Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C:19](=[CH:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[C:11](=[CH2:25])[CH2:10]3)[CH2:7][C@@H:6]1[CH3:26])[C:3](=[O:5])[CH3:4].F[C:28](F)(F)[C:29](OC(=O)C(F)(F)F)=[O:30]>C(O)(=O)C>[C:29]([O:1][C@:2]1([C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C:19](=[CH:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[C:11](=[CH2:25])[CH2:10]3)[CH2:7][C@@H:6]1[CH3:26])[C:3](=[O:5])[CH3:4])(=[O:30])[CH3:28]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Solvent: CC(=O)O
Product: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(OC(C)=O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 1 h

Procedure:
A solution of 3.3 g of 17α-hydroxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione in 40 ml of glacial acetic acid is cooled to 0° C. and stirred, after adding 15 ml of trifluoroacetic acid anhydride dropwise, for one hour at room temperature. After precipitation into ice water-sodium chloride, the mixture is filtered off and worked up as usual. The crude product is purified on 450 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus obtaining 2.3 g of 17α-acetoxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione, mp 197°-198° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]([NH2:24])([CH3:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]([NH:24][C:10](=[O:12])[CH2:9][CH:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)([CH3:22])[CH3:23])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: COc1cccc(C(C)(C)N)c1
Product: COc1cccc(C(C)(C)NC(=O)CC2CN3CCC2CC3)c1
Yield: 39.8 %

Procedure:
Using general procedure I, 2-(quinuclidin-3-yl)acetic acid (169 mg, 1.00 mmol) and 2-(3-methoxyphenyl)propan-2-amine (182 mg, 1.10 mmol) gave the title compound as a white solid (126 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.71 (dd, J=8.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.31-3.42 (m, 2H), 3.00-3.19 (m, 4H), 2.47-2.60 (m, 2H), 2.27 (dd, J=14.0, 6.0 Hz, 1H), 1.83-2.06 (m, 4H), 1.64-1.74 (m, 1H), 1.61 (d, J=12.4 Hz, 6H) ppm. 13C NMR (400 MHz, CDCl3) δ 170.0, 159.7, 149.3, 129.5, 117.5, 111.8, 111.0, 55.9, 55.4, 52.0, 50.6, 46.6, 46.0, 39.7, 30.9, 29.7, 29.1, 24.3, 18.8 ppm. Purity: 93.7% HPLCMS (210 nm); retention time 0.76 min; (M+1) 317.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[NH:14][CH:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9][CH2:10]4)=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1CCN(Cc2ccccc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCN(Cc5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-piperidin-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C(O)C>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC=Cc1cccc(OCc2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C=CCC(=O)O)c1

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-3-butenoate (Step F) in abs ethanol at low temp, add aqueous sodium hydroxide, after an hour, concentrate and purify by flash chromatography on silica gel column (chloroform:methanol 95:5 spiked with acetic acid).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:45])[NH:12][CH:13]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:22]([NH:24][N:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:22]([NH:24][N:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])=[O:45]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)N)CC1
Reaction time: 0.5 h
Yield: 102 %

Procedure:
To a solution of (1-(2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester (0.29 g, 0.46 mmol) in methylene chloride (3 ml) at 0° C. was added trifluoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol (20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.25 g of 2-amino-N-[(1R)-2-[4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide as a white amorphous powder.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=O)[N:5]=[CH:4]1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=[S:16])[N:5]=[CH:4]1)[CH3:2]
Reactant: CCc1nc2c([nH]1)c(=O)ncn2CC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)c(=S)ncn2CC
Yield: 63.7 %

Procedure:
The product of stage (i) (8.65 g) and phosphorus pentasulfide (12.0 g) was refluxed in 150 ml of pyridine for 1 hr. Under cooling 59.4 ml of 2N NaOH was added dropwise, the solid filtered off and washed with water. The filtrate was concentrated in vacuo to dryness and the residue suspended in 200 ml of water and collected. The filtrate was extracted three times with 600 ml of chloroform. The residue of the phase was combined with the solid collected (total 6.08 g), dissolved in 500 ml of chloroform and filtered through 24 g of silicagel. Fractions 2 and 3 eluted 4.63 g of crude product which was crystallized from 120 ml of methanol to give 3,8-diethyl-6-thiohypoxanthine (3.58 g) with mp (sublimation at 210° C.) 250-270° C. under decomposition. A second crop gave 0.58 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=O)C.[H][H]>[Pt].C(O)(C)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Yield: 73 %

