Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1C=C(F)C=C(F)C=1.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C@H:22]3[CH2:27][C@@H:26]([CH3:28])[C@@H:25]([NH2:29])[CH2:24][C@H:23]3[CH3:30])=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl[C:32]1[CH:41]=[C:40]2[C:35]([C:36](NC3CCC(N)CC3)=CC=N2)=[CH:34][CH:33]=1>>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C@H:22]3[CH2:27][C@@H:26]([CH3:28])[C@@H:25]([NH:29][C:33]4[CH:32]=[C:41]([CH3:2])[CH:40]=[C:35]([CH3:36])[CH:34]=4)[CH2:24][C@H:23]3[CH3:30])=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1Nc1ccnc2cc(Cl)ccc12
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Product: Cc1cc(C)cc(N[C@H]2C[C@@H](C)[C@@H](Nc3ccnc4cc(Cl)ccc34)C[C@H]2C)c1

Procedure:
The titled compound was prepared according to the methods described in Example 140, substituting 5-bromo-m-xylene for 1-bromo-3,5-difluorobenzene and (1S,2R,4S,5R)-N-(7-chloroquinolin-4-yl)-2,5-dimethylcyclohexane-1,4-diamine for N-(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine. 1H NMR (300 MHz, DMSO) δ ppm 8.89 (d, 1 H), 8.56 (m, 2 H), 7.92 (d, 1 H), 7.82 (dd, 1 H), 6.99 (d, 1 H), 6.31 (s, 2 H), 6.17 (s, 1 H), 4.10 (br.s, 2 H), 2.14 (s, 6 H), 2.03-2.33 (m, 4 H), 1.69 (m, 2 H), 0.97 (br.d, 6 H). MS(ESI(+)Q1MS m/z 408 (M+H)+).
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH:9]1([C:12]2[S:49][C:15]3[N:16]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)[C:17](=[O:33])[N:18]([CH2:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][CH3:32])=[O:23])[C:19](=[O:20])[C:14]=3[CH:13]=2)[CH2:11][CH2:10]1.[N:50]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH:9]1([C:12]2[S:49][C:15]3[N:16]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:50][C:4](=[O:7])[O:5][N:48]=5)=[CH:37][CH:36]=4)[C:17](=[O:33])[N:18]([CH2:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][CH3:32])=[O:23])[C:19](=[O:20])[C:14]=3[CH:13]=2)[CH2:11][CH2:10]1
Reactant: O=C([O-])O
Reactant: COc1cc(F)ccc1C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)ccc1C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
A mixture of hydroxylammonium chloride (1.15 g), sodium hydrogencarbonate (2.09 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-cyclopropyl-3-[2-(4-fluoro-2-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.94 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.027 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added 25% sulfuric acid (10 mL) and 1-butanol (25 ml), and the mixture was stirred at 100° C. for 1 hr, and extracted with chloroform and water. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.16 g, 15%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:23]N1C(=O)CCC1=O.CN(C)C=O>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:23])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)c(Br)c1

Procedure:
A mixture of 10.0 g. (0.034 mol.) of 2-n-butyl-3-(4'-hydroxybenzoyl)benzofuran and 6.1 g. (0.034 mol.) of N-bromosuccinimide in 150 ml. of damp dimethylformamide was refluxed for 12 hours. The reaction mixture was poured into water and extracted with chloroform. The extracts were washed repeatedly with water, then dried (Na2SO4) and concentrated to give 2-n-butyl-3-(3'-bromo-4'-hydroxybenzoyl)-benzofuran.
Reaction SMILES: [NH:1]([C:3]([CH2:5][NH:6][C:7]([C:9]1[C:10]2[CH:17]=[N:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]=2[CH:12]=[N:13][CH:14]=1)=[O:8])=O)[NH2:2].[CH3:25][N:26]=[C:27]=[S:28]>CCO>[CH3:25][NH:26][C:27]1[S:28][C:3]([CH2:5][NH:6][C:7]([C:9]2[C:10]3[CH:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:11]=3[CH:12]=[N:13][CH:14]=2)=[O:8])=[N:1][N:2]=1
Reactant: CN=C=S
Reactant: NNC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Solvent: CCO
Product: CNc1nnc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid hydrazinocarbonylmethyl-amide (104 mg, 0.32 mmol) in EtOH (4 mL) was added methyl isothiocyanate (50 mg, 0.7 mmol). The mixture was warmed at reflux for 6 days, and was then cooled to room temperature, and the product was collected by filtration. The crude material was suspended in concentrated sulfuric acid (1 mL) and stirred for 10 minutes. After standing for 10 minutes, the mixture was poured into ice water. The solution was made basic by addition of aqueous ammonia followed by a minimal amount of saturated aqueous sodium bicarbonate to pH=8 and the solid collected by filtration to afford title compound.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[CH:14]=[C:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)=O>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[CH2:14][CH:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Agent: [Pd]
Solvent: O=CO
Product: CCN1CC(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Temperature: 80 °C
Yield: 73.7 %

