Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C([O:17][C@@H:18]1[C@H:22]([O:23]C(=O)C2C=CC=CC=2)[C@@H:21]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[O:20][C@H:19]1[N:42]1[CH:50]=[N:49][C:48]2[C:43]1=[N:44][C:45]([Cl:52])=[N:46][C:47]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:52][C:45]1[N:46]=[C:47]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]2)[C:48]2[N:49]=[CH:50][N:42]([C:43]=2[N:44]=1)[C@@H:19]1[O:20][C@H:21]([CH2:32][OH:33])[C@@H:22]([OH:23])[C@H:18]1[OH:17]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCCC(O)C1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCC(O)C4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 7.6 %

Procedure:
The title compound was prepared according to method A as described above by reacting 1-amino-3-hydroxypiperidine (prepared from 3-hydroxypiperidine as outlined in Example 6) (0.60 g, 5.9 mmol) with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 3.94 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-(3-hydroxypiperidinyl)adenosine (0.12 g, 8%) (after column chromatography) as a foam (a mixture of diastereoisomers); 1H NMR (DMSO-d6) δ3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, m, H-2'), 5.08 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1 H, d, H-1'), 8.43 (1H, br s, H-8), 9.45 (1H, 2 br s, N-H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:22])[C:5]([C:8]2([F:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl-].[Li+].[CH:25]([Mg]Cl)([CH3:27])[CH3:26].C(Br)C=C>C1COCC1.[Cu]I>[CH2:27]([C:2]1[CH:3]=[C:4]([F:22])[C:5]([C:8]2([F:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH:25]=[CH2:26]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(Br)cc2F)CC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cnc(C2(F)CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 23 (3.77 g, 10.0 mmol) in THF (50 mL) at 0° C. was added isopropyl magnesium chloride lithium chloride complex (1.3 M in THF, 10 mL, 13 mmol) over 10 min. After additional 10 min of stirring at 0° C., CuI (0.2 eq, 0.38 g) was added, the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (1.73 mL, 20 mmol) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were combined which was washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with EtOAc/hexane (0-10%) to afford 2.84 g (84%) of 24 as a colorless oil. NMR (CDCl3) δ 1.48 (9 H, s), 2.21 (4 H, m), 3.28 (2 H, m), 3.41 (2 H, d, J=6.16 Hz), 4.05 (2 H, m), 5.92 (1 H, m), 7.26 (1 H, dd, J=1.56, 12.08 Hz); LC/MS (M+1) 339.
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: Fc1ccc(CCl)cc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-fluorobenzyl chloride to form 1-(4-fluorobenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 242° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(NC1C=C(OC(=O)C)C=CC=1)=O.[CH3:25][C:26](=[CH2:30])[CH2:27][CH2:28]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC=CC=1.O>[CH3:30][C:26](=[CH2:25])[CH2:27][CH2:28][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: C=C(C)CCO
Agent: CC(=O)Oc1cccc(NC=O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=C(C)CCOc1cccc(NC(C)=O)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3-formylamino-phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.O>CS(C)=O>[CH3:14][C:9]1[C:10](=[O:13])[NH:11][CH2:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH3:18])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: Cc1ncc[nH]1
Reactant: CC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O
Solvent: CS(C)=O
Solvent: O
Product: CC1=C(c2ccc(-n3ccnc3C)c([N+](=O)[O-])c2)CNC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(4-Fluoro-3-nitrophenyl)-1,5-dihydro-3-methyl-2H-pyrrol-2-one (6.5g, 28 mmol) and 2-methylimidazole (6.8 g, 83 mmol) are combined in dimethylsulfoxide (50 mL) and the mixture is heated to 50° C. under a nitrogen atmosphere for 4 hr. The mixture is then cooled to room temperature, and water is added to give a precipitate. The mixture is kept cold for 1 hr, and the precipitate is collected by filtration, washed with water, and air-dried to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:23][N:24]([CH:34]([C:38]1[N:47]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](=[O:55])[C:45]2[C:40](=[CH:41][C:42]([Cl:56])=[CH:43][CH:44]=2)[N:39]=1)[CH:35]([CH3:37])[CH3:36])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=O)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:23][N:24]([C@@H:34]([C:38]2[N:47]([CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:46](=[O:55])[C:45]3[C:40](=[CH:41][C:42]([Cl:56])=[CH:43][CH:44]=3)[N:39]=2)[CH:35]([CH3:37])[CH3:36])[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)N(CC(CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2=N[C@@H](CCCNC(=O)OCc3ccccc3)CN2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 240 h
Yield: 32.4 %

