Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[O:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)=[CH:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[O:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)=[CH:45][CH:44]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1ccc(Cn2ncc(N)n2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCc1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (52 mg, 0.26 mmol) in CH2Cl2 (3.0 mL) was treated at rt with DMAP (8.1 mg, 0.07 mmol), HOBt (42.8 mg, 0.32 mmol), EDC (127 mg, 0.66 mmol) and DIPEA (0.2 mL, 1.17 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((5-(methoxymethyl)furan-2-yl)methyl)-2H-1,2,3-triazol-4-amine (55 mg, 0.26 mmol) in CH2Cl2 (3.0 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10.0 mL), the layers were separated and the org. phase was washed with water (10.0 mL), followed by brine (10.0 mL) and dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a colorless oil: TLC: rf (6:4 hept-EA)=0.23. LC-MS-conditions 07: tR=0.87 min, [M+H]+=380.26
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12](O)=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]>CO.ClCCl>[NH2:1][C:2]1[C:7]([CH:8]2[NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]=3[O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(=O)c1cccc(N)c1O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2c1OC(c1cccnc1N)N2
Temperature: 50 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
A 2-aminopyridine-3-carbaldehyde (650 mg) was added to a stirred solution of methyl 3-amino-2-hydroxy-benzoate (890 mg) in methanol (10 ml) and dichloromethane (5 ml). The resulting solution was stirred at 50° C. for 10 hours. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-(2-amino-3-pyridyl)-2,3-dihydro-1,3-benzoxazole-7-carboxylate (400 mg) as a pale yellow solid. Manganese(IV) oxide (4629 mg) was added to a solution of this yellow solid (400 mg) in dichloromethane (5 ml) and tetrahydrofuran (10 ml), the mixture was stirred at 25° C. for 15 hours. The mixture was filtered and the filtrate was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 30 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carboxylate (345 mg) as a pale yellow solid. NMR Spectrum: (CDCl3) 4.06 (s, 3H), 6.79 (dd, 1H), 6.89 (bs, 2H), 7.43 (dd, 1H), 7.92 (dd, 1H), 8.00 (dd, 1H), 8.26 (dd, 1H), 8.44 (dd, 1H); Mass spectrum: M+H+ 270;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].Cl[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])(=[O:17])=[O:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1C(=O)O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (200 mg, 1.128 mmol) in pyridine (3 mL) was added 5-(chlorosulfonyl)-2-methoxybenzoic acid (283 mg, 1.128 mmol) and the reaction stirred at 20° C. for 4 hours. The solvent was removed in vacuo and the crude purified by flash silica (Si) chromatography (using a 0-100%, ethyl acetate-dichloromethane gradient, with extra 0-20% methanol added). The appropriate fractions were combined and evaporated in vacuo to give the required product, 108 mg. LCMS (M+1) 392, RT 1.18 mins.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21][O:22][C:23]1[C:27]([CH:28]=O)=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:28]/[C:27]2[C:23]([O:22][CH2:21][O:20][CH3:19])=[N:24][N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(CC)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)cs1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of diethyl [(2-ethyl-1,3-thiazol-4-yl)methyl]phosphonate (4.64 g) in tetrahydrofuran (75 mL) was added sodium hydride (60% in oil, 0.96 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (6.32 g) was added to the reaction mixture, and the mixture was heated under reflux for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (4.49 g, yield 66%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:11][C@@H:10]([C:12](=[O:17])[N:13]([O:15][CH3:16])[CH3:14])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:16][O:15][N:13]([CH3:14])[C:12]([C@@H:10]1[CH2:11][C@H:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:9]1)=[O:17]
Reactant: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 2 g of cis-[3-(methoxy-methyl-carbamoyl)-cyclobutyl]-acetic acid tert-butyl ester in 25 mL of dichloromethane was added 10 mL of trifluoroacetic acid. The mixture was allowed to warm and stir for 2 h then concentrated under reduced pressure. The residue was taken up in 3×50 mL of toluene and repeatedly concentrated under reduced pressure to remove trifluoroacetic acid. Drying under vacuum overnight gave 1.6 g of product as a colorless oil: MS (m+1)=202.3; 1H NMR (400 MHz, CDCl3) 9.0 (br s, 1H), 3.62 (s, 3H), 3.18 (s, 3H), 2.65 (m, 1H), 2.5 (overlapping d and m, 3H), 2.4 (dd, 1H), 2.0 (, m, 2H).
