Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([O:13][CH2:14][CH2:15][C:16]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(O)[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:36](#[N:38])[CH3:37]>>[CH2:6]([O:13][CH2:14][CH2:15][C:16]([NH:38][C:36](=[O:2])[CH3:37])([CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: O=S(=O)(O)O
Reactant: OC(CCOCc1ccccc1)(CCOCc1ccccc1)CCc1ccccc1
Product: CC(=O)NC(CCOCc1ccccc1)(CCOCc1ccccc1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sulfuric acid (4.2 g) was added to a solution of 1,5-dibenzyloxy-3-(2-phenylethyl)-3-pentanol (5.8 g) in acetonitrile (50 ml) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=7:3) to give the subject compound (2.2 g) as a yellowish oily substance.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([F:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[F:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: CC(F)c1ncnc(Cl)c1I
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(F)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-fluoro-ethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [B:1](Cl)(Cl)[Cl:2].[C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[Cl-:2].[Cl-:2].[C:12]1([N:11]([BH2:1])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClB(Cl)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: ClCCl
Product: BN(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: -70 °C
Yield: 27.7 %

Procedure:
To a solution of boron trichloride (4.5 g) in methylene chloride (3 ml), a solution of diphenylamine (6.5 g) in methylene chloride (12 ml) is added with cooling at -70° C., and the resultant mixture is stirred for 1 hour. The precipitated crystals are filtered at room temperature, washed with benzene, mixed with benzene (10 ml), and refluxed for 20 hours. After cooling, the reaction mixture is filtered to remove the insoluble material and evaporated under reduced pressure to remove the solvent. The residue is distilled under reduced pressure to give diphenylaminoborane dichloride (1.34 g) as an oil boiling at 117° to 120° C./0.9 mm Hg. M.P. 65°-69° C. [Gerrard, et al., J. Chem. Soc., 5168 (1960)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[NH2:19][C@H:20]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[C:38]([CH2:44][CH3:45])[CH:37]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[O:22]>>[N:29]1([CH:26]2[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C@H:20]([NH:19]/[C:4](=[N:7]/[C:8]#[N:9])/[N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:13][CH2:12][C:11]5[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=5[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH2:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[C:38]([CH2:44][CH3:45])[CH:37]=3)[CH2:24][CH2:25]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 73 from 3-piperidin-4-yl-1,3,4,5-tetrahydrobenzo[d][1,3]diazepin-2-one and (R)-2-amino-1-[1,4′]bipiperidinyl-1′-yl-3-(3,4-diethylphenyl)-propan-1-one
Reaction SMILES: C(OC)(=O)C(C)=C.C(O)(=O)C(C)=C.CN([C:17]1[CH:18]=[CH:19][C:20]([C:23]([C:25]2[CH:26]=[CH:27][C:28](N(C)C)=[CH:29][CH:30]=2)=[O:24])=[CH:21][CH:22]=1)C>C(OCCO)C>[C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC
Solvent: CCOCCO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2.5 g of a 9:1 copolymer of methyl methacrylate and methacrylic acid, 3.50 g of Epocryl® DRH 303, 0.24 g of 2-(o-chlorophenyl)-4,5-diphenylimidazolyl dimer, and 0.06 g of Michler's ketone was dissolved in 25.20 g of 2-ethoxyethanol (Solution A). Solutions B, C and D were prepared by varying the quantities of Michler's ketone and 2-ethoxyethanol as follows:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH2:20][CH3:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[CH:13]=[C:12]([CH2:20][CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#Cc1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(CC)sc1N