Procedure:
A solution of (1-([[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(1-p-tolyl-methanoyl)-amino]-methyl}-4-benzyloxycarbonylamino-butyl)-carbamic acid tert-butyl ester (235 mg, 0.37 mmol) in CH2Cl2/TFA (4:1, 5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was diluted with THF (10 mL) and saturated aqueous NaHCO3 (1 mL). The mixture was stirred at room temperature for 10 days, diluted with ether (20 mL) and washed with brine. The aqueous layer was extracted with two 10 mL portions of EtOAc and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (19:1 CH2Cl2:MeOH) to provide 81 mg (40%) of the title compound as a pale white powder. MS(ES+) m/e 675.6 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cc([N+](=O)[O-])ccc1C
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
To a mixture of 2-methyl-5-nitrophenol (2.5 g, 16.3 mmol) and 1M aqueous sodium hydroxide (24.5 ml) was added at ambient temperature acetic anhydride (1.9 ml, 20.3 mmol). The mixture was stirred for 40 minutes, the solid was filtered off and the filtrate extracted with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and evaporated to yield 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture of this material (3.1 g, 15.9 mmol) and 10% palladium-on-charcoal catalyst (0.12 g) in ethyl acetate (50 ml) was stirred at ambient temperature under an atmosphere of hydrogen for 2 hours. The catalyst was filtered off and the filtrate evaporated to give 3-acetoxy-4-methylaniline (2.45 g, 94%).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2[CH2:54][C:55]#[N:56])O1>CCCCCCC.CCOC(C)=O>[CH3:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH2:54][C:55]#[N:56]
Reactant: CC1(C)OB(c2ccccc2CC#N)OC1(C)C
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1ccccc1CC#N

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile (CAS RN 325141-71-7) after a reaction time of 6 days and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Light yellow solid (69%). MS (ESI): m/z=224.118 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C1CCCC1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCC2)C1
Yield: 86.2 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), cyclopentanone (0.095 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 78 mg (87%) of the title compound.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][N:18]([C:25]4[N:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][N:26]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Nc1nc(Cl)ncc1F
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1nc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C(F)(F)F)n2)ncc1F

Procedure:
A solution of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (adamantan-1-ylmethyl)-amide (100 mg, 0.306 mmol), 2-chloro-5-fluoro-pyrimidin-4-ylamine (52 mg, 0.35 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in NMP (1.0 mL) is heated in a microwave reactor at 150° C. for 1 h. The mixture is poured into H2O. The crude product is filtered out, dissolved in 10% MeOH in DCM, and dried over anhydrous Na2SO4. The title compound is purified by PTLC (eluted with 5% MeOH in DCM). 1H NMR (CD3OD): 8.96 (s, 1H), 8.11 (s, 1H), 3.0 (s, 2H), 1.98 (m, 3H), 1.78-1.68 (m, 6H), 1.58 (s, 611). MS (M+1)=439.29; RT=1.34 min. *IC50.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](I)[C:20]=1[Cl:26]>>[Cl:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Clc1cccc(I)c1Cl
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cccc(Cl)c3Cl)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,2-dichloro-3-iodobenzene according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 7.83 (s, 1H), 7.17 (m, 2H), 7.06 (d, J=8.7 Hz, 1H), 7.03 (m, 2H), 6.94 (dd, J=8.3, 1.4 Hz, 1H), 3.28 (s, 3H), 1.97 (m, 4H), 0.81 (t, J=7.3 Hz, 6H); MS (ESI) m/z [M+H]+ (379/381/383); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.80; H, 4.96; N, 7.13.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Br:15][C@@H:16]1[CH2:18][C@H:17]1[C:19](Cl)=[O:20]>O1CCCC1>[Br:15][C@@H:16]1[CH2:18][C@H:17]1[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)[C@@H]1C[C@H]1Br
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(NC(=O)[C@@H]3C[C@H]3Br)cc2)=NN1
Yield: 58 %

Procedure:
4.0 g (21.1 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone of trans-2-bromocyclopropanecarboxylic acid chloride, 4.3 g (23.4 millimoles) and 100 ml of absolute tetrahydrofuran are kept for 20 hours at room temperature and then refluxed for 6 hours. The product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 4.1 g (58% of theory) of trans-6-[p-(2-bromocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 260°-261° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[CH2:10](OC(OCC)OCC)C>>[Cl:1][C:2]1[N:3]2[CH:10]=[N:9][N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1cccc(Cl)n1
Product: Clc1cccc2nncn12
Temperature: 25 °C
Yield: 53.8 %