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:10]3[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:10]3[N:9]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1nc(N2CCCNCC2)nc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(N2CCCN(Cc3ccccc3Cl)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[1,4]Diazepan-1-yl-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2-chloro-benzaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (PMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.9-7.2 (m, 4H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 10 H). MS: m/z: 426 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH3:16].[C:17](OC(=O)C)(=O)[CH3:18]>C(O)(=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:17]2[CH3:18])=[C:10]([CH3:16])[CH:11]=1
Reactant: Cc1cc(Br)ccc1Nc1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1-n1c(C)nc2ccccc21
Reaction time: 30 h

Procedure:
A mixture of 5.22 g (18.8 mmol) of N-(2-aminophenyl)-4-bromo-2-methyl-aniline and 7.1 ml (75.2 mmol) of acetic acid anhydride is heated to boiling for 30 hours, combined with 15 ml of glacial acetic acid and heated to boiling for another 30 hours. Then the reaction mixture is concentrated and purified by flash chromatography (silica gel; methylene chloride).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH:25][C:26](=O)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[O:23][C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[N:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NNC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OCCn2c1nc(-c1nnc(Cc3ccc(F)cc3)o1)c(OCc1ccccc1)c2=O
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To stirred solution of 3-(benzyloxy)-N′-(2-(4-fluorophenyl)acetyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide (0.075 g, 0.16 mmol), Ph3P (0.074 g, 0.28 mmol) and DIEA (0.16 mL, 0.91 mmol) in anhydrous CH3CN (3 mL) was added hexachloroethane (0.048 g, 0.20 mmol) all at once at room temperature. After 4 h, the resulting greenish-yellow reaction mixture was purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford title compound (0.072 g, 86% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 7.42-7.40 (2H, m), 7.30-7.28 (3H, m), 7.24 (2H, dd, J=8.2, 5.55.34 (2H, s), 4.20 (2H, s), 4.07-4.01 (4H, m), 1.64 (6H, s). Hz)), 6.99 (2H, t, J=8.6 Hz), HRMS (M+H) calcd for C25H24N4O4F: 463.1782. found: 463.1788.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].F[C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25].O>CN(C)C=O.Cl>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:21][C:22]=1[N+:29]([O-:31])=[O:30])=[O:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 25 h

Procedure:
To a solution of diethyl malonate (8.04 ml, 52.9 mmol) in N,N-dimethylformamide (30.0 ml), potassium tert-butoxide (5.94 g, 52.9 mmol) was added, and, after complete dissolution, methyl 5-fluoro-2-nitrobenzoate (4.69 g, 26.5 mmol) obtained in Reference Example 107 was added. The reaction mixture was stirred at 60° C. for 25 hours and poured onto an iced water, made acidic with iN hydrochloric acid, and then extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure to give the title compound as an oil. This product was used in the next reaction without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([F:28])[C:11]1=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C(=O)=O>CO>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[S:16]2)[C@@H:12]([F:28])[C@H:11]1[OH:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@H]2[C@H](O[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)[C@@H]2F)S1
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Yield: 36.9 %

Procedure:
To a solution of tert-butyl ((3aR,5R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (2.57 g, 5.72 mmol) in dry MeOH (50 mL), at 0° C., was added NaBH4 (0.295 g, 7.80 mmol). After the mixture was stirred at 0° C. for 20 min a chip of dry ice was added, and the solvent was evaporated. The residue was dissolved in DCM (50 mL) and washed with satd. aqueous NaHCO3 (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording tert-butyl ((3aR,5R,6S,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.95 g, 37%), as a sticky oil. 1H NMR (400 MHz, CDCl3) δ 6.11 (d, J=6.7 Hz, 1H), 4.84 (ddd, J=3.2, 6.7, 48.2 Hz, 1H), 4.45 (td, J=6.7, 16.6 Hz, 1H), 4.32-4.29 (m, 1H), 4.00-3.93 (m, 2H), 3.90-3.86 (m, 1H), 3.36 (s, 3H), 3.19 (s, br., 1H, (OH)), 1.53 (s, 9H), 0.90 (s, 9H), 0.093 (s, 3H), 0.087 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:11]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
5-Hydroxyindazole (3.00 g, 22.37 mmol), tert-butyldimethylsilyl chloride (4.05 g, 26.8 mmol) and imidazole (2.28 g, 33.5 mmol) were mixed in DCM (50 mL) and stirred at room temperature for 18 hours. The reaction mixture was poured into 0.5 N aqueous citric acid solution and extracted with DCM (3×25 mL). The combined organics were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 0 to 50% EtOAc in hexane to yield the title compound as an orange solid (5.09 g, 90%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:38][C:32]2[C:37]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.C([O:18][NH:19][CH2:20][C@@H:21]1[C@@H:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]CC2C=CC=CC=2)[C:22]1=[O:43])C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([C@H:25]1[CH2:24][N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:22](=[O:43])[C@@H:21]1[CH2:20][N:19]([OH:18])[CH:1]=[O:3])[CH2:27][CH2:28][CH3:29]
Reactant: O=CO
Reactant: CCCC[C@H]1CN(CCCCCOCc2ccccc2)C(=O)[C@@H]1CNOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCCC[C@H]1CN(CCCCCO)C(=O)[C@@H]1CN(O)C=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A mixture of formic acid (0.011 mL, 0.29 mmol) and acetic anhydride (0.026 mL, 0.28 mmol) was heated to 50° C. for 1 h. To this mixture at room temperature was added a mixture of [(3S,4R)-3-(benzyloxyaminomethyl)-1-(5-benzyloxypentyl)-4-butyl-pyrrolidin-2-one (65 mg, 0.14 mmol) and triethylamine (0.02 mL, 0.18 mmol) in methylene chloride (3 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was diluted with methylene chloride (5 mL) and quenched with water (5 mL). The organic phase was washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in methanol (3 mL) and stirred under a hydrogen balloon in the presence of palladium on activated carbon (40 mg) for 4 h. The reaction mixture was filtered, concentrated, and the residue was purified by HPLC to afford 25 mg (58%) of N-[(3S,4R)-4-butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide as a colorless glass: 1H NMR (CD3OD) δ 8.33 (s, 0.5 H), 7.98 (s, 0.5 H), 3.80 (m, 1 H), 3.57 (m, 3 H), 3.33 (m, 3 H), 3.07 (t, 1H), 2.55 (m, 1 H), 2.12-2.26 (m, 1H), 1.33-1.71 (m, 12 H), 0.94 (t, 3 H). MS(ES) m/e 301 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:19])=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)C=C.[CH:20]1[C:25](Cl)=CC=C(Cl)[CH:21]=1>>[CH2:25]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:19])[C:10]=2[C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: C=CCOc1cccc2oc(C(=O)OCC)c(C)c12
Reactant: Clc1ccc(Cl)cc1
Product: C=CCc1ccc2oc(C(=O)OCC)c(C)c2c1O
Yield: 85 %

Procedure:
A solution of ethyl 4-allyloxy-3-methylbenzofuran-2-carboxylate (1.04 g, 4 mmol, Example 116) in dichlorobenzene was refluxed for 3 hours. The resulting solution was chromatographed (silica gel, 5% ethyl acetate in hexane) to give 8.7 g of the title compound (85% yield), m.p. 123° C.