Product: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 3-cyanopyridine and 2-amino-5-ethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C1N=C[N:17](C(N2C=NC=C2)=O)[CH:16]=1.CN.C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([NH:17][CH3:16])=[O:14]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A mixture of (2,4-dimethoxyphenyl)acetic acid (577 mg, 3.0 mmol) and N,N-carbonyldiimidazole (608 mg, 3.75 mmol) in DMF (10 mL) was stirred at room temperature for 45 min, aqueous 40% methyl amine (4.5 mL) was added and the reaction mixture was stirred at room temperature over the week-end. The reaction mixture was is partitoned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum spirit) to give the subtitled compound (460 mg).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:4]=2[N:3]=1.[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([O:28][CH3:29])[CH:21]=1.CN1CCCC1=O>O>[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:4]=3[N:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: COc1cc(Cl)cc(C)c1N
Reactant: CCC(CC)c1ccc(OC)c2nc(Cl)n(C)c12
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(OC)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 55.3 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole (120 mg, 0.450 mmol), 4-chloro-2-methoxy-6-methylaniline (231 mg, 1.35 mmol) and 1-methyl-2-pyrrolidone (0.5 mL) was stirred at 130° C. for 2 days under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (100 mg, 55%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].Cl[CH2:21][P:22](=[O:25])([CH3:24])[CH3:23]>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:21][P:22](=[O:25])([CH3:24])[CH3:23])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: CP(C)(=O)CCl
Product: CCCCn1cnc2c1c(=O)n(CP(C)(C)=O)c(=O)n2CCCC

Procedure:
The title substance was prepared from 5 g (0.0189 mol) of 3,7-dibutyl-xanthine and 2.9 g (0.0227 mol) of chloromethyldimethylphosphine oxide analogously to Example 67.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[S:21][C:20]([C:22](O)=O)=[CH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl-].[Cl-].[NH2:39][C:40]1[C:48]([NH2:49])=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43]>N1C=CC=CC=1.CN(C=O)C>[C:42]([C:41]1[C:40]2[N:39]=[C:22]([C:20]3[S:21][C:17]([CH:12]4[CH2:13][CH2:14][CH2:15][CH2:16][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:18][CH:19]=3)[NH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1)(=[O:43])[NH2:44]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(C2CCCCN2C(=O)OCc2ccccc2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4C(=O)OCc4ccccc4)s3)nc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 28D (0.35 g) in pyridine (10 mL) and DMF (10 mL) was added CDI (0.23 g), and the mixture was heated at 40° C. for 1 hour. 2,3-Diaminobenzamide dichloride (0.22 g) was added, and the mixture stirred at ambient temperature overnight and concentrated. The concentrate was stirred in acetic acid (20 mL) at 80° C. for 4 hours and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The extract was washed with water and concentrated, and the concentrate was flash chromatographed on silica gel with 40-80% ethyl acetate in hexane.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=O)([O-])[O-].[Cs+].[Cs+].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.O>CN(C=O)C>[CH3:8][C:19]1[C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
A solution of phenol (0.30 g, 3.1 mmol) in DMF (10 mL) was treated with cesium carbonate (1.41 g, 4.3 mmol) and stirred for 15 min. 2-Chloro-5-nitro pyridine (0.5 g, 2.9 mmol) was added, and the reaction mixture was stirred and monitored via TLC. After the reaction was complete, the reaction mixture was treated with water, extracted into EtOAc, and the organic extract washed with 1N NaOH and brine, dried (Na2SO4) and concentrated to yield 4-methyl-5-nitro-2-phenoxypyridine as a solid.