Procedure:
Palladium-on-carbon (10% w/w, 0.5 g.) was added to a mixture of methyl 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoate (0.5 g., prepared as described in Example 80), and formic acid (99%, 20 ml.), under an atmosphere of nitrogen. The mixture was vigorously stirred and heated at 80° C. for one hour. The cooled mixture was filtered through a pad of diatomaceous earth, the filter cake washed with methanol, and the filtrate evaporated. The resulting oil was dissolved in ethyl acetate (30 ml.) washed with water, brine, then dried (MgSO4) and evaporated. The product was purified by flash chromatography on silica gel (4 cm. diameter column), eluting with 2:3 v/v ethyl acetate:hexane, to give the title compound (0.37 g., 80%) as a foam; NMR (250 MHz, DMSO-d6): 1.04(t,3H, --CH2CH3); 1.15(m,2H, cyclopentyl ring); 1.4-1.8(m,6H, cyclopentyl ring); 2.2(m,3H); 2.7(dd,1H); 2.85-3.2(m,5H); 3.45(m,1H); 3.86(s,3H, OCH3); 3.87(s,3H, OCH3); 6.43(d,1H); 7.20 (m,2H); 7.30(d,1H); 7.50(m,2H); 9.47(s,1H, NH).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)=[N+]=[N-].[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH:22]=O>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:26]([O:25][C:21](=[O:24])[CH:22]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(C=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
cis-2-Azidomethyl-3-benzyloxycarbonylamino-4-oxoazetidine is treated with zinc dust in 50% aqueous acetic acid as described in Preparation 7. Reaction of the crude reduction product with benzyl glyoxalate in methylene dichloride as described in the procedure of Example 1 gives N-(cis-3-benzyloxycarbonylamino-4-oxo-2-azetidinylmethyl)iminoacetic acid benzyl ester which, when treated with acetyl chloride according to the procedure of Example 1, gives 3-acetyl-6β-benzyloxycarbonylamino-7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester.
Reaction SMILES: [OH:1]C1C=CC2C(C=1)=NC1C(=CC=C(O)C=1)C=2.NC1C=CC2C(C=1)=NC1C(=CC=C(N)C=1)C=2.N[C:34]1[CH:35]=[CH:36][C:37]2[C:46]([C:47]=1[CH3:48])=[N:45][C:44]1[C:39](=[CH:40][CH:41]=[C:42](N)[C:43]=1[CH3:49])[CH:38]=2.S(=O)(=O)(O)O.[OH2:56]>>[OH:56][C:34]1[CH:35]=[CH:36][C:37]2[C:46]([C:47]=1[CH3:48])=[N:45][C:44]1[C:39](=[CH:40][CH:41]=[C:42]([OH:1])[C:43]=1[CH3:49])[CH:38]=2
Reactant: Oc1ccc2cc3ccc(O)cc3nc2c1
Reactant: Cc1c(N)ccc2cc3ccc(N)c(C)c3nc12
Reactant: O
Agent: Nc1ccc2cc3ccc(N)cc3nc2c1
Agent: O=S(=O)(O)O
Product: Cc1c(O)ccc2cc3ccc(O)c(C)c3nc12

