.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([I:14])[CH:4]=1.Cl.C1([O:22][C:23](=O)[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)C=CC=CC=1>>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:23](=[O:22])[NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([I:14])[CH:4]=2)=[CH:27][CH:28]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1I
Reactant: CC(C)(C)c1ccc(CNC(=O)Oc2ccccc2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(NS(C)(=O)=O)c(I)c2)cc1

Procedure:
N-(4-Aminomethyl-2-iodo-phenyl)-methanesulfonamide and HCl salt (297 mg, 0.820 mmol) were reacted with (4-t-butyl-benzyl)-carbamic acid phenyl ester following the general procedure to give a white solid (152 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C([O:22][C:23](=O)[C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])C>C(O)C>[OH:31][C:24]1[C:23](=[O:22])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NCCCn1ccnc1
Reactant: CCCCCCC(=O)C(=O)OCC
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 4-Methoxy-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:11])=[N:6][CH:7]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ncc(Br)c1O
Temperature: 70 °C
Yield: 80 %

Procedure:
A 100 mL 3-necked round bottom flask was charged with 3-nitropyridine-2,4-diol (3.5 g, 22 mmol), bromine (1.15 mL) and acetic acid (30 mL). The resulting mixture was heated at 70° C. for 15 minutes. Work-up: the mixture was poured onto crushed ice and chilled in freezer. The resulting precipitate was collected by filtration, washed with cold water and dried in vacuo, to afford 3.7 g (80%) of the product as a colorless solid.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=1[CH:9]=O.[C:16]([O:23]C)(=O)[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=1[CH:9]1[CH:4]([CH3:5])[NH:1][C:16](=[O:23])[CH:17]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC[N+](=O)[O-]
Reactant: COC(=O)CC(=O)OC
Product: CC(=Cc1c(Cl)cccc1Cl)[N+](=O)[O-]
Product: COC(=O)C1C(=O)NC(C)C1c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-2-nitropropylene (m.p. 49°-50° C., b.p. 90°-102° C./0.33 mm. Hg.) is prepared from nitroethane and 2,6-dichlorobenzaldehyde by a similar process to that described in the second and third parts of Example 4. This compound is reacted with dimethyl malonate and the product hydrogenated by a similar process to that described in the fourth and fifth parts of Example 4, and the 4-(2,6-dichlorophenyl)-3-methoxycarbonyl-5-methylpyrrolidin-2-one thus obtained is separated into two geometrical isomers thereof by repeated chromatography on a silica gel column, using a 2:1 v/v mixture of toluene and ethyl acetate as eluant. The two isomers have m.p. 157°-158° C. (first isomer) and 143°-144° C. (second isomer). These two esters are separately hydrolysed and decarboxylated by a similar process to that described in the sixth part of Example 4, and there are thus obtained a first isomer, m.p. 182°-184° C., and a second isomer, m.p. 173.5°-175° C., of 4-(2,6-dichlorophenyl)-5-methylpyrrolidin-2-one, the isomers differing by cis- and trans- relationship of the 4-(2,6-dichlorophenyl)- and 5-methyl-subsitutents.
Reaction SMILES: [C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c(C(=O)c2ccccc2)c1

Procedure:
Methyl 5-benzoylpyrrole-3-carboxylate (7.5 g.) was combined with 100 ml. of 1N sodium hydroxide and 100 ml. of ethanol and boiled in an open flask for 1 hour, by which time most of the ethanol had evaporated. The aqueous residue was diluted with 100 ml. of water and acidified with conc. hydrochloric acid to precipitate crystalline 5-benzoylpyrrole-3-carboxylic acid [6.3 g., m.p. 289°-290° C. (dec.), m/e 215].
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(C2CC2)cc1F
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (800 MHz, CDCl3): δ 0.68-0.73 (2H, m), 0.99-1.04 (2H, m), 1.86-1.92 (1H, m), 5.24 (2H, s), 5.80 (1H, d, J=4.0 Hz), 6.78 (1H, dd, J=4.0 Hz, 23.2 Hz), 6.88 (1H, dd, J=3.2 Hz, 16.0 Hz), 7.30-7.34 (1H, m), 7.39 (1H, dd, J=1.6 Hz, 9.6 Hz), 7.57 (1H, d, J=3.2 Hz), 8.00 (1H, s), 8.69 (1H, d, J=9.6 Hz). [M+H] Calc'd for C19H15FN4O, 335; Found, 335.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8]([N:16]2[CH2:17][CH2:18][C:19](=[N:22][O:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH2:20][CH2:21]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1cnc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (0.2 g, 0.78 mmol), 2d (0.2 g, 0.71 mmol), and diisopropylethylamine (0.2 mL, 1.2 mmol) were combined in 2 mL of DMSO and stirred at 110° C. for 18 h. The mixture was cooled to room temperature, diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum to afford the crude 57a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.Br[CH2:19][O:20][CH3:21]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:19][O:20][CH3:21])[C:3]=1[F:9]
Reactant: COCBr
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 71 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50° C. After addition the solution was warmed to −20° C. and then cooled to −50° C. a solution of bromomethoxymethane (25 g, 0.200 mol) in THF (25 mL) was slowly added and the reaction mixture was warmed to ambient temperature. The reaction was quenched with water (400 mL) and extracted with diethyl ether (2×150 mL). The combined organic phases were dried (sodium sulfate) and concentrated. The residual oil was distilled (70°-75° C./0.5 mm) to give 1-bromo-4-chloro-2-fluoro-3-methoxymethylbenzene (18.0 g, 0.071 mol): 1H NMR (CDCl3): δ 7.50 (m, 1H), 7.15 (dd, 1H), 4.65 (s, 1H), 3.40 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[OH2:7].[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:28]3[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCN)C[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCNc2ncccc2C#N)C[C@H]1OC
Product: O
Temperature: 70 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
A mixture of 3.78 parts of cis-4-amino-N-[1-(4-aminobutyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.66 parts of 2-chloro-3-pyridinecarbonitrile, 1.58 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred for 24 hours at 70° C. The reaction mixture was evaporated. The residue was taken up in water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was taken up in acetonitrile. The product was filtered off and dried, yielding 1.12 parts (23%) of cis-4-amino-5-chloro-N-[1-[4-[(3-cyano-2-pyridinyl)amino]butyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate; mp. 103.4° C. (compound 40).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20](C)C.Cl.CNC1CC1>CS(C)=O>[CH:23]1([N:19]([CH3:20])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC1CC1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 4.20 mmol) in DMSO (6 mL) was added DIEA (1.35 g, 10.47 mmol), and N-methylcyclopropanamine hydrochloride (490 mg, 4.58 mmol). The solution was stirred 10 mins at room temperature and 2 h at 75° C. Then the reaction was quenched by the addition of water (100 mL) and the solids were collected by filtration to afford methyl 3-(cyclopropyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (405 mg, 35%).