Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([N:28]1[C:32]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:31][C:30]([CH:37]=O)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[C:32]([CH2:33][CH:34]([CH3:35])[CH3:36])=[CH:31][C:30]([CH2:37][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1C(C)(C)C
Yield: 68 %

Procedure:
Compound 95 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28][C:29]#[CH:30]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:30]#[C:29][CH2:28][CH2:27][NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: C#CCCNC(=O)C(C)(C)C
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 101.9 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with N-but-3-ynyl-2,2-dimethyl-propionamide (306 mg, 2 mmol) in DMF (10 mL). Purify by chromatography on silica gel eluting with cyclohexane/EtOAc (85:15 to 0:100 gradient) to obtain 7-chloro-6-[4-(2,2-dimethyl-propionylamino)-but-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (437 mg, 99%).
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]=1[N:20]=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[C:18]1[CH3:22])=[S+:13]2)[CH3:7].[CH2:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:38]=1[N:37]=[C:36]1[C:31]([CH:32]=[CH:33][CH:34]=[C:35]1[CH3:39])=[S+:30]2)[CH3:24].[CH2:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:55]=1[N:54]=[C:53]1[C:48]([CH:49]=[CH:50][CH:51]=[C:52]1[CH3:56])=[S+:47]2)[CH3:41].C(C1C=CC=C2[C:72]=1[N:71]=[C:70]1C(C=CC=C1C)=[S+]2)C.C(Cl)(Cl)Cl>>[I-:2].[I-:2].[I-:2].[CH3:36][N:37]([CH3:38])[C:10]1[CH:9]=[C:8]([CH2:6][CH3:7])[C:21]2[C:12]([CH:11]=1)=[S+:13][C:14]1[C:19](=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=1)[N:20]=2.[CH3:70][N:71]([C:44]1[CH:43]=[C:42]([CH2:40][CH3:41])[C:55]2[C:46]([CH:45]=1)=[S+:47][C:48]1[C:53](=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=1)[N:54]=2)[CH3:72].[CH3:19][N:20]([C:27]1[CH:26]=[C:25]([CH2:23][CH3:24])[C:38]2[C:29]([CH:28]=1)=[S+:30][C:31]1[C:36](=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=1)[N:37]=2)[CH3:21]
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(N(C)C)cc2[s+]c3cccc(C)c3nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred mixture of 9-ethyl-1-methylphenothiazin-5-ium tetraiodide hydrate (383 mg, 0.5 mmol) in anhydrous CHCl3 (20 mL) dimethylamine (0.5 mL, 1.0 mmol, 2 M solution in THF) was added drop wise over 4 h. The resulting mixture was stirred at room temperature overnight, concentrated to dryness.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].O.[NH2:25][NH2:26]>O1CCOCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH:25][NH2:26])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=S)NN)cc3)CC2)cc1
Yield: 89 %

Procedure:
A mixture of 47.8 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 100 parts of hydrazine hydrate and 400 parts of 1,4-dioxane is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off, washed with water and with methanol and dried, yielding 46 parts (89%) of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarbothioamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH2:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2nccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-3-[4-([2,6]naphthyridin-1-yloxy)phenyl]propionic acid methyl ester (271 mg, 0.64 mmol) in dichloromethane (7.5 ml) was treated with trifluoroacetic acid (7.5 ml) and stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (60 ml) and saturated aqueous NaHCO3 (25 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×25 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford the title compound (206 mg, 100%) as an oil that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17]>O1CCOCC1>[O:17]=[C:12]1[NH:11][CH2:16][CH2:15][N:14]([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:13]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C1CNCCN1
Solvent: C1COCCO1
Product: O=C1CN(c2ncc(B(O)O)cn2)CCN1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
(2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100° C. under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with methanol and diethyl ether. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. Method B HPLC-MS: MH+ m/z 223, RT 0.25 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:27])[CH2:19][C@@H:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23].O.[OH-].[Li+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:27])[CH2:19][C@@H:20]([CH3:26])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)OC)c2cc(Cl)ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)O)c2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of Methyl 5-(5-chloro-2-hexyl-1-methyl-1H-indol-3-yl)-3-(R)-methyl-5-oxopentanoate in iso-propanol and water was added lithium hydroxide monohydrate and was stirred at RT for three hours. The product was purified by column chromatography.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.009 g of product in 39% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][NH:5][CH:4]=[C:3]1[C:12]([O:14][CH3:15])=[O:13].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]cc(C(=O)OC)c1=O
Product: COC(=O)c1cncc(C(=O)OC)c1Cl
Temperature: 140 °C
Yield: 33.7 %

