Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([NH2:10])=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)[C:23](Cl)=[O:24].C(OC1C=C(C=CC=1OC(=O)C)C(N)=O)(=O)C>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([N:10]=[C:23]=[O:24])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(N)=O)cc(OC(C)=O)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(=O)Oc1ccc(C(N)=O)cc1OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)N=C=O)cc(OC(C)=O)c1OC(C)=O

Procedure:
The procedure used in Example 1 (1) was repeated except that 3,4,5-triacetoxybenzamide (8.0 g) and oxalyl chloride (8.6 g) were used instead of 3,4-diacetoxybenzamide (7.5 g) and oxalyl chloride (10.1 g) to give a solution of 3,4,5-triacetoxybenzoyl isocyanate in anhydrous dichloromethane (40 ml).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[OH:15][C:16]([CH3:46])([CH3:45])[CH2:17][C@@:18]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:23][C:22](=[O:24])[N:21]([C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH3:26])[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[C:8]([N:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([C@@H:25]([N:21]3[CH2:20][CH2:19][C@:18]([CH2:17][C:16]([OH:15])([CH3:45])[CH3:46])([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:23][C:22]3=[O:24])[CH3:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (0.10 mL), acetic anhydride (50 μL), and 4-dimethylaminopyridine (5 mg) were added consecutively to (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (0.12 g) dissolved in tetrahydrofuran (5 mL) at room temperature. The solution was stirred at room temperature for 4 h and then diluted with ethyl acetate. The resulting solution was washed with aqueous saturated NaHCO3 solution and brine and dried (Na2SO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→90:10) to afford the title compound as a colorless foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](F)=[CH:13][C:12]=2[F:21])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH3:22][CH2:23][CH2:24][CH2:25][O:26][C:27]([CH2:29][OH:30])=[O:28].[F-].[K+].O>O1CCOCC1>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:30][CH2:29][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:28])=[CH:13][C:12]=2[F:21])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CCCCOC(=O)CO
Reactant: O=[N+]([O-])c1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(=O)COc1cc(F)c(-n2nc3c(c2Cl)CCCC3)cc1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
A suspension of 3-chloro-2-(2,4-difluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (10 g), butyl glycollate (5 g) and potassium fluoride (10 g) in dioxane (30 g) was refluxed for 1 hour. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was purified by liquid column chromatography using a mixture of hexane and ethyl acetate as an eluent to give 3-chloro-2-(2-fluoro-4-butyloxycarbonylmethoxy-5-nitro-phenyl)-4,5,6,7-tetrahydro-2H-indazole (10.2 g). m.p., 138°-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:40]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of compound A (46.2 mmol) in EtOAc (175 mL) at room temperature was added piperidine (4.57 mL, 46.2 mmol) and the reaction mixture was stirred for 18 h at room temperature. Next the solvent was removed in vacuo and the resulting residue dissolved in minimum amount of EtOAc (˜50 mL) and hexane (˜1 L) was added. Precipitated crude product was filtered off and recrystallised again with EtOAc (˜30 mL) and hexane (˜750 mL). The precipitate was filtered off, washed with hexane and dried in vacuo to afford compound B (28.0 g, 46.2 mmol). LC-MS [M+H] 595.4 (C28H46N6O6S+H, calc: 595.3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH2:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:30][C@H:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: C[C@H](N)c1ccc2ccccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: C[C@H](Nc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (S)-(−)-1-(2-naphthyl)ethylamine and DBU in DME. ES-MS m/e(%): 356 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25](O)=[O:26].[Cl-].[NH4+].C([N:32](CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25]([NH2:32])=[O:26]
Reactant: CCN(CC)CC
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(C(N)=O)c3cc(OC)c(OC)cc23)c1

