Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([C:12]([NH:14][C:15]2[C:16](Cl)=[N:17][CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1>>[CH:1]1([N:4]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[NH:14][C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[N:17][C:16]2=3)[CH2:3][CH2:2]1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 l of diglyme (diethylene glycol-dimethylether) to 135°-145° C. for about 30 minutes in a 1200 l VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material (4) is reacted. To this mixture, over about 30 minutes at 135°-145° C., a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material (4) is reacted. The mixture is then kept at 135°-145 ° C. for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 144 l of diglyme. The filtrates are combined and 400 l of solvent is distilled off. The residue is then diluted with a further 287 l of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 144 l of diglyme and the mixture is stirred at a temperature of 130° to 140° C. for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 l of water. After the reaction mixture has been cooled to a temperature of about 25° C., 575 l of cyclohexane and 147 l of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 l of methyl-tert.-butylether, followed by 862 l of water and finally with 575 l of ethanol. In this way, after drying, 225 kg (83.0% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b :2',3'-e][1,4 ]diazepin-6-one (nevirapine) is obtained.
Reaction SMILES: [N:1]1[CH:6]=[N:5][CH:4]=[N:3][CH:2]=1.Cl.[F:8][C:9]1[CH:10]=C(NN)[CH:12]=[CH:13][CH:14]=1>C(O)C>[F:8][C:9]1[CH:10]=[C:2]([N:1]2[CH:6]=[N:5][CH:4]=[N:3]2)[CH:12]=[CH:13][CH:14]=1
Reactant: c1ncncn1
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: CCO
Product: Fc1cccc(-n2cncn2)c1
Yield: 89.7 %

Procedure:
A mixture of 1,3,5-triazine (1 g, 12.3 mmol) and 3-Fluorophenylhydrazine hydrochloride (2 g, 12.3 mmol) in ethanol (20 mL) is heated at reflux overnight. After concentrating, ethyl acetate is added, the mixture is washed with aqueous bicarbonate followed by saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1.8 g of crude 1-(3-Fluorophenyl)-1,2,4-triazole. 1H NMR (CDCl3): δ 8.57 (s, 1H), 8.12 (s, 1H), 7.46-7.51 (m, 3H), 7.08-7.15 (m, 1H). LCMS 164.1 (MH+).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:12][C@H:11]2[N:7]([CH2:8][CH2:9][CH2:10]2)[C:6]([CH3:14])([CH3:13])[CH2:5]1)=[N+]=[N-]>CO.[OH-].[OH-].[Pd+2]>[CH3:13][C:6]1([CH3:14])[CH2:5][C@H:4]([NH2:1])[CH2:12][C@H:11]2[N:7]1[CH2:8][CH2:9][CH2:10]2
Reactant: CC1(C)C[C@H](N=[N+]=[N-])C[C@@H]2CCCN21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C[C@H](N)C[C@@H]2CCCN21

Procedure:
A solution of crude (7R,8aS)-7-azido-octahydro-5,5-dimethylindolizine (Compound 3-8) (assumed 8.7 g) and Pd(OH)2 (20% weight on carbon; 1.7 g) in MeOH (150 mL) was hydrogenated at 30 psi at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated under vacuum to give the product, which was used directly in the next step—yield assumed quantitative (7.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=[O:30])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:22]([C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH3:23])([CH3:13])([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:30])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:22]([C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH3:23])[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cccnc1C=O
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1nccn1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)C(C)c1nccn1C

Procedure:
Using General Procedure B, reaction of 3-methylpyridine-2-carboxaldehyde, {4-[1-(1-methyl-1H-imidazol-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave {4-[[1-(1-methyl-1H-imidazol-2-yl)-ethyl]-(3-methylpyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a light yellow oil. 1H NMR (CDCl3) δ 1.10-1.35 (m, 4H), 1.37 (s, 9H), 1.53 (d, 3H, J=7.5 Hz), 2.11 (s, 3H), 2.51 (m, 1H), 2.62 (m, 1H), 2.90 (br, 2H), 3.37 (s, 3H), 3.62 (d, 1H, J=13.5 Hz), 3.95 (d, 1H, J=13.5 Hz), 4.04 (q, 1H, J=7.5 Hz), 4.57 (br, 1H, NH), 6.76 (s, 1H), 6.92 (s, 1H), 7.09 (m, 1H), 7.40 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz). Conversion to the HBr salt using General Procedure D gave COMPOUND 231 as a white solid. 1H NMR (D2O) δ 1.50 (br, 4H), 1.52 (d, 3H, J=6.9 Hz), 2.44 (s, 3H), 2.72 (br, 2H), 2.89 (br t, 2H), 3.89 (s, 3H), 4.24 (s, 2H), 4.68 (q, 1H, J=6.9 Hz), 7.38 (d, 1H, J=1.8 Hz), 7.40 (d, 1H, J=1.8 Hz), 7.85 (t, 1H, J=6.6 Hz), 8.36 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 14.17, 16.90, 24.18, 25.00, 35.16, 39.54, 50.20, 52.57, 53.23, 119.09, 124.44, 125.99, 137.29, 138.34, 146.69, 148.46, 152.08. ES-MS m/z 302 (M+H). Anal. Calcd. for C17H27N5.3.5HBr.1.9H2O.C4H10O: C, 34.45; H, 5.95; N, 10.80; Br, 43.12. Found: C, 34.57; H, 5.73; N, 10.77; Br, 42.98.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[S:4]
Reactant: O=C(CNC(=O)C1CCCCC1)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CNC(=O)C1CCCCC1)c1ccccc1
Yield: 105.1 %