Procedure:
A mixture of dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylate (3 g, crude) and POCl3 (10 mL) was heated to 140° C. in the sealed tube for 15 hours. The mixture was cooled to RT, poured into ice and extracted with ether. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as solid (yield 33.7%).
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[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[Cl:52]>>[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[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1cccc(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), 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 1-(bromomethyl)-2,3-dichlorobenzene and isolated as white solid (5.5 mg, 30%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [N+:1](=[C:3]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C@H:4]1[CH2:5][CH2:6][C@@H:7]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:26])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:12]([CH3:15])[CH2:13][OH:14])=[N-:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[N+:1](=[C:3]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C@H:4]1[CH2:5][CH2:6][C@@H:7]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:26])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH:13]=[O:14])[CH3:15])=[N-:2]
Reactant: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C(=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](C=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C(=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 60 mg of (5α,20R)-4-diazo-21-hydroxy-20-methyl-pregnane-3-one in 5 ml of dichloromethane is added 60 mg of pyridinium chlorochromate and the mixture is stirred for 16 hours at room temperature. It is then diluted with ether and filtered through a small column of silica gel in ether. Evaporation of the solvent leaves a solid which is recrystallized from ether to give (5α,20R)-4-diazo-3-oxopregnane-20-carboxaldehyde which melts with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][O:13][Si](C(C)C)(C(C)C)C(C)C)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][CH:33]1O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:35][CH:33]1[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)[Si](OCc1cc(Br)cc2ccccc12)(C(C)C)C(C)C
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc2ccccc12

Procedure:
With similar method described in Step 3 of Example 92, ((3-bromonaphthalen-1-yl)methoxy)triisopropylsilane (compound 76, 18.0 g, 45.6 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (2, 20.5 g, 38.0 mmol) were converted to title compound (23.3 g, 90%, ca. 2:1 mixture of anomers (13:0) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:42](Cl)(=[O:44])=[O:43])[CH2:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[O:32][CH2:33][CH2:34][CH2:35]2)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1cccc2c1OCCC2
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2c1OCCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. chromane-8-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Yield: 88.3 %

Procedure:
A mixture of 1-benzyl-3-[3-(1-naphthylsulfonylmethyl)-4-nitro-phenoxy]-piperidine (1.2 g, 2.3 mmoles) and 10% Pd/C in THF and methanol was hydrogenated in a Parr hydrogenation bottle at 52 lb/in2 overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (1.0 g, 2.03 mmoles).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([O:8]C(C)=O)[C@H:3]1[O:12]C(C)=O.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([OH:8])[C@H:3]1[OH:12]
Reactant: CC(=O)O[C@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1OC=C[C@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
10 grams of 3,4-di-O-acetyl-L-rhamnal is dissolved in 100 milliliters of methanol, and the pH is adjusted to 8 to 9 by the dropwise addition of a freshly prepared solution of sodium methoxide in methanol. The flask is sealed and allowed to stand at 0°-5° C. overnight after which time deacetylation is complete. The solution is neutralized by the careful dropwise addition of glacial acetic acid, and then the solvent is removed under reduced pressure. The resulting clear syrup is co-evaporated several times with toluene to remove any excess acetic acid, and the syrup crystallizes during these evaporations to give L-rhamnal. The yield of this compound is 6 grams.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 84.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (50 mg, 0.0815 mmol) prepared in Example 42a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (32 mg, 85%) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[CH2:25]([O:24][P:23]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])([O:27][CH2:28][CH3:29])=[O:30])[CH3:26]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCBr
Product: CCOP(=O)(CCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 150 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
A mixture of 8.24 g of 1-bromo-8-(nonafluorobutyl)octane and 8.31 g of triethyl phosphite was heated at 150° C. After 15 hr an additional 4.30 g of triethyl phosphite was added, and heating was continued for 4 hr. Diethyl ethylphosphonate and other volatiles were removed by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa). Bulb-to-bulb distillation of the concentrate provided 8.72 g of 1-(diethylphosphono)-8-(nonafluorobutyl)octane as a clear, colorless liquid, b.p. 115-125° C. at 0.08 torr (11 Pa).
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH2:16]1[CH:23]2[C:19]3([C:25](O)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8]/[C:7]/1=[N:15]\[C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COCCn1c2c(sc1=N)CCCC2
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCCC2