Procedure:
3,6-Dihydroxy-4,5-dimethylacridine is prepared by the procedure of Benda, L., Ber., 45, 1787 (1912), for the preparation of 3,6-dihydroxyacridine from 3,6-diaminoacridine. In this reaction 3,6-diamino-4,5-dimethylacridine is heated in a bomb with two parts of water and one part concentrated sulfuric acid at 200° C. for 8 hours. The reaction mixture is diluted with water and the crude solid collected by filtration. This material is purified by dissolution in excess 1N sodium hydroxide, followed by treatment with charcoal and then acidification with acetic acid, giving an orange solid.
Reaction SMILES: NC1C=CC=CC=1NC(=O)/C=C/C1C=CN(S(C2C=CC(C)=CC=2)(=O)=O)C=1.C(OC(=O)[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:65])/[CH:43]=[CH:44]/[C:45]1[CH:49]=[CH:48][N:47]([S:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH:46]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:65])/[CH:43]=[CH:44]/[C:45]1[CH:49]=[CH:48][N:47]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:57][CH:58]=2)(=[O:52])=[O:51])[CH:46]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
The method used for preparation of this compound is analogous to the method described for compound 5. Starting materials: (2-{(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A7) (0.460 mmol), CH2Cl2 (50 ml), TFA (5 ml). Reaction conditions: room temperature, 18 hours.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC(C)([O-])C.[K+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1cccc(Cn2nnc3ccccc32)c1
Reaction time: 4 h

Procedure:
To a solution of 1H-benzotriazole (0.52 g, 4.4 mmol) in THF (25 mL) was added potassium tert-butoxide (4.6 mL, 4.6 mmol, 1M in THF) followed by the addition of 1-bromo-3-(bromomethyl)benzene (1.0 g, 4.0 mmol). The solution was allowed to stir for 4 hours before the reaction was quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer was separated and washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/hexanes) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2OC(=O)[C:11](=[C:15]=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.O.[NH2:18][NH2:19].[C:20]([OH:23])(=O)C>C(O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]([CH2:20][OH:23])[CH2:11][C:15](=[O:16])[NH:18][N:19]=2)=[CH:7][CH:8]=1
Reactant: CSc1ccc(C2CC(=C=O)C(=O)O2)cc1
Reactant: CC(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1ccc(C2=NNC(=O)CC2CO)cc1