Procedure:
Thiosemicarbazide (2.23 g, 24.5 mmol) was added to a solution of cyclohexane carboxylic acid (2-oxo-2-phenyl-ethyl)-amide (6.0 g, 24.5 mmol), prepared in the previous step, in 87 ml of methanol plus 6.75 ml of 1N HCl plus 6.25 ml of water and the reaction stirred at room temperature for 4 days. The solvent was removed under reduced pressure to give 8.2 g of a green oil which was chromatographed on 400 g of silica gel (230-400 mesh) using ethyl acetate-methylene chloride as the eluent. The material isolated was recrystallized from isopropyl alcohol to give the title compound (3.55 g, 46%) as a white solid, mp 104-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Mg].[CH3:13][C:14]1([CH3:21])[CH2:18][C:17](=[O:19])[O:16][C:15]1=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17](=[O:19])[CH2:18][C:14]([CH3:21])([CH3:13])[C:15]([OH:20])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cc1OC
Reactant: CC1(C)CC(=O)OC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)(C)C(=O)O)cc1OC
Temperature: 25 °C

Procedure:
Under an atmosphere of dry nitrogen a grignard solution, prepared from 43.4 g 3,4-dimethoxybromo-benzene and 6.1 g magnesium in 200 ml of tetrahydrofuran, is added dropwise to a solution of 20.5 g 3,3-dimethyl-dihydro-furan-2,5-dione in 200 ml of tetrahydrofuran cooled in an ice-bath. The reaction mixture is stirred for an additional hour at RT. 100 ml of a 20% ammonium chloride solution is added and the water layer is extracted twice with 75 ml of ethyl acetate. The combined organic layers are washed twice with 100 ml of half saturated brine and extracted with 3×100 ml 1M sodium hydroxide solution. The aqueous layers are washed with 75 ml of ethyl acetate, acidified with concentrated hydrochloric acid and extracted 3 times with 100 ml of dichloromethane. The organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The oily residue is crystallized from ethyl acetate/petroleum ether (60-80° C.). M. p. 114-116° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][C:16](F)=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:8][CH:5]3[CH2:6][CH2:7][O:3][CH2:4]3)=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:11]=1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC1CCOC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
NaH (70 mg) was carefully added to a solution of tetrahydro-furan-3-ol (0.2 ml) in DMF (3 ml) and the mixture was stirred for 1 hour. [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added under N2, and the mixture was heated at 90° C. overnight. The mixture was poured to 50 ml of water. The mixture was extracted by ethyl acetate (50 ml×3). The organic layer was evaporated to give [1-Chloro-7-(2-methoxy-ethoxy)-6-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as oil (100 mg). LC-MS: m/e 419(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2nc3ccccc3o2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4o3)cc2)ccc1Cl
Yield: 33.3 %

Procedure:
2-(4-Aminophenylthio)benzoxazole (10.0 mmoles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (10.0 mmoles, 2.4 g) were reacted according to procedure A to yield of the title compound 1.6 g, 33%. Mass Spec (FD) 479. Calculated for C21H13ClF3 N3OS2 : C, 52.56; H, 2.73; N, 8.75. Found: C, 52.47; H, 2.70; N, 8.48.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:11]2[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]2)=[C:6]([F:21])[CH:5]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Cl:3][C:4]1[C:9]([O:10][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:8][C:7]([N:11]2[C:15](=[O:16])[N:14]([CH:17]([F:18])[F:19])[C:13]([CH3:20])=[N:12]2)=[C:6]([F:21])[CH:5]=1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 80 °C
Yield: 76.1 %

Procedure:
To a stirred mixture of 0.91 g (0.019 mole) of sodium hydride in 30 mL of N,N-dimethylformamide was added slowly a solution of 5.50 g (0.019 mole) of 1-[4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 30 mL of N,N-dimethylformamide. To this mixture was added 2.68 g (0.019 mole) of 4-fluoronitrobenzene. The resultant mixture was stirred at room temperature for approximately 18 hours and then was heated at 80° C. for one hour. The mixture was allowed to cool and was poured into ice water. The aqueous mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 6.0 g of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 115°-117° C., Compound 4 of Table 1.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)O
Reaction time: 3.75 h

