Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5](OCC)=[O:6].[C-]#N.[Na+]>CO>[C:10]1([C@@H:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC[C@@H](N)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: O=C1CC[C@H](c2ccccc2)N1
Temperature: 55 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a stirred solution of ethyl 4(R)-amino-4-phenylbutyrate (515 mg, 2.48 mmol) in 20 mL of anhydrous methanol was added sodium cyanide (25 mg, 0.5 mmol) at room temperature. The reaction mixture was stirred at 55° C. for 4 h, cooled to room temperature, concentrated under reduced pressure. The residue was taken up in methylene chloride, washed with water, brine, dried over anhydrous MgSO4, concentrated to afford 391 mg of product (98% yield) as a colorless crystal, mp 103-105° C. (lit.17 102-104° C.). 1H NMR (CDCl3) δ 1.80-1.95 (m, 1H), 2.27-2.42 (m, 2H), 2.45-2.58 (m, 1H), 4.709 (t, 1H, J=7.2 Hz), 7.22-7.38 (m, 5H), 7.425 (br, 1H); 13C NMR (CDCl3) δ 30.19, 30.93, 57.91, 125.34, 127.46, 128.56, 142.43, 178.85.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH:19]=O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH2:19][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1COCCN1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C=O)CCOCC3)cc2C2=CCCCC2)n1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(CN4CCOCC4)CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-formyl-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in the previous step, 30.5 mg, 0.0754 mmol), morpholine (14 μL, 0.15 mmol) and sodium borohydride (6.0 mg, 0.16 mmol) in 2 mL of 1:1 DCM/THF was stirred at RT for 3 h. The mixture was then treated with saturated NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (10-30% EtOAc/DCM) to afford the title compound (28 mg, 77%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.61 (s, 1H), 9.66 (s, 1H), 8.31 (d, 1H, J=8.6 Hz), 7.76 (s, 1H), 7.28 (dd, 1H, J=8.6, 2.3 Hz), 7.17 (d, 1H, J=2.3 Hz), 5.86 (m, 1H), 3.79 (m, 2H), 3.59 (m, 2H), 3.53 (m, 4H), 2.45 (s, 2H), 2.29 (m, 4H), 2.13-2.21 (m, 6H), 1.77-1.98 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H33N5O3, 476.3 (M+H). found 476.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.7 %

Procedure:
To a solution of 2-(1-benzylpiperidin-4-ylamino)-5-methylpyridine (11.3 g) in ethanol (250 mL) was added 20% palladium hydroxide (4 g). After stirring the solution at room temperature under hydrogen atmosphere for 48 hours, 20% palladium hydroxide (2 g) was further added. The solution was then stirred at room temperature under hydrogen atmosphere for additional 99 hours. The catalyst was filtered off. After concentration under reduced pressure, the resulting residue was purified by chromatography [NH silica gel, chloroform:methanol=10:1]. The resulting crude product was crystallized from ethyl acetate/hexane to give the title compound (5.97 g).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.C(OC([N:21]1[C@H:25]([CH3:26])[CH2:24]OS1(=O)=O)=O)(C)(C)C>>[CH2:13]1[C:3]2=[C:2]([CH2:24][C@H:25]([NH2:21])[CH3:26])[C:10]3[CH:9]=[N:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12]1
Reactant: Brc1c2n(c3ccncc13)CCC2
Reactant: C[C@@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Product: C[C@@H](N)Cc1c2n(c3ccncc13)CCC2

Procedure:
By the same general procedure as in example 3(R)-2-(2,3-Dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine was obtained from 8-Bromo-2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]indene and (R)-4-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:21](C)[N:22]=[C:16]2[CH2:15]1)=[O:13].[Cl-].[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[NH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: Cn1nc2c(c1-c1ccc(F)cc1)CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(n[nH]c2-c2ccc(F)cc2)C1
Temperature: 170 °C
Yield: 19.3 %