Procedure:
A solution of 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine (120 g), acetic acid (300 mL), isopropyl alcohol (300 mL), and 5% platinum on carbon (7.2 g) was allowed to stand at room temperature for 30 h under 2 bars of hydrogen pressure. The resulting solution was filtered, and the solvent was removed from the filtrate at reduced pressure. The residue was dissolved in aqueous hydrochloric acid (1 L, 4N). The product was precipitated by adding this solution to a solution of sodium hydroxide. The precipitate was filtered and washed with water to afford the product 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine in 73% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25])[C:19]([Cl:30])=[CH:18][N:17]=1>>[Cl:30][C:19]1[C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: CC(C)[C@H](Nc1nc(Cl)ncc1Cl)C(N)=O
Product: CC(C)[C@H](Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl)C(N)=O

Procedure:
Following a procedure analogous to Example 1742a, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and (S)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide were converted to (S)-2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-methyl-butyramide, HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.51 (dd, 1H), 7.39 (m, 2H), 4.52 (m, 3H), 3.41 (s, 3H), 3.11 (t, 2H), 2.32 (m, 1H), 1.08 (d, 3H), 1.02 (d, 3H); MS (m/e) 419 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].[NH4+:21].[OH-]>CO.CCO>[NH2:21][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(S(=O)(=O)c2cccc(F)c2C#N)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1cccc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C

Procedure:
To a solution of 0.7 g (2.4 mmol) of 2-fluoro-6-[(3-methoxyphenyl)sulfonyl]benzonitrile (Example 14) in 110 ml of MeOH/EtOH (7:4) was added 20 mL of concentrated NH4OH, This mixture was sealed in a glass-lined bomb and heated at 130° C. for 3 h. After solvent removal, the resultant concentrate was purified by flash column chromatography on silica gel with 5% MeOH in methylene chloride as the eluent. This resulted in 0.16 g (23%) of 2-amino-6-[(3-methoxyphenyl)sulfonyl]benzonitrile as a solid: mp 186°-191° C.; NMR (Me2SO-d6, 200MHz) δ 3.82 (s, 3H), 6.6 (br s, 2H), 7.1 (apparent d, 1H), 7.2-7.7 (m, 6H); mass spec (CI) 289 (M+ +1, 100%). Anal. Calc. for C14H12N2 O3S: C, 58.32; H, 4.20;N, 9.72; S, 11.12. Found: C, 58.13; H, 4.17; N, 9.51; S, 10.95.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and benzyl isocyanate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[S:20]([O:1][CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Commercially available (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (1.8 g, 9.61 mmol) in pyridine was treated with p-toluenesulfonyl chloride (1.83 g, 9.61 mmol). The reaction mixture was stirred at room temperature for 20 h then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water (3×75 mL) and then dried (MgSO4), filtered, and concentrated in vacuo to afford the titled compound. MS (DCI) m/z 342 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:45])[CH2:40][CH2:41][CH2:42][NH:43][CH3:44]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH2:42][CH2:41][CH2:40][N:39]([CH3:45])[CH3:38])[CH3:44])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNCCCN(C)C
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N,N′-trimethyl-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.70 (m, 2 H), 2.04 (m, 2 H), 2.20 (s, 6 H), 2.36 (s, 3 H), 2.89-3.21 (m, 3 H), 3.36-3.70 (m, 2 H), 6.36 (d, J=8.4 Hz, 1 H), 7.16 (m, 1 H), 7.27 (m, 2 H), 7.50 (m, 2 H), 7.59 (m, 2 H), 8.01 (s, 1 H), 8.13 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:15]#[N:16])[CH:22]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2cc(-c3ccccc3)nc(Cl)n2)c1

Procedure:
2-chloro-4-(3-cyanophenyl)-6-phenylpyrimidine was synthesized by the same method as in syntheses of 2,4-dichloro-6-phenylpyrimidine in the above (4-1-1), except that 2,4-dichloro-6-phenylpyrimidine was used in place of 2,4,6-trichloropyrimidine and that 3-cyanophenylboronic acid was used in place of phenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:29][CH2:30][CH2:31][CH2:32]O>>[Br:29][CH2:30][CH2:31][CH2:32][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: OCCCBr
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCCCBr

Procedure:
Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-bromo-1-propanol (Aldrich), the title compound was prepared as a solid (mp=138-142° C.). The reaction was monitored by tlc (Rf=0.75 in 60% EtOAc/hexanes) and the product was purified by flash column chromatography using 60% EtOAc/hexanes as the eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:29])[CH2:24]C(OC)=O)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CCCCCCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:24]2[O:10][N:9]=[C:7]([C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:8]=2)=[O:29])=[CH:18][CH:17]=1
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)Cc1ccc(OC)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)c2nc(-c3cccc([N+](=O)[O-])c3)no2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
In a 100 ml flask, place 5 g (0.0276 m) of 3-nitrobenzamidoxime (9a), 8.6 g (0.0414 m) of methyl p-methoxyphenyacetoacetate (10c; R1=p-methoxyphenyl), and 50 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 14 hrs. Cool the reaction mixture to room temperature, add 40 ml of heptane and stir for 30 min. Collect solid, wash with heptane, and dry in air to give 8.4 g (85%) of 5-(p-methoxyphenyl)acetyl-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=p-methoxyphenyl and R2=3-nitrophenyl].
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[C:14]=[S:15]>>[OH:4][CH2:3][CH:2]([NH:1][C:14]([NH:13][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(N)CO)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: COc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(C(F)(F)F)cc4)n3)cc2)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-methoxyphenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.42 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.1 Hz, 3H), 6.76 (d, J=8.3 Hz, 2H), 6.66 (s, 3H), 6.30 (d, J=8.2 Hz, 3H), 5.19-5.01 (m, 1H), 3.50-3.23 (m, 2H), 3.20 (s, 3H); ESIMS m/z 514 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[OH-].[NH4+:17]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12]([NH2:17])=[O:13])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)CC1CC(=O)c2ccc(F)cc21
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)CC1CC(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride (prepared from 0.024 mol of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid) in dichloromethane (150 ml) was cooled to 0C and stirred rapidly while 50 ml of ammonium hydroxide, 28-30%, was added. The resulting mixture was allowed to warm to room temperature and stirring was continued for 18 hr. The volatiles from this mixture were removed by spin evaporation in vacuo and the residue was dissolved in dichloromethane (250 ml) and washed with water (3×50 ml). The dichloromethane phase was then slurried with Silica Gel 60 and the volatiles were removed by spin evaporation in vacuo. This silica was then applied to a column of Silica Gel 60 (51×400 mm) wet with dichloromethane and the product was removed by elution with methanol:dichloromethane (3:97) to give, after recrystallization from methanol, 2.4 g (48%) of 2-(6-fluoro-3-oxo-1-indanyl)acetamide as a yellow solid: m.p., 150°-152° C.;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:23]=1.Br[CH2:25][CH2:26][CH2:27][C:28]#[N:29]>C(#N)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:23]=1
Reactant: N#CCCCBr
Reactant: Fc1ccc2c(N3CCCNCC3)csc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Yield: 42.8 %

Procedure:
Add potassium carbonate (39.3 g, 284 mmol) to a solution of 1-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepane (Example 4) (23.7 g, 95 mmol) and 4-bromobutyronitrile (21.0 g, 142 mmol) in acetonitrile (400 mL) and stir the mixture under reflux for 10 h. Filter the mixture, evaporate the solvent, and dissolve the residue in ethyl acetate (EtOAc). Wash with water and saturated sodium chloride solution, and dry the organic phase over MgSO4. Evaporate the solvent under vacuum, and purify the crude product by column chromatography (EtOAc/MeOH 9:1) to give 12.9 g of a yellow oil LC/MS, (LiChrospher 5μ, RP-18, 250 mm
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCC1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(NCC2CCCN2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
Pyrrolidin-2-ylmethylamine (527 mg) in dichloromethane (10 mL) was treated with triphenylmethyl chloride (1.47 g) and triethylamine (1.5 mL), stirred for 3 hours, treated with dichloromethane, washed with water, saturated NaHCO3, and water, and concentrated. The concentrate was flash chromatographed on silica gel with a gradient of 3%-10% methanol in 99:1 dichloromethane/triethylamine. 1H NMR (DMSO-d6) δ 7.4 (m, 6H), 7.3 (m, 6H), 7.2 (m, 3H), 3.2 (m, 1H), 2.8-2.5 (m, 2H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H), 1.5 (m, 2H), 1.2 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].C(O[C:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[N:21]4[C:25]([C:26](=[O:27])[C:14]([C:15]=23)=[CH:13][N:12]=1)=[CH:24][CH:23]=[C:22]4[N+:28]([O-:30])=[O:29])C>CN(C)C=O>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[N:21]4[C:25]([C:26](=[O:27])[C:14]([C:15]=23)=[CH:13][N:12]=1)=[CH:24][CH:23]=[C:22]4[N+:28]([O-:30])=[O:29]
Reactant: NCCNCCO
Reactant: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Solvent: CN(C)C=O
Product: O=c1c2cnc(NCCNCCO)c3cccc(c32)n2c([N+](=O)[O-])ccc12
Yield: 85.5 %

Procedure:
N-(2-Hydroxyethyl)ethylenediamine (1.77 g) is added all at once to a solution, stirred and heated to 70° C., of 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (5 g) in dimethylformamide (200 cc). The red solution thus obtained is allowed to return to ambient temperature (about 20° C.) in the course of 2 hours. A suspension of red crystals is thus obtained, to which distilled water (200 cc) is added. The crystals are filtered off and then washed with water (3 × 10 cc). After drying under reduced pressure (1 mm Hg) at 24° C., brick-red crystals of crude 4-[2-(2-hydroxyethylamino)ethylamino]-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (5.08 g) are obtained.