Procedure:
Boc-Gly-L-Phe-L-Leu-OH (44 mg, 0.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflurophsophate (14 mg, 0.104 mmol) are dissolved in dry DMF (1 mL). DIEA (20 μL, 0.115 mmol) is added and about 0.5-1.0 mL of this solution is transferred to a test tube containing amino derivatized ELAMS™. The tube is sealed, vortexed for about 3.5-4 hours and the ELAMS™ pelleted and washed with DMF (3×) and methylene chloride (2×). The ELAMS™ are then deprotected with a solution of 50% triluoroacetic acid (TFA) in methylene chloride for 30 min., washed with methylene chloride (2×), ethanol (2×) and methylene chloride (2×), and dried at 55° C. for about 1 hour. The identifier tag from each ELAMS™, is detected and recorded.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=O)[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.[CH3:17][NH2:18]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[N:18][CH3:17])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CN
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Solvent: CO
Product: CN=C1c2c(O)ccc(C)c2C2CCCCC12

Procedure:
To a methanol solution containing 2 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 20 ml of methanol was added 7.18 ml of methanol solution of 40% methylamine and the mixture was refluxed under heating for 5 hours. After left to stand for cooling, the solvent was removed by concentration and the residue was recrystallized from ethanol to obtain 0.35 g of 8-hydroxy-5-methyl-9-methylimino-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:34]=[C:35]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 79 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-acetylphenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 79%. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (496 mg, 3.72 mmol), 1,1-dimethylethyl 4-formylhexahydro-1H-azepine-1-carboxylate (871 mg, 3.83 mmol) and AcOH (1 μL, 0.017 mmol) in chloroform (5 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (950 mg, 4.48 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-40% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to afford the desired product (168 mg, 12%) as a pale yellow oil LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23](O)[C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)(=O)C.S(=O)(=O)(O)O>[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23]([C:8]1[CH:7]=[C:5]([OH:6])[C:4]([OH:9])=[CH:3][C:2]=1[Br:1])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: Oc1ccc(Br)cc1O
Reactant: CCN1CCN(C(=O)NC(O)C(=O)O)C(=O)C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2cc(O)c(O)cc2Br)C(=O)C1=O
Reaction time: 18 h

Procedure:
4-Bromocatechol (4.77 g, 25.2 mmole) was added to an ice bath cooled suspension of N-(2,3-dioxo-4-ethylpiperazin-1-yl-carbonyl)-2-hydroxyglycine (2.59 g. 10 mmole) in glacial acetic acid (9 ml) and concentrated sulphuric acid (1 ml). The mixture was stirred for 18 hours then poured onto a mixture of ice, saturated sodium carbonate and ethyl acetate and adjusted to pH7 with sodium carbonate. The aqueous layer was collected, washed with ethyl acetate (50 ml), acidified to pH1 and extracted with ethyl acetate (3×50 ml). The extracts were dried and evaporated in vacuo to a buff solid, 2.4 g, 79%, δ[(CD3)2CO]1.13(3H, t, J7 Hz, CH2CH3), 3.57(2H, q, J7 Hz, CH2CH3), 3.5-4.3(4H, m, 2×NCH2), 5.3-7.6(3H, broad, 2×OH, CO2H), 5.73 (1H, d, J6.5 Hz, CHNH), 6.87 and 7.03 (2H, 2×s, Ar), 9.73(1H, d, J6.5 Hz, CHNH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[C:25]=1[C:31]1[C:32](=[O:34])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Reactant: CCOC(=O)C(=O)c1c(Cl)cccc1Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 37.2 %

Procedure:
A mixture of 0.60 g (2 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.74 g (3 mmol) ethyl 2-(2,6-dichlorophenyl)-2-oxoacetate (T. H. Kress and M. R. Leanna, Synthesis, 1988:803–805), and 0.3 mL HOAc in 25 mL of 2-methoxyethanol is heated under reflux for 16 hours before the solvent is removed under vacuum. The residue is extracted into EtOAc and, after being washed with water, the solution is dried over Na2SO4. Removal of the solvent and chromatography on silica, eluting with hexane/EtOAc 3:2 gives 0.36 g (37%) of the title compound (Compound 2 in Tables 1 and 2): mp (EtOH) 292–293° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 3-(4-Methyl-piperazin-1-yl)-propylamine (0.361 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution diisopropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜30 mL), and with brine (2×˜30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.365 g, 1.31 mmol, 74% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCOCC1
Yield: 87.8 %

Procedure:
N-(t-Butoxycarbonyl)-α-(4-hydroxy-2,3,5,6-tetrahydro-4-pyranyl)glycine, benzyl ester (10.34 g, 28.3 mmoles) and 10% palladium on charcoal (2.0 g) in 200 ml of absolute ethanol was treated with hydrogen at 1 atmosphere for 2 hours. The catalyst was filtered and the solvent removed in vacuo finally by co-evaporation with benzene. A small amount of ethyl acetate induced crystallization. The slurry was triturated with isopropyl ether, filtered and washed with isopropyl ether and hexane and dried in air to give 6.84 g of product as a white solid, melting point 140°-141° C.