Procedure:
To a vial containing 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (50 mg, 0.11 mmol) was added pyridinium chloride (270 mg, 2.30 mmol). The vial was flushed with N2 and heated to 170° C. for 30 min in a microwave reactor. To the reaction was added EtOAc and 1M NaOH. The layers were separated and the water layer was extracted with EtOAc three times. The combined organic layers were concentrated in vacuo and the residue was purified by HPLC (Gilson prep system, inertsil ODS-3, C18, 3 μm 30×100 mm column at 45° C., gradient of 5-70% MeCN/water with 0.05% TFA over 7 min, flow rate of 80 mL/min). The product was isolated as orange oil (9 mg, 19%) MS (ESI): mass calcd. for C20H14ClF4N3O, 423.8. m/z found, 424.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.82-7.69 (m, 1H), 7.58-7.38 (m, 4H), 7.18-7.13 (m, 2H), 5.01 (m, 1H), 4.48-4.39 (m, 1H), 4.30-3.87 (m, 1H), 3.60-3.40 (m, 1H), 2.94 (t, J=5.8 Hz, 1H), 2.86-2.65 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[CH3:14][S:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>CN(C)C=O>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CNCc1ccc(CSCCN)o1
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Yield: 26.6 %

Procedure:
A solution of 2-[[5-[(methylamino)methyl]-2-furanylmethyl]thio]ethanamine (6.0 g) and 1,1-bis-(methylthio)-2-nitroethene (19.8 g) in dry dimethylformamide (150 ml) was stirred for 1 hour at 0° and for 5 hours at room temperature. A solution of oxalic acid (4.0 g) in dry dimethylformamide (16 ml) was added and the solid which formed during 18 hours was filtered, washed with dimethylformamide, ethanol and ether and dried. The solid was suspended in water (200 ml) at 55° and on cooling was filtered, washed with water and dried to give the title compound (3.25 g) m.p. 158°-160° dec.
Reaction SMILES: FC1C=CC([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[N:11][N:10](C(C)C)[C:9]2=[O:21])=CC=1.S(=O)(=O)(O)O.C(OC(C1C(=O)N(C2C=CC(F)=CC=2)C(=O)N(C(C)C)N=1)=O)C.[Na+].[Cl-]>O>[O:21]=[C:9]1[NH:8][C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[N:11][NH:10]1
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Agent: CCOC(=O)c1nn(C(C)C)c(=O)n(-c2ccc(F)cc2)c1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1n[nH]c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylic acid. Sulfuric acid (10 mL, 200 mmol) was carefully added to a mixture of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester (1100 mg, 3.4 mmol) and water (2 mL). The mixture became homogenous after a few minutes. The reaction mixture was stirred at 40° C. overnight, was cooled to rt and was carefully added to ice. The mixture was saturated with solid NaCl and was extracted repeatedly from EtOAc (3×). The combined EtOAc layer was washed with brine, dried over magnesium sulfate, and concentrated to give the product as foam (100%). LCMS m/z=294 (M+1); 1H NMR (Methanol d4) δ: 7.35-7.31 (2 m, 4H), 4.95 (m, 1H), 4.31 (q, 2H, J=7.0 Hz), 1.41 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][O:5][C:6]([C:8]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:12][C:13]=1[CH3:14])=[O:7]>C(O)C>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][O:5][C:6](=[O:7])/[CH:8]=[C:13](\[NH2:12])/[CH3:14]
Reactant: CC1=C(C(=O)OCc2ccccc2Cl)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1Cl
Yield: 73 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 2-chlorobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 2-chlorobenzyl ester of melting point 103° C (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:17]([C@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:12]2)=[O:19])=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccc(F)cc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(F)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.264 mmol) in N,N-Dimethylformamide (DMF) (4 ml) was added ({[4-fluoro-2-(trifluoromethyl)phenyl]methyl}amine (0.051 g, 0.264 mmol) followed by diisopropylethylamine (0.101 ml, 0.580 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.128 g, 0.290 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (82 mg, 0.148 mmol, 56%). MS (ES) m/e 441 [M+H]+. 1H NMR (400 MHz, DMSO-D6) □ 7.6 (bs, 1H), 6.8 (m, 1H), 6.7 (m, 1H), 6.5 (m, 1H), 3.8 (m, 2H), 3.3 (m, 1H), 2.2 (s, 3H), 2.2-2.1 (m, 1H), 1.7-1.6 (bm, 1H), 1.5 (s, 3H), 1.3-1.1 (bm, 4H), 0.8-0.5 (bm, 4H)
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].Br[Mg][CH:25]=[CH2:26]>O1CCCC1.C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:12]([N:8]2[CH2:7][C@H:6]([C:4](=[O:5])[CH:25]=[CH2:26])[CH2:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: -66 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R)-N-methoxy-1-[(1R)-1-(4-methoxyphenyl)ethyl]-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (15 g, 48.96 mmol, 1.00 equiv) in tetrahydrofuran (150 mL), followed by the addition of bromo(ethenyl)magnesium in THF (1 M) (147 mL, 3.00 equiv) dropwise with stirring at −66° C. The resulting solution was stirred at −66° C. for 3 h, poured into 250 mL of water/ice and diluted with 250 mL of ethyl acetate. The resulting solution was extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(prop-2-enoyl)pyrrolidin-2-one 1.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])[C:26]([Cl:44])=[CH:25][N:24]=1>>[Cl:44][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.072 g, 61%). MP: 68-88° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.42 (s, 1H), 8.54 (d, 1H, J=8.3 Hz), 8.13 (s, 1H), 7.97 (s, 1H), 7.93 (d, 1H, J=7.8 Hz), 7.55 (t, 1H, J=7.7 Hz), 7.47 (s, 1H), 7.21 (t, 1H, J=7.7 Hz), 6.65 (s, 1H), 3.86 (s, 3H), 3.58-3.50 (m, 2H), 3.48-3.40 (m, 2H), 3.33 (s, 6H), 3.29-3.23 (m, 4H), 3.07-2.98 (m, 1H), 2.87-2.75 (m, 6H), 2.74-2.68 (m, 2H). MS: 631.25 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl>O>[Cl:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:7]=1[C:8]([NH:1][CH2:2][CH2:3][OH:4])=[O:9]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: NCCO
Agent: Cl
Solvent: O
Product: O=C(NCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
2-Aminoethanol (2.9 g, 47 mmol) in 5 mL of water was added in one portion to a solution of crude 2-chloro-3,5-dinitrobenzoic acid chloride [prepared from 2-chloro-3,5-dinitrobenzoic acid 11 (5.0 g, 18.3 mmol) with SOCl2] in Me2CO (50 mL) while cooling in an ice-bath. The mixture was stirred for 30 min, then acidified with 1N HCl to pH4-5 and concentrated under reduced pressure to remove the Me2CO. EtOAc (100 mL) was added, and after 2 h a white solid was collected, washed with EtOAc and air-dried to give 2-chloro-3,5-dinitro-N-(2-hydroxyethyl)benzamide (12b) (3.0 g, 36%):
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].N1C=CC=CC=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:18](=[O:21])[CH2:19][CH3:20])=[O:6]
Reactant: CCC(=O)Cl
Reactant: NNC(=O)c1cccc(I)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(=O)NNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 65.8 %