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30mg, 81.7 mmol), ammonium chloride (43.5 mg. 0.817 mM) and triethylamine (0.115 mL, 0.817 mM) in 2 mL of dimethylformamide was stirred with O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium hexafluorophosphate (61.9 mg. 0.163 mM) at room temperature for 20 hours. Poured into 20 mL of water and 20 mL of ethyl acetate, extracted ethyl acetate layer with saturated sodium bicarbonate, dried ethyl acetate solution. over anhydrous magnesium sulfate and evaporated to give 5.4 mg of an off-white solid pure product: APCI-MS m/e calcd for C20H18N2O6 (M+H.) 367.4, found 367; H NMR (300 MHz) compatible.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:22](O)([CH3:24])[CH3:23])[CH:5]=[C:6]([CH2:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH3:10])[CH:7]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>N1C=CC=CC=1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:9]([CH2:8][C:6]2[CH:5]=[C:4]([C:22]([CH3:24])=[CH2:23])[CH:3]=[C:2]([Br:1])[CH:7]=2)[CH3:10])=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cc(Br)cc(C(C)(C)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)c1cc(Br)cc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
Compound 140 (3.11 g; 7.69 mmol) was dissolved in pyridine (50 ml). While the solution was stirred at room temperature, phosphorus oxychloride (11.8 g; 76.9 mmol) was added dropwise. After completion of the addition, the mixture was stirred for 3 hours at 120° C. The mixture was brought to room temperature, and poured into ice/water. The mixture was alkalinized with sodium hydroxide, and extracted with chloroform (150 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 1.83 g of the target compound as pale yellow oily matter (yield: 61.6%).
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>O1CCCC1>[Br-:8].[Br-:8].[CH2:1]([N+:17]1[CH:18]=[CH:19][N:15]([CH2:9][N:10]2[CH:14]=[CH:13][N+:12]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: c1cn(Cn2ccnc2)cn1
Solvent: C1CCOC1
Product: [Br-]
Product: c1ccc(C[n+]2ccn(Cn3cc[n+](Cc4ccccc4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2 ml of benzyl bromide in 8 ml of tetrahydrofuran are added to 0.0034 mol of 1,1′-methylenediimidazole 4 in an ACE pressure tube, and the mixture is stirred at room temperature for 4 days. The precipitated solid is washed with tetrahydrofuran and then taken up in acetonitrile, admixed once again with 1 ml of benzyl bromide and stirred at 60° C. for 24 hours, at room temperature for 3 days and at 80° C. for a further 30 hours. The resulting solid is filtered off, washed again with tetrahydrofuran and dried. This forms a white solid 19.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11]C23C=CC=CC2C(NC3=O)=O)=[CH:5][CH:4]=1.O.[NH2:26]N>C(O)C>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][NH2:26])=[CH:5][CH:4]=1
Reactant: NN
Reactant: O=C1NC(=O)C2(CC=Cc3ccc(C(F)(F)F)cc3)C=CC=CC12
Solvent: CCO
Solvent: O
Product: NCC=Cc1ccc(C(F)(F)F)cc1
Yield: 100.2 %

Procedure:
A mixture of 2-[3-(4-trifluoromethylphenyl)-2-propenyl]phthalimide (4.57 g, 13.79 mmol) prepared in Reference Example 102 and hydrazine hydrate (897 mg, 17.93 mmol) in ethanol (80 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to return to room temperature and filtered, and the filtrate was concentrated under reduced pressure. To the residue, ethyl acetate was added, and the resulting mixture was washed with 1 N sodium hydroxide aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(4-trifluoromethylphenyl)-2-propenylamine (2.78 g, quantitative) as a pale brown crystalline powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>>[F:26][C:25]([F:28])([F:27])[S:22]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1)(=[O:23])=[O:21]
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCCCC3)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCCCC3)c12

Procedure:
This compound was prepared by treating (4-hydroxy-8-methylnaphthalen-1-yl)(piperidin-1-yl)methanone (above step-2 intermediate) with Tf2O by following the similar procedure as described in Step-8 of Intermediate-22
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([SH:29])[S:28][C:24]=2[CH:23]=1)([CH3:20])[CH3:19]>ClCCl.N1C=CC=CC=1>[C:1]([CH2:3][C:4]([N:21]([CH:18]([CH3:20])[CH3:19])[C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([SH:29])[S:28][C:24]=2[CH:23]=1)=[O:6])#[N:2]
