Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][OH:25])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A mixture of [1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methanol (5.57 g), activated manganese dioxide (16.11 g), and tetrahydrofuran (100 ml) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (5.39 g, yield: 98%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 115˜116° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: NCCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)NCCC(=O)O

Procedure:
72.69 g (311.3 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 40 g (448.98 mmol) of β-alanine and 90 g (889.5 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=O)[N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12>C(N)C=C>[CH2:4]([NH:5][C:8]([C:6]1[N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]2=[C:2]([Cl:1])[CH:7]=1)=[O:10])[CH:3]=[CH2:2]
Reactant: CCOC(=O)c1cc(Cl)c2[nH]ncc2n1
Solvent: C=CCN
Product: C=CCNC(=O)c1cc(Cl)c2[nH]ncc2n1

Procedure:
A solution of ethyl 7chloro-1H-pyrazolo[4,3-b]-pyridine-5-carboxylate (1.5 g, 6.65 mmol) in allylamine (25 ml) was heated under reflux for 3 days. The solvent was evaporated in vacuo and the residue was extracted into warm ether to give 7-chloro-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid allyl amide as a pale yellow solid, m.p. 121°-125° C. Without further purification, this material was dissolved in allylamine (10 ml) and water (10 ml) and heated under reflux for 6 days. Excess allylamine was removed in vacuo and the precipitated solid was collected and washed well with water, to give the crude product (940 mg, 55%). Recrystallisation from ethyl acetate gave the title compound, m.p. 194°-197° C.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([CH:20]=[CH2:21])[CH:10]=1)(C)(C)C.C(N(CC)CC)C.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(#N)C>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:6](=[O:22])[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[C:11]([CH:20]=[CH2:21])[CH:10]=2)=[CH:33][CH:32]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1cc(CNC(=O)NCc2ccc(Cl)cc2)ccc1NS(C)(=O)=O
Yield: 14.9 %

Procedure:
As described in scheme 12, (4-methanesulfonylamino-3-vinylbenzyl)carbamic acid t-butylester (50 mg, 0.153 mmol) and triethylamine (0.1 ml) and 4-chlorobenzylamine (26 mg) were stirred for one night in the presence of acetonitrile solvent. The solvent was removed from the reaction mixture and purified by column chromatography to yield the purposed compound (9 mg).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[S:13]>ClCCl>[C:1]1([N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]2=[S:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCCCNc1ccccc1
Solvent: ClCCl
Product: S=C1NCCCN1c1ccccc1
Yield: 78 %

Procedure:
Prepared in the manner of Example 1, Step B from N-phenyl-propane-1,3-diamine of Step A and 1,1′-thiocarbonyldiimidazole, except that the cyclization was effected in dichloromethane. Workup consisted of washing with water, drying over magnesium sulfate, filtration and removal of solvent in vacuo. Purfication by flash chromatography on silica gel Merck-60 eluting with 1% methanol in dichloromethane followed by trituration with ethyl ether to provide the title compound as a white solid (2.74 g, 78%), m.p: 211-212° C., identical to the material described by Kashima et al., J. Chem. Soc. Perkin I, 1622 (1981).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=1[CH3:38].C1CCN(C(Cl)=[N+]2CCCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=3[CH3:38])=[O:18])=[CH:20][CH:21]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)COc1ccc(N)c(C)c1
Agent: Cl
Agent: ClC(N1CCCCC1)=[N+]1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl) piperazinyl)benzoic acid (0.75 g, 2.45 mmol), ethyl 4-amino-3-methylphenoxyacetate hydrochloride (0.60 g, 2.45 mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (0.97 g, 2.69 mmol), and CH2Cl2 (30 mL). This mixture was cooled in an ice bath and diisopropylethylamine (1.74 mL, 10.0 mmol) was added. The ice bath was allowed to expire and the solution was stirred at ambient temperature for 48 h. The solution was diluted with CHCl3 and washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 75 g of silica gel using 50% EtOAc-hexane as eluant. There was obtained 1.22 g (100%) of ethyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)-3-methylphenoxy)acetate as a crystalline solid.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([O:4][CH2:1][CH:2]=[CH2:3])=[O:16]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: C=CCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1ccccc1Cl

Procedure:
Sixty parts of allyl alcohol were dissolved in 240 parts of chloroform, followed by an addition of 105 parts of triethylamine. While stirring the resultant mixture at 10°-15° C., 175 parts of o-chlorobenzoyl chloride were added dropwise over 2 hours. After the resultant mixture was heated at 45°-50° C. for 3 hours, the liquid reaction mixture was poured in a separation funnel and washed first with dilute hydrochloric acid and then with water. The thus-formed light-yellowish organic layer was dried with calcium chloride and then treated with activated carbon. After driving chloroform off, the residue was distilled under reduced pressures to obtain 153 parts of allyl o-chlorobenzoate (hereinafter called "Compound A"; b.p. 101° C./3.5 mmHg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(O)=O>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.0 g (25.0 mmol) tert-butyl piperidin-4-yl-carbamate and 4.46 mL (25.0 mmol) 1-benzyl-piperidin-4-one in 150 mL THF was adjusted with AcOH to a pH of 5 and then combined batchwise with 5.61 g (26.5 mmol) NaBH(OAc)3 within 3 h while cooling with ice. The reaction mixture was stirred overnight at RT, then made alkaline with 500 mL 30% K2CO3 solution, stirred for 1 h at RT, extracted three times with 100 mL EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was reacted further without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: O=C1CNCCN1
Reactant: Fc1ccc(CCCl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCc2ccc(F)cc2)CCN1
Temperature: 85 °C
Yield: 48.3 %