Procedure:
10.6 g (0.045 mol) of 4-(4-methylmercaptophenyl)-carbonyl-γ-butyrolactone are stirred in 70 ml of ethanol with 2.5 g (0.05 mol) of hydrazine hydrate at room temperature for 90 minutes. After addition of 8 ml of acetic acid, the mixture is heated under reflux for 1 hour and cooled and the precipitate is filtered off with suction and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28](=[O:34])[N:27]([CH2:35][CH2:36][O:37][CH3:38])[C:26]=2[CH:39]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[C:31]([CH3:32])([CH3:33])[CH2:30][CH2:29][C:28](=[O:34])[N:27]([CH2:35][CH2:36][O:37][CH3:38])[C:26]=3[CH:39]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC#N)n3)cc21
Yield: 48 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenoxy]-acetonitrile and 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. Product isolated as a yellow foam (50 mg, 48%). mp: 235-238° C., MS (ESI+): 539.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.26 (s, 1H), 8.61 (s, 1H), 8.11 (s, 1H), 7.40 (m, 2H), 7.29 (d, J=9 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.06 (t, J=9 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 5.19 (s, 2H), 3.54 (q, 7 Hz, 2H), 2.07 (br m, 2H), 1.87 (br m, 2H), 1.20 (s, 6H), 1.12 (m, 4H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:34]([CH3:36])[CH3:35])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C.O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:34]([CH3:35])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)N1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid (2-hydroxyethyl)-isopropylamide (439) (70 mg, 0.143 mmol), in dichloromethane (10 mL), TPP (131 mg, 0.5 mmol) diisopropyl azodicarboxylate (0.084 mL, 0.429 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.2). After completion of the reaction, water (10 mL) was added and the mixture was extracted with dichloromethane (2×30 mL). The organic part was dried over sodium sulfate, then concentrated and the resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 70-80% ethyl acetate in hexane as gradient polarity mobile phase to get 9-benzyloxy-2-isopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (440) (60.0 mg, 90.2%) as a white sticky liquid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][N:15]=[N+:16]=[N-:17].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.COC(C)(C)C>C1(O)CCCCC1>[N:25]1([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@@H:3]3[CH2:14][N:15]=[N+:16]=[N-:17])[N:24]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H]1CN=[N+]=[N-]
Reactant: Clc1nccc(N2CCCCCC2)n1
Solvent: OC1CCCCC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nccc(N3CCCCCC3)n2)[C@H]1CN=[N+]=[N-]
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
To a solution of the compound 7 (240 mg) in cyclohexanol (0.4 mL), 1-(2-chloro-4-pyrimidinyl)azepane (210 mg) was added. The reaction mixture was stirred at 120° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was added tert-butyl methyl ether, washed with aqueous 2N sodium hydroxide solution, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol:27% aqueous ammonia=100:0:0→90:10:0→90:10:1) to obtain the title compound (190 mg) having the following physical properties.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]2[OH:23])=[C:5]([NH:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[N:4]=1.[CH:36]([N:39]([CH:50]([CH3:52])[CH3:51])[CH2:40][CH2:41][NH:42][C:43](N1C=CN=C1)=[O:44])([CH3:38])[CH3:37]>>[CH:50]([N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41][NH:42][C:43]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]2[OH:23])=[C:5]([NH:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[N:4]=1)=[O:44])([CH3:52])[CH3:51]
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(CN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(CNC(=O)NCCN(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared from (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 69) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) by similar procedure to that used in Example 3.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C([O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:24]=2[O:23][N:22]=1)=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:29][C:24]=3[O:23][N:22]=2)=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1noc2cc(OCc3ccccc3)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(OCc3ccccc3)ccc12
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 99 μl (0.79 mMol) 3-trifluoromethyl-aniline are dissolved in 14 ml toluene and cooled to 10° C. Then 1.2 ml Me3Al (2 M in toluene; 2.4 mMol) are added via syringe. After 1 h at rt, a solution of 236 mg (0.79 mMol) 6-benzyloxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 3 ml THF is added and the reaction mixture stirred for 25 min in an oil bath at 110° C. The solution is cooled in ice and hydrolyzed with 30 ml of a sat. NH4Cl. After 15 min stirring, EtOAc and Celite are added. The mixture is filtered through Celite, the solid washed with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Crystallisation from EtOAc/hexane gives the title compound: MS: [M−1]=411; TLC(hexane/EtOAc 3:1): Rf=0.51.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(CC)CC)C.CS(C)=O.O>[CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in WO2010079443A1. To a solution of compound 1-benzhydrylazetidin-3-ol (20 g, 28.4 mmol) in the triethyl amine (60 mL) was added a solution of sulfur trioxide pyridine complex (SO3.Py) (40 g, 251.6 mmol) in dimethylsulfoxide (260 mL) under a nitrogen atmosphere at 25° C. The reaction was stirred at 50° C. for 2 h. Then the reaction mixture was cooled back to 25° C., diluted with water (500 mL), and extracted with ethyl acetate (2×500 mL). Organic part was dried over sodium sulfate, filtered, and concentrated under a vacuum to give a crude compound which was further purified by column chromatography using silica gel (100 to 200 mesh) eluting with 0% to 20% ethyl acetate in hexanes to provide 1-benzhydrylazetidin-3-one (11.7 g) as a white solid. MS (ESI, positive ion) m/z (M+1): 238.30. 1H NMR (400 MHz, DMSO) δ 7.50 (d, J=7.5 Hz, 4H), 7.30 (t, J=7.5 Hz, 4H), 7.20 (t, J=7.3 Hz, 2H), 4.82 (s, 1H), 4.00 (s, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11][C:5]2=[N:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:9]2[C:10]([CH3:13])([CH3:12])[CH2:11][C:5]3=[N:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]2=3)=[CH:21][CH:20]=1
Reactant: Clc1ccc(I)cc1
Reactant: Cc1nnc2n1-c1ccccc1NC(C)(C)C2
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(C)(C)C2
Temperature: 90 °C

Procedure:
A disposable tube was charged with 1,5,5-trimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (150 mg, 0.657 mmol), 1-chloro-4-iodobenzene (204 mg, 0.854 mmol), RuPhos precat. (23.94 mg, 0.033 mmol), sodium 2-methylpropan-2-olate (126 mg, 1.314 mmol), and a stirbar before being evacuated and purged with nitrogen three times. Toluene (3 mL, 0.5 M) was added, and the mixture was stirred at 90° C. 48 h. The mixture was cooled, diluted with ethyl acetate, filtered, and purified by reverse phase HPLC to yield the title compound as an off-white amorphous solid.