Procedure:
Charge a 125 mL round-bottomed flask with 2-chloro-6-hydrazinylpyridine (3.0 g, 20.9 mmol), triethoxymethane (20 mL, 120.2 mmol). The mixture was heated at reflux for 4 hours and allowed to cool to ambient temperature overnight. The mixture was concentrated to dryness and 50 ml POCl3 was added. The mixture was refluxed overnight. The reaction was quenched over ice and washed with CH2Cl2. The aqueous layer was adjusted to pH 6 with 1N NaOH and extracted with CH2Cl2 and the organics concentrated and purified on Si gel eluting with 100% EtOAc (500 ml) followed by 5% MeOH/CH2Cl2 to give 5-chloro-[1,2,4]triazolo[4,3-a]pyridine (1.73 g, 11.25 mmol, 53% yield) as a solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH:13]=[CH:14][CH:15]=2)[N:8]=[C:7]([C:23]([OH:25])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:32]C=2C=1.C(N(CC)C(C)C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH:13]=[CH:14][CH:15]=2)[N:8]=[C:7]([C:23]([NH2:32])=[O:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)c1cc(C(=O)O)nn1-c1cccc(-c2ccccc2Cl)c1
Agent: CCN(CC)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(N)=O)nn1-c1cccc(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
To a solution of the carboxylic acid (0.062 g, 0.17 mmol) in DMF (1 ml) were added pyBOP (0.138 g, 0.26 mmol), HOBT (0.035 g, 0.2 mmol), diethylisopropylamine (0.147 ml, 0.87 mmol) and ammonium chloride (0.056 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 16 hours, then cooled and partitioned between ethylacetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by silica-gel chromatography (3:2 hexanes/ethylacetate) yielded the product (0.062 g, 64%) as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:44]2[CH:43]=[N:42][C:41]([Sn](CCCC)(CCCC)CCCC)=[N:40][C:39]=2[C:38]([CH3:58])=[N:37]1>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:41]4[N:42]=[CH:43][C:44]5[N:36]([CH3:35])[N:37]=[C:38]([CH3:58])[C:39]=5[N:40]=4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc2c(n1)c(C)nn2C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ncc5c(n4)c(C)nn5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (0.055 g, 0.107 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-pyrazolo[4,3-d]pyrimidine (0.058 mg, 0.133 mmol), copper(I) iodide (6 mg, 0.032 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.012 mmol) in dioxane was heated at 90° C. for 16 hr. Reaction mixture was cooled to rt, filtered through a syringe filter and purified by CombiFlash (12 g, Gold, 10-100% EtOAc/Hex, then 15% MeOH/CH2Cl2 to elute product) to give impure product that was used in next step without further purification. LCMS-ESI+: calc'd for C33H32ClN6O3S: 627.2 (M+H+); Found: 627.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH:9]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:8](=[O:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1.O>CO>[CH3:3][CH:4]1[CH:9]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:8]([OH:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1
Reactant: CC1Oc2ccccc2C(=O)C1n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1Oc2ccccc2C(O)C1n1ccnc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
NaBH4 (0.6 g) was added portionwise to a solution of 2-methyl-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4 one (1.3 g) in MeOH (70 ml) at room temperature. The mixture, stirred for 2 hours, added with water (300 ml), extracted with CHCl3, dried and evaporated to dryness gave 2-methyl-3-(1-imidazolyl)-2.3-dihydro-4H-1-benzopyran-4-ol (1.3 g); m.p.=160°-175° C.;
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46](O)=[O:47])([CH3:45])[CH3:44])=[CH:33][CH:32]=2)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)=[O:47])([CH3:45])[CH3:44])=[CH:35][CH:36]=3)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CN1CCNCC1
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])=[O:3].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]([NH:4][C:5]1[CH:10]=[C:9]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=2)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 4, N-methylcarbonyl 2-nitro-5-fluoroaniline (3.1 g, 15.4 mmol), 4-trifluoromethylphenol (2.5 g, 15.4 mmol) and potassium carbonate (4.3 g, 31.0 mmol) are reacted together to give N-methylcarbonyl 2-nitro-5-(4-trifluoromethylphenoxy)aniline, 4.0 g of which is then reacted with 20% hydrochloric acid (~50 ml) to give 2-nitro-5-(4-trifluoromethylphenoxy)aniline. 2-Nitro-5-(4-trifluoromethylphenoxy)aniline (2.0 g, 6.7 mmol) is reacted with potassium hydroxide (0.4 g, 7.0 mmol) and sodium hypochlorite (19 ml of 5.2% solution, 1.0 g, 13.4 mmol) to yield 5-(4-trifluormethylphenoxy)benzo-2,1,3-oxadiazole N-oxide, m.p. 40°-42°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[S:15][C:16]([CH3:19])=[N:17][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)C>[CH2:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:13][C:14]3[S:15][C:16]([CH3:19])=[N:17][N:18]=3)[C:3]=2[CH:10]=1)[CH3:12]
Reactant: Cc1nnc(N)s1
Reactant: CCc1cc2c(Cl)ncnc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC(C)O
Product: CCc1cc2c(Nc3nnc(C)s3)ncnc2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of Example 1C (0.20 g, 1.01 mmol) in isopropanol (2 mL) was treated with 2-amino-5-methyl-1,3,4-thiadiazole (0.115 g, 1.726 mmol) and sodium carbonate (0.18 g, 1.7 mmol), stirred at room temperature for 48 hours, treated with cesium carbonate (0.55 g, 1.7 mmol), stirred at reflux for 24 hours, concentrated, treated with water, and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The residue was recrystallized with ethanol/water to provide the title compound.