Reaction SMILES: NC1N=C(N)C2C(CN(C3C=CC=CC=3)C3C=CC=CC=3)=CSC=2N=1.[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH3:36])=[CH:34][S:33][C:31]=2[N:32]=1.[CH:38]1[C:48]2[CH:47]=[CH:46][C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1>>[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH2:36][C:49]3[C:45]4[CH:46]=[CH:47][C:48]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=5[NH:43][C:44]=4[CH:52]=[CH:51][CH:50]=3)=[CH:34][S:33][C:31]=2[N:32]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: Cc1csc2nc(N)nc(N)c12
Agent: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Product: Nc1nc(N)c2c(Cc3cccc4c3C=Cc3ccccc3N4)csc2n1

Procedure:
9-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminothieno[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed above by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.4 mmol) in Step 1 and dibenz[b,f]azepine (154 mg, 0.8 mmol) in Step 3. The final product and its intermediates can be purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]>CO.[Pd]>[NH2:16][C:3]1[C:2]([CH3:1])=[C:7]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH:6]=[CH:5][C:4]=1[OH:15]
Reactant: Cc1c(NC(=O)C(F)(F)F)ccc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1c(NC(=O)C(F)(F)F)ccc(O)c1N
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 3-methyl-2-nitro-4-trifluoroacetamidophenol (4.81 g, 18.21 mmol) and 10% palladium-on-carbon (0.45 g) in methanol (100 mL) is shaken under an atmosphere of hydrogen (50 psi) for three hours. The mixture is filtered through Celite and concentrated under reduced pressure to yield 4.25 g of 2-amino-3-methyl-4-trifluoroacetamidophenol as a red solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: CO
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of pyridin-3-yl-acetic acid hydrochloride (10 g, 57.6 mmol) in MeOH (30 mL) was treated with thionyl chloride (4.2 mL, 57.6 mmol) and the mixture was stirred at room temperature for 2 h. Solvent was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was collected, dried over MgSO4 and evaporated to give the title compound (7.9 g) as a colourless oil. 1H NMR (CDCl3): 8.53 (2H, m), 7.64 (1H, d), 7.33-7.20 (1H, m), 3.72 (3H, s), 3.64 (2H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:15]([Cl:28])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:28][C:15]1[CH:14]=[N:13][C:12]2[NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:6]=3)[CH2:4][CH2:3][CH2:2][O:27][C:23]3[CH:22]=[C:21]([CH2:20][CH2:19][NH:18][C:16]=1[N:17]=2)[CH:26]=[CH:25][CH:24]=3
Reactant: Oc1cccc(CCNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCCc1cccc(c1)OCCCc1cccc(c1)N2
Yield: 9.7 %

Procedure:
To a solution of 3-{2-[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethyl}phenol (50.0 mg, 0.108 mmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium hydroxide in water (1.0 mL, 1.0 M). The resultant solution was stirred at rt for 60 hours until the reaction was complete. The reaction mixture was neutralized with HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to give the desired product as a white powder (4.0 mg, 10%). LCMS for C21H22ClN4O (M+H)+: m/z=381.0. 1H NMR (400 MHz, CD3OD): δ 7.95 (s, 1H), 7.90 (s, 1H), 7.30 (m, 3H), 7.12 (t, J=7.4 Hz, 1H), 6.94 (m, 1H), 6.65 (m, 2H), 3.70 (t, J=7.6 Hz, 2H), 3.48 (t, J=6.8 Hz, 2H), 2.80 (m, 2H), 2.72 (m, 2H), 2.10 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]([CH:50]2[CH2:52][CH2:51]2)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH:50]4[CH2:52][CH2:51]4)[N:48]=[N:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: ClCc1nnnn1C1CC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nnnn3C3CC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as red gum. MS(m/e): 405.3 (MH+).