Procedure:
3-Iodobenzohydrazide (500 mg, 1.91 mmol) obtained in Step 1 was dissolved in DMF (3.8 mL), and the mixture was stirred at room temperature for 10.5 hours after adding pyridine (0.231 mL, 2.86 mmol) and propionyl chloride (0.183 mL, 2.10 mmol) at 0° C. Water was added to the mixture, stirred, and the precipitated solid was filtered off and dried to give 3-iodo-N′-propionylbenzohydrazide (400 mg, 66%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:22])([C:18]([F:21])([F:20])[F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([CH3:23])[C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[Br:30][C:31]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34].CN(C)C(=O)C>O1CCCC1>[CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:22])([C:18]([F:19])([F:20])[F:21])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])[CH:7]=[C:6]([CH3:23])[C:4]=1[NH:5][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:39]([N+:40]([O-:42])=[O:41])[C:31]=1[Br:30])[CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Br
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of 2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylaniline (preparation as described in WO 08/074427) (106 mg, 0.3 mmol) in tetrahydrofuran (0.5 ml) was added pyridine (72.6 μl, 0.9 mmol) at 0 to 5° C. A solution of 2-bromo-3-nitrobenzoic acid chloride (87 mg, 0.33 mmol) in tetrahydrofuran (0.5 ml) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then at reflux for 15 hours. After 15 hours, the reaction was not complete so N,N-dimethylacetamide (“DMA”) (0.1 equivalents) and more 2-bromo-3-nitrobenzoic acid chloride (0.2 equivalents) were added. The reaction mixture was stirred at ambient temperature for 41 hours. After 41 hours, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (10 ml) and the mixture extracted twice with ethyl acetate (2×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 6:1) to give N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-bromo-3-nitrobenzamide (0.133 g, 76% yield).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:36])[C:7]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:8][CH2:9][CH2:10][C:11](=[O:28])[CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([O:18]CC)=[O:17])C>O.C(O)C>[CH3:27][C:15]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH2:14][CH2:13][CH2:12][C:11](=[O:28])[CH2:10][CH2:9][CH2:8][C:7]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:6]([OH:36])=[O:5])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(CCCC(=O)CCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCC(=O)CCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Yield: 31.3 %