Procedure:
piperazinone (1.20 g, 12.1 mmol), 1-fluoro-4-(2-chloroethyl)benzene (2.45 g, 12.1 mmol) and i-Pr2NEt (3.25 g, 4.5 ml, 25 mmol) were combined in acetonitrile (25 mL) and heated to 85° C. for 2 h. The mixture was concentrated and partitioned between H2O (20 mL) and CH2Cl2 (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH2Cl2 (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH2Cl2 (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.30 g, 48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 7.00-6.94 (m, 2H), 6.45 (s, 1H), 3.39-3.35 (m, 2H), 3.20 (s, 2H), 2.78-2.62 (m, 6H).
Reaction SMILES: ON1C(=O)C2=CC=CC=C2C1=O.C(N(CC)CC)C.[N+]([C:23]1[CH:24]=[CH:25][C:26]2[N:32]3C(CCl)=NN=[C:31]3[CH2:30][N:29]=[C:28](C3C=CC=CC=3Cl)[C:27]=2[CH:45]=1)([O-])=O>CC(N(C)C)=O>[NH:32]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:45][C:27]=2[CH:28]=[N:29][CH:30]=[CH:31]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-nitro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-nitro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo][4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(OO)(=[O:18])C>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(=O)OO
Reactant: CC(C)COc1ncc(B(O)O)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COc1ncc(O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.6 %

Procedure:
To a suspension of 5-chloro-6-isobutoxypyridin-3-ylboronic acid (3.02 g, 13.1 mmol) in acetic acid/water (1:1, 20 mL) cooled to 0° C. was slowly added peracetic acid (3.9 mL, 20.0 mmol) and the reaction mixture was maintained at 0° C. for 1.5 hours and then at room temperature for 1 hour. Additional peracetic acid (3.9 mL, 20.0 mmol) was added and the reaction stirred at room temperature for 40 minutes after which time the suspension dissolved. The reaction mixture was quenched with sodium thiosulphate solution (15 mL) and stirred for 5 minutes. The mixture was extracted with EtOAc (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to afford a yellow oil (3.66 g). The oil was purified by silica gel chromatography (Biotage™ 50 g) eluting with 80 to 100% methanol in DCM to afford the title compound as a white solid (1.94 g, 73%):
Reaction SMILES: Cl.N(OCCC(C)C)=O.[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:40]([N:42]=[N+]=[N-])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17].Cl.[CH2:46]([O:48][C:49](=[O:70])[CH2:50][NH:51][C:52](=[O:69])[C@H:53]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=1)[NH:54][C:55](=[O:60])[C@H:56]([CH2:58][OH:59])N)[CH3:47]>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[CH2:46]([O:48][C:49](=[O:70])[CH2:50][NH:51][C:52](=[O:69])[C@H:53]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=1)[NH:54][C:55](=[O:60])[C@H:56]([CH2:58][OH:59])[NH:42][C:40](=[O:41])[C@H:29]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:28][C:26](=[O:27])[C@H:19]([CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)[NH:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[NH:10]1)[CH3:47]
Reactant: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: -50 °C
Reaction time: 21 h

Procedure:
To a stirred suspension of 1.165 g. of L-pyroglutamyl-L-histidyl-L-tryptophanyl hydrazide (prepared as described in Example 1(b) above) in 30 ml. of N,N-dimethylformamide, cooled to -20° C., is added 6.13 ml. of 2.45 N hydrogen chloride in tetrahydrofuran and 0.5 ml. of isoamyl nitrite, and the resulting mixture is stirred at -10° to -20° C. for one hour. The mixture, which contains L-pyroglutamyl-L-histidyl-L-tryptophanyl azide, is next cooled to -50° C. and to it are added first 2.1 ml. of triethylamine, then 975 mg. of L-seryl-L-tyrosylglycine ethyl ester hydrochloride (prepared as described in (b) above), and finally 0.35 ml. more of triethylamine. The stirred mixture is allowed to warm to 0° C. during one hour and is kept at -5° C. for 21 hours. It is then filtered, and the filtrate is evaporated under reduced pressure to give a residue of L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosylglycine ethyl ester, which is dissolved in 50 ml. of methanol. To the solution is added 2 ml. of 99% hydrazine hydrate, and the resulting mixture is kept at room temperature for 16 hours. The solid that forms is isolated by filtration and stirred well with 20 ml. of water. The aqueous mixture is heated on the steam bath for 20 minutes, filtered, and the isolated solid is mixed with 15 ml. of methanol. The methanolic mixture is heated on the steam bath for 15 minutes, and the solid product is again isolated by filtration and dried. It is L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosylglycyl hydrazide monohydrate; m.p. 218°-220° C.; [α]D25 -22.7° (1% in 1 N hydrochloric acid).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][OH:17])=O.O.[OH-].[Na+]>O1CCCC1>[NH2:7][CH2:8][CH2:9][N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][OH:17]
Reactant: NCC(=O)N1CCC[C@@H]1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCC[C@@H]1CO
Yield: 78.8 %