Reaction SMILES: [CH3:1][N:2]([N:6]1[CH:10]=[N:9][N:8]=[C:7]1[N:11](C(=O)C)[N:12]=[CH:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])C(=O)C>C(O)(=O)C.Cl.O>[ClH:20].[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:13]=[N:12][NH:11][C:7]1[N:6]([NH:2][CH3:1])[CH:10]=[N:9][N:8]=1
Reactant: CC(=O)N(N=Cc1c(Cl)cccc1Cl)c1nncn1N(C)C(C)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CNn1cnnc1NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 6.2 g of 4-(N-Methylacetamido)-3-[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole in 50 ml of acetic acid, 50 ml of concentrated hydrochloric acid and 50 ml of water is heated at reflux overnight. The solution is evaporated and the residue is recrystallized from ethanolisopropyl ether.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4][C:5]1=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)oc(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a solution of isatoic anhydride (8.16 g, 50.0 mmol) in DMF (100 mL) was added sodium hydride (66% in oil, 2.00 g, 55 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 10 min. 1-Iodobutane (8.5 mL, 75 mmol) was added to the obtained mixture and the mixture was stirred at room temperature for 64 hr. Ice water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure to give the title compound (10.5 g), which was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH2:31][S:32][CH3:33])[CH:30]=1)[NH:27][CH:26]=[CH:25]2>C(#N)C.N1CCCC1C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:25]2[C:24]3[C:28](=[C:29]([CH2:31][S:32][CH3:33])[CH:30]=[C:22]([F:21])[CH:23]=3)[NH:27][CH:26]=2)[CH:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
0.70 g (4.41 mmol) of 4-chloro-2-fluorobenzaldehyde, 0.64 g (4.41 mmol) of Meldrum's acid and 24 mg (0.21 mmol) of D,L-proline were added to a solution of 1.00 g of the compound of Example 11A with a purity of 82% (4.20 mmol) in 35 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.20 g of the title compound were obtained with a purity of 71% (78% of theory) and were reacted without further purification.
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[O:18][CH3:19])(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CCSC)N.CCN=C=NCCCN(C)C.[CH3:42][O:43][C:44](=[O:67])[C@H:45]([CH2:63][CH2:64][S:65][CH3:66])[N:46](C(=O)C1C=CC(N)=CC=1)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>>[CH3:42][O:43][C:44](=[O:67])[C@H:45]([CH2:63][CH2:64][S:65][CH3:66])[N:46]([C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH2:8])=[C:10]([O:18][CH3:19])[CH:11]=1)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c(OC)c1
Yield: 57.2 %

Procedure:
N-BOC-4-amino-3-methoxybenzoic acid (0.35 g, 1.31 mmol) was reacted with methionine methyl ester hydrochloride (0.9 g, 1.43 mmol) using EDCI as in N-BOC-4-aminobenzoyl methionine methyl ester. After recrystallization from ethyl acetate and hexanes, 0.36 g (57.2%) of pure product was obtained. mp 163-165° C.; 1H NMR (CDCl3) 1.53 (9H, s), 2.09-2.18 (4H, m), 2.23-2.35 (1H, m), 2.60 (2H, t, J=6.9 Hz), 3.80 (3H, s), 3.93 (3H, s), 4.92 (1H, br s), 6.93 (1H, d, J=7.6 Hz), 7.25 (1H, m), 7.31 (1H, d, J=10.2 Hz), 7.44(1H, s), 8.15(1H, d, J=8.5 Hz); 13C NMR (CDCl3) 15.47, 28.23, 30.09, 31.48, 52.06, 52.54, 55.81, 80.82, 98.06, 109.38, 116.66, 119.31, 131.52, 147.23, 152.31, 166.57, 172.58; m/z (FAB) 413 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][C:7]=1[CH:15]=[O:16].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:8][C:7]=1[CH:15]=[O:16]
Reactant: CN(C)CCOc1ccc(B(O)O)cc1C=O
Reactant: Brc1ccccn1
Product: CN(C)CCOc1ccc(-c2ccccn2)cc1C=O
Yield: 40 %

Procedure:
General procedure G using 4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and 2-bromo-pyridine gave the title product as yellow oil in 40% yield. 1H-NMR (CDCl3) δ 10.47 (s, 1H), 8.60(dt, 1H), 8.34 (d, 1H), 8.26 (dd, 1H), 7.69-7.67 (m, 2H), 7.17-7.14 (m, 1H), 7.05 (d, 1H), 4.24 (t, 2H), 2.83 (t, 2H), 2.36 (s, 6H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=O)(C)(C)C.