Procedure:
A mixture of the product of Example 68A (293 mg, 1.00 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (199 mg, 1.20 mmol), HATU (570 mg, 1.50 mmol) and triethylamine (836 mL, 6.00 mmol) in 15 mL of DMF was processed according to the method of Example 3B to afford the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.53-1.62 (m, 4H) 1.67-1.82 (m, 8H) 2.07-2.12 (m, 2H) 2.23-2.27 (m, 2H) 2.45-2.49 (m, 3H) 2.54-2.59 (m, 2H) 3.23 (s, 3H) 3.63 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.5 Hz, 2H); MS (DCI/NH3) m/z 361 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2].[N+](=[CH2:20])=[N-]>O1CCOCC1.C(OCC)C>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][O:17][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)C(=NO)c1nccc(NC=O)n1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)C(=NOC)c1nccc(NC=O)n1

Procedure:
Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g.) was dissolved in dioxane (200 ml.) under heating and the resultant solution was cooled to ambient temperature in an ice bath, and then thereto was added a solution of diazomethane in diethyl ether with stirring until complete consumption of the starting materials. The reaction mixture was concentrated to give a brown oil, which was purified by column chromatography on silica gel (140 g.) using benzene as an developing solvent and a mixture of benzene and ethyl acetate (3:1) as an eluent to give a pale brown semisolid of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.4 g.).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C)C=O>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCc2ccccc2Cl)c1
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
To 1.31 g (9.22 mmol) of orcinol monohydrate in 20 mL anhydrous N,N-dimethylformamide under a nitrogen atmosphere was added 220 mg (9.17 mmol) of NaH (100%). After 5 min, 1.30 mL (10.0 mmol) of 2-chlorobenzyl bromide was added. The reaction mixture was stirred for 2 h and then quenched with 1N HCl. The reaction mixture was extracted into ethyl acetate (200 mL). The organic phase was washed with water (4×100 mL), dried (MgSO4), and concentrated in vacuo. Purification by flash chormatography (diethyl ether/hexane (50:50 to 100:0) gave 656 mg of the title compound as a glass. 1H-NMR (300 MHz, CDCl3) δ 7.54 (dd, 1H, J=3, 7 Hz), 7.39 (dd, 1H, J=3, 7 Hz), 7.2-7.3 (m, 2H), 6.41 (s, 1H), 6.29-6.30 (m, 2H), 5.29 (s, 2H), and 2.28 (s, 3H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26].[ClH:28]>C(O)C>[ClH:28].[ClH:28].[C:2]1([C:1](=[N:23][NH:24][C:25](=[NH:26])[NH2:27])[CH2:9][CH2:10][C:11](=[N:23][NH:24][C:25](=[NH:27])[NH2:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: O=C(CCC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Product: N=C(N)NN=C(CCC(=NNC(=N)N)c1ccccc1)c1ccccc1

Procedure:
1,2-dibenzoylethane (4.76 g), aminoguanidine bicarbonate (5.45 g), and concentrated hydrochloric acid (3.33 mL) were heated in 50% ethanol (60 mL) for 24 hr. Cooling, concentration and filtration gave 4.3 g of 2,2'-(1,4-diphenyl-1,4-butanediylidene)bis(hydrazinecarboximidamide) dihydrochloride, mp 285-6° C.