Reactant: CC(C)Nc1ccc2nc(S)sc2c1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cyanoacetic acid (1.63 g, 19.17 mmol) was suspended in anhydrous dichloromethane (40 ml). A catalytic amount of N,N-dimethylformamide (0.1 ml) was added and the mixture cooled to 0° C. under an atmosphere of Argon. After 20 minutes stirring at 0° C., oxalyl chloride (1.67 ml, 19.17 mmol) was slowly added to the reaction mixture, which was then allowed to warm to ambient temperature. This mixture was added slowly, after stirring 1 hour, to a 1 M solution of 6-isopropylamino-1,3-benzothiazole-2-thiol (2.16 g, 9.57 mmol) in anhydrous pyridine. After 2 hours the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and 1 M aqueous citric acid. The resulting precipitate was collected by filtration, combined with the organic extract and concentrated in vacuo. The residue was triturated with diethyl ether to yield 2.32 g (83%). 1H NMR (DMSO-d6) δ=0.98 (m, 6H), 3.43 (s, 2H), 4.75 (sep, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.63 (s, 1H), 13.94 (s, 1H); ESIMS: m/z290 (M-H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:24]#[N:25])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.Cl.[CH2:28]([NH2:32])[CH:29]([CH3:31])[CH3:30]>CO>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:24](=[NH:25])[NH:32][CH2:28][CH:29]([CH3:31])[CH3:30])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:3])=[O:26])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(C#N)n3)cc(C)c21
Reactant: CC(C)CN
Agent: Cl
Solvent: CO
Product: Cc1cc(Oc2cncc(C(=N)NCC(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.8 %

Procedure:
A solution of [6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.57 mmol) in methanol (4.7 mL) was bubbled through gaseous HCl for 40 minutes at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The solvent was removed under reduced pressure. To the residue was added methanol (2.5 mL) and ammonia solution (28%, 0.27 mL). The reaction mixture was refluxed for overnight. LC-MS showed all material converted to methyl imidate while the ethyl ester group was also hydrolyzed to free acid. The solvent was removed under reduced pressure. Half of the residue (0.28 mmol) was dissolved in methanol (2 mL) and isobutylamine (0.29 mL, 2.9 mmol) was added. The reaction mixture was refluxed overnight. The pH was adjusted to pH 3 with aqueous HCl (6 N). Prep-HPLC separation (C18 column) gave the title compound (11 mg, 10%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.90 (1H, s), 8.58 (1H, s), 7.25 (1H, s), 7.14 (1H, s), 5.65 (1H, dd), 3.15 (1H, m), 3.02 (2H, m), 2.60 (3H, s), 2.30 (1H, m), 1.78 (1H, m), 0.95 (3H, d), 0.94 (3H, d). MS found (electrospray): (M+H)+=399.2.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Cl:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24].C(OC(C)C)(C)C>>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Cl:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Cl
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1noc(-c2ccccc2)c1Cl)NCCO[N+](=O)[O-]
Yield: 45.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.70 g of 5-phenyl-4-chloro-3-isoxazolyloxyacetic acid and 0.46 g of nitroxyethylamine nitrate, 0.42 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][NH:35][NH2:36])=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:35]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:36]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: COc1ccc(CNN)cc1
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)cc1
Reaction time: 17 h
Yield: 91.4 %

Procedure:
Triethylamine (83.68 ml) was added to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one (61.23 g), (4-methoxybenzyl)-hydrazine hydrochloride (41.50 g) produced by the method described in U.S. Patent No. U.S.2003/18197, and dichloromethane (600 ml) over 30 minutes under cooling in an ice bath. Thereafter, while the temperature of the reaction solution was gradually raised, it was stirred for 17 hours. Thereafter, a 10% citric acid aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. A 5% citric acid aqueous solution was added to the resulting residue, and the precipitate was then collected by filtration. The resultant was washed with water, so as to obtain the title compound (73.84 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)[N:9]=[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>N1C=CC=CC=1>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])=[C:15]([NH2:17])[N:16]=[C:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:9]2)[N:12]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