[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:34]1[CH:39]=CC=C[CH:35]=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH:32][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][CH3:13])[NH:8][CH2:6][C:34]([CH3:39])([CH3:35])[CH3:33])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@H](NCC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(neopentylamino)pentanoic acid from Step A for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step E of Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.00-8.03 (m, 1H), 7.43-7.45 (m, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.3 Hz, 1H), 4.40-4.45 (m, 1H), 3.60 (d, J=13.1 Hz, 1H), 3.45 (d, J=13.1 Hz, 1H), 3.20 (t, J=6.5 Hz, 1H), 2.85 (dd, J=8.8, 2.6 Hz, 1H), 2.52-2.60 (m, 1H), 2.46-2.52 (m, 1H), 2.38-2.46 (m, 2H), 2.31-2.38 (m, 2H), 2.28 (dd, J=8.8, 7.3 Hz, 1H), 2.13 (dq, J=12.1, 6.0 Hz, 1H), 1.79-1.92 (m, 2H), 1.71-1.80 (m, 1H), 1.65-1.73 (m, 1H), 1.57-1.65 (m, 1H), 1.39-1.57 (m, 3H), 0.93 (s, 9H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI−) m/z 384 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH3:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:23](=[O:29])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][N:10]([CH3:11])[C:23](=[O:29])[NH:8]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCc1c(N)cccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2c(Br)cccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-methylaminomethyl-phenylamine (1.153 g, 5.36 mmol) in CH2Cl2 (50 ml) was added NEt3 (1.5 ml, 10.76 mmol), triphosgen (555 mg, 1.87 mmol) at 0° C. The reaction was allowed to warm up to room temperature and stirred overnight. After the solvent was removed by using a rotary evaporator, the residue was partitioned between water and ethyl acetate. The organic layer was washed by H2O and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one as white solid. (650 mg, 50%) MS: (M+H)+ 241.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N+:24]([O-])=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][N:8]=1)=[O:5].CC(O)=O.[H][H]>CO.C(Cl)Cl.[Pt]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][C:11]2[N:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ncn1

Procedure:
A solution of 2-methoxy-N-(6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-yl)acetamide (400 mg, 1.13 mmol) in a mixture of MeOH and DCM and AcOH (2:2:1 v/v/v, 15 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 55 mm CatCart, 10% Pt/C, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate M1, as a brown oil (400 mg, 90% purity, 98%); Rt 3.57 min (Method 1 basic); m/z 325 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25](Br)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][S-:43].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[S:43][CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(Br)C2CCCCC2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(bromo-cyclohexyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine (26 mg; 0.039 mmol) in THF (1 mL) was added sodium thiomethoxide (8 mg; 0.114 mmol). Reaction stirred at room temperature for 16 hours. Reaction was diluted with ethyl acetate and washed twice with water. The organic layer was dried sodium sulfate and concentrated to give 23 mg (93% yield) of the title compound as a gum. MS (ES+): Calc: 625.6, Found: 626.0 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (s, 1H), 7.67 (s, 2H), 7.57 (d, J=7.88 Hz, 1H), 7.75-7.56 (bs, 1H), 7.27 (s, 1H), 4.79 (t, J=15.35 Hz, 2H), 4.69 (t, J=15.77 Hz, 2H), 4.23 (s, 3H), 3.81 (bs, 1H), 2.21 (d, J=12.86 Hz, 1H), 1.76 (s, 3H), 1.76-1.57 (m, 4H), 1.36 (d, J=12.45 Hz, 1H), 1.25-1.03 (m, 3H), 1.0-0.76 (m, 2H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[NH:5]1[C:10]2=[N:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3/[C:14](=[N:1]/[OH:3])/[C:15](=[O:16])[C:9]2=[CH:8][CH:7]=[CH:6]1
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2ccc[nH]c-2nc2cnccc2/c1=N/O
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A solution of sodium nitrite (3.3 g, 0.048 mol) in water (14.4 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (4.22 g, 0.02 mol) in acetic acid (80 mL) at room temperature. After the addition was completed, the reaction was stirred for 1.5 hours and 100 mL of water was then added. The mixture was stirred for additional 10 minutes, filtered and dried to give 4.18 g of the desired product. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.48-8.51 (m, 2H), 8.32 (d, 1H, J=5.2 Hz), 7.56 (d, 1H, J=5.6 Hz), 7.07 (dd, 1H, J1=8 Hz, J2=4.8 Hz). MS [M+H]=241.