Procedure:
To tetrahydrofuran (30 ml) was added lithium aluminum hydride (720 mg, 19.0 mmol) and the mixture was stirred under ice-cooling. Then, a solution (20 ml) of the compound (1.00 g, 6.32 mmol) obtained in step A in tetrahydrofuran was gradually added, and the mixture was heated under reflux for 2 hr. The reaction mixture was cooled, water (0.72 ml), 1N aqueous sodium hydroxide solution (1.44 ml) and water (0.72 ml) were slowly added in this order with stirring, and the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered off through celite, and the solution was concentrated under reduced pressure to give the title compound (718 mg, yield 79%) as a yellow oil.
Reaction SMILES: C([C:3]1[CH:7]=[CH:6][O:5][N:4]=1)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20]C3OC=NC=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH2:15][C:14]=2[CH:41]=1)#[N:9].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][C:6]3[O:5][N:4]=[CH:3][CH:7]=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:35])[CH2:15][C:14]=2[CH:41]=1)#[N:9]
Reactant: O=Cc1ccon1
Reactant: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2cnco2)C[C@H]1Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2ccno2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-formylisoxazole (19.4 mg, 0.2 mmol) and Compound B of Example 25 (39.9 mg, 0.1 mmol) in DCM (0.5 mL) at rt was added TFA (45 mg, 0.4 mmol), followed by triethylsilane (35 mg, 0.3 mmol). The resulting mixture was stirred at rt for 1 hour, neutrallized with NaHCO3 solution and extracted with DCM (2×5 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (SiO2; ethyl acetate: methanol ammonia/100:10:0.1) to afford the title compound, 45 mg (87%). MS: m/e (M+H)+=480.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=O)[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[Cl:15][C:16]1[C:17]([N:22]2[C:26](C(Cl)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:26]3[N:22]([C:17]4[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:23]=[C:24]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1
Reactant: O=c1[nH]c2c(Br)cc(Cl)cc2c(=O)o1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Br)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a suspension of 8-Bromo-6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (5.0 g, 18.1 mmol) in acetonitrile (10 mL) was added a solution of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (6.45 g, 20.8 mmol) in acetonitrile (8 mL). After stirring for 5 min pyridine (10.4 mL) was added dropwise. The reaction was stirred for a further 30 min at room temperature, then heated to 100° C. for 4 h and stirred for a further 16 h at room temperature. The reaction was then cooled in an ice-bath and the resulting white solid filtered and washed with cold acetonitrile to obtain the title compound (5.88 g, 64%).
Reaction SMILES: [Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([OH:21])=O)=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:23]3[CH2:26][CH2:25][CH2:24]3)=[O:21])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(Br)nc2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (929 mg, 2.54 mmol), azetidine (206 μl, 3.05 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.75 ml, 6.36 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.63 mmol) in tetrahydrofuran (20 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was triturated with sat. sodium hydrogencarbonate solution. The solid was filtered off, washed with water and dried in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (910 mg, 88.5%) as a light yellow solid. mp: >250° C., MS: m/z=402.2/404.0 (M−H+)
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[CH2:22][C:23]1[N:24]([CH3:49])[C:25]2[C:30]([N:31]=1)=[C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[N:28]=[C:27]([N:38]1[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]1[CH2:47][CH3:48])[N:26]=2)=O)(C)(C)C>C(Cl)Cl>[C@H:19]12[CH2:21][C@H:16]([NH:15][CH2:20]1)[CH2:17][N:18]2[CH2:22][C:23]1[N:24]([CH3:49])[C:25]2[C:30]([N:31]=1)=[C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[N:28]=[C:27]([N:38]1[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]1[CH2:47][CH3:48])[N:26]=2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (122 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 520 mg) in DCE (10 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 85:15) to give (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid. TFA (3 mL) was added to a solution of (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; gradient from 100:0 to 85:15) to afford 395 as a white solid (153 mg, 63%). LCMS (Method G): RT=5.78 min, M+H+=474. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.26 (m, 2 H); 4.34 (m, 4 H); 4.00 (d, J=13.6 Hz, 1 H); 3.92-3.83 (m, 8 H); 3.70 (s, 1 H); 3.45 (s, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.25 (d, J=10.2 Hz, 1 H); 2.97-2.91 (m, 2 H); 2.70 (d, J=10.2 Hz, 1 H); 1.85 (d, J=10.1 Hz, 1 H); 1.70 (d, J=10.1 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)