Procedure:
To a homogenous solution of KOH (85%, 7.17 g, 108.90 mmol) in water (15 mL) and ethanol (45 mL) was added 2,10-dimethyl-6-oxo-2,10-diphenyl-undecanedioic acid diethyl ester (14.5 g, 31.12 mmol). The reaction solution was heated to reflux for 6 h. The ethanol was removed in reduced pressure and the residue was diluted with water (300 mL). The solution was acidified with concd. HCl (18 mL) to pH 1 and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/20, 1/10, 1/2) to furnish 2,10-dimethyl-6-oxo-2,10-diphenyl-undecanedioic acid (4 g, 31.4%) as a white solid. Mp.: 44-46° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 10.25 (br, 2H), 7.35-7.22 (m, 10H), 2.32 (m, 4H), 1.94-1.86 (m, 4H), 1.57 (s, 6H), 1.51-1.22 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 210.64, 182.66, 142.69, 128.66, 127.18; 126.29, 50.07, 42.97, 38.62, 22.20, 19.11. HRMS (LSIMS, nba): Calcd. for C25H31O5 (MH+): 411.2171, found: 411.2144.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=2[F:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=2[CH3:15])=[CH:18][CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Product: Cc1c(N(Cc2ccc(OCc3ccccc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]

Procedure:
The product from Example 33A and benzyl bromide were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]1[N:33]=[CH:34][O:35][CH:36]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]4[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]4)=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]1[N:33]=[CH:34][O:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ncc3c2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)c(-c2cocn2)c1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(cnn3S(=O)(=O)c3ccc(F)c(-c4cocn4)c3)c2)C1

Procedure:
This compound was prepared from tert-butyl 3-(1H-indazol-5-yl)azetidine-1-carboxylate and 4-fluoro-3-(oxazol-4-yl)benzene-1-sulfonyl chloride by analogy to the method outlined in example 44.c, below).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:21])[CH:10]=[C:11]([CH2:16][CH2:17][C:18]([NH2:20])=O)[C:12]=2[O:14][CH3:15])[N:7]([CH2:22][CH3:23])[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:21])[CH:10]=[C:11]([CH2:16][CH2:17][CH2:18][NH2:20])[C:12]=2[O:14][CH3:15])[N:7]([CH2:22][CH3:23])[CH:6]=1
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(N)=O)cc(F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cc(CCN(C)C)c2c(OC)c(CCCN)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
To a solution of 28-3 (100 mg, 0.28 mmol) in THF (10 mL) was added lithium aluminum hydride (44 mg, 1.15 mmol) in portions. The mixture was stirred at room temperature overnight. NaSO4.10H2O was added, then the mixture was filtered and the filtrate was evaporated. The crude product was purified by preparative HPLC (acid conditions) to afford 28-4 (10 mg, 11%) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm) 6.83 (s, 1H), 6.66 (d, J=6.6 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.04 (t, J=7.2 Hz, 2H), 2.77-2.69 (m, 6H), 2.62-2.60 (br.s, 2H), 2.40 (s, 6H), 1.85-1.78 (m, 2H), 1.42 (t, J=6.8 Hz, 3H). LRMS: calc 321.4 and found: 322.0 [M+1].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[C:17]([Cl:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C@H:3]1[CH3:23].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[Cl:21])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][CH2:8][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[C@@H:3]1[CH3:23])=[O:22]
Reactant: O=C1CCOCC1
Reactant: C[C@H]1[C@H](N)CCN1C(=O)CNc1ncnc2cc(Cl)c(Cl)cc12
Product: C[C@H]1[C@H](NC2CCOCC2)CCN1C(=O)CNc1ncnc2cc(Cl)c(Cl)cc12

Procedure:
2-(6,7-Dichloroquinazolin-4-ylamino)-1-((2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-4-ylamino)pyrrolidin-1-yl)ethanone was synthesized from 1-((2S,3R)-3-Amino-2-methylpyrrolidin-1-yl)-2-(6,7-dichloroquinazolin-4-ylamino)ethanone and dihydro-2H-pyran-4(3H)-one using general procedure E. RP-HPLC (Table 1, Method a) Rt 1.52; m/z: (M+H)+ 438.