300 mg (0.81 mmol) of the compound from example 8A were initially charged in 10 ml of pyridine, and the mixture was cooled to 0° C. 0.81 ml (0.81 mmol) of isopropyl chloroformate was then added dropwise, and the mixture was stirred at 0° C. for a further 60 min. The reaction mixture was brought to RT and purified directly by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient). This gave 88 mg of the target compound (24% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].Cl>ClCCl.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (5.93 g, 48.56 mmol) and triethylamine (10 mL) in 50 mL of dichloromethane was added tosyl chloride (11.8 g, 61.89 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with water, acidified with 1 N HCl, and extracted into methylene chloride. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (9:1 hexanes:ethyl acetate to 5:1 hexanes:ethyl acetate) to afford 9.50 g (71%) of the title compound of Step A. 1HNMR (CDCl3): δ 9.81 (s, 1H), 7.69 (d, 2H, J=8.8 Hz), 7.57 (d, 2H, J=8.4 Hz), 7.19 (d, 2H, J=8.4 Hz), 7.03 (d, 2H, J=8.4 Hz), and 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[H][H]>C(O)C.[C].[Pd]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 83.7 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (545 mg) was dissolved in ethanol (10 ml), then triethylamine (840 μl) and 10% palladium-carbon (54 mg) were added, the reaction mixture was subjected to hydrogenation at hydrogen pressure of 4 kg/cm2 by use of Pearl reduction equipment, there was obtained 2-chloro-4-nitroimidazole (246 mg, yield: 83.4%) as colorless solid matter.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1>CS(C)=O.C(OCC)(=O)C>[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Reactant: CNCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To sodium hydride (60% in mineral oil, 2.3 g, 57.6 mmol) in 20 mL of dimethylsulfoxide at room temperature is added a solution of 3-(methylamino)propan-1-ol (5.14 g, 57.6 mmol) in 10 mL of dimethylsulfoxide. The solution is stirred at room temperature for 1 h, and 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (5.7 g, 14.4 mmol) is added. The mixture is heated at 60° C. for 3 h, and cooled to room temperature. The reaction mixture is diluted with ethyl acetate, and washed with water and saturated sodium chloride. The organic layer is dried over magnesium sulfate, and concentrated to a residue. The residue is triturated with small amount of acetone, then hexanes, and chromatographed over silica gel, eluting with a gradient of 100% ethyl acetate to 100% methyl alcohol. Concentration provides 5-chloro-6-{2,6-difluoro-4-[3-(methylamino) propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a white solid (2.7 g). MS: m/z 465.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1.C(OCC)(OCC)OCC.[N-:26]=[N+:27]=[N-:28].[Na+].[C:30](=O)(O)[O-].[Na+]>C(O)(=O)C.O>[C:12]([O:11][C:9](=[O:10])[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[CH:30]=[N:28][N:27]=[N:26]2)[CH:7]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Cc1ccnc(N)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccnc(-n2cnnn2)c1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl (2-aminopyridin-4-yl)acetate (18 mg, 0.087 mmol) in glacial acetic acid (1 mL) was added triethyl orthoformate (43 μL, 0.261 mmol) and sodium azide (17 mg, 0.261 mmol). The reaction mixture was heated at 80° C. for 3 hours in a sealed vial and then cooled to ambient temperature. Once cooled, water (1.5 mL) and solid sodium bicarbonate were added until a pH range of 6-7 was achieved. The aqueous layer was extracted with ethyl acetate (3×6 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via reverse phase reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford tert-butyl[2-(1H-tetrazol-1-yl)pyridin-4-yl]acetate: LC-MS: (M+H-28)+234.