Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11]O>Cl>[O:1]([CH3:11])[CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Product: COC1O[C@@H](CO)[C@@H](O)[C@@H]1O

Procedure:
This compound is prepared according to the procedure described in J. Med. Chem. 41: 3865 (1998). L-Xylose is stirred in 0.5N HCl in anhydrous MeOH for 5-10 h at room temperature. The reaction mixture is neutralized with Amberlite IRA-400 OH or Dowex—X200 anion exchange resin. The resin is removed by filtration. The combined filtrate and washings are concentrated to an oil which is subjected to column chromatography on silica gel using a mixture of CH2Cl2 and MeOH as the eluent to afford compound 1-1 as an α/β anomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(OC(Cl)=O)C(C)C.[N:22]1([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Cl-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:25]1[CH2:26][CH2:27][N:22]([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:23][CH2:24]1)=[O:8]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 4.8 g of 3,4-dimethoxybenzoic acid and 4 ml of triethylamine in 50 ml of dimethylformamide, a solution of 3.87 g of isobutylchloroformate in 2 ml of dimethylformamide was added dropwise. After the reaction mixture was stirred at a room temperature for 30 minutes, then a solution of 8.1 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril in 3 ml of dimethylformamide was added dropwise to the reaction mixture and stirred at a room temperature for 30 minutes, and further stirred at 50°-60° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into a voluminous amount of a saturated sodium chloride aqueous solution and then extracted with chloroform and the chloroform extract was washed with water and dried. The solvent was removed by distillation, and the residue was recrystallized from ethanol-chloroform to obtain 2.5 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.O[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:8]1([C:6]2[CH:7]=[C:3]([CH2:2][O:1][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)[S:4][C:5]=2[C:14]([F:17])([F:15])[F:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2cc(-c3ccccc3)c(C(F)(F)F)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 1.95 g (7.5 mmol) of 2-hydroxymethyl-4-phenyl-5-trifluoromethyl-thiophene (from Step A), 925 mg (7.6 mmol) of 4-hydroxybenzaldehyde and 3.0 g (11.4 mmol) of triphenylphosphene in 40 mL of THF at 0° C. was treated with 2.0 g (11.4 mmol) of diethylazodicarboxylate. The resulting mixture was warmed to rt, stirred for 2 h, then concentrated. Chromatography on a Biotage 75S cartridge using 9:1 v/v heptane/EtOAc as the eluant afforded 2.5 g of impure title compound. Chromatography on a Biotage 40M cartridge using 19:1 v/v hexanes/EtOAc (1L), then 4:1 v/v hexanes/EtOAc (1L) as the eluant afforded 1.65 g (60%) of the title compound: 1H NMR (500 Mhz) δ 5.32 (s, 2H), 7.10 (d, J=8.5, 2H), 7.12 (s, 1H), 7.41-7.43 (5H), 7.85-7.90 (2H), 9.92 (s, 1H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C@@H:7]([N:10]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C@@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:13][C@H:12]([CH2:30][CH:31]=[CH2:32])[C:11]1=[O:33])[CH2:8][CH3:9])(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClC(Cl)C.O>[CH2:30]([C@H:12]1[CH2:13][C@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:10]([C@H:7]([C:6]2[O:3][C:1]([CH3:2])=[N:4][N:5]=2)[CH2:8][CH3:9])[C:11]1=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NNC(C)=O)C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: CC(Cl)Cl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)c2nnc(C)o2)C1=O

Procedure:
A solution of 58 mg (0.115 mmol) of (S)-N′-acetyl-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanehydrazide (Example 34, Step A) and Burgess' reagent (110 mg, 0.462 mmol) in dichloroethane (1154 μL) was heated in the microwave at 120° C. for 30 min. Then the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Separation by reversed phase HPLC (55 to 90% MeCN/H2O in 35 min, 29 mg injection each time) provided the title compound as a colorless film. MS (ESI) 484.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH:4]([CH3:18])[N:3]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CO.[Pd]>[CH3:18][CH:4]1[CH2:5][NH:6][CH2:7][CH:2]([CH3:1])[N:3]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1CNCC(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 4-benzyl 1-tert-butyl 2,6-dimethylpiperazine-1,4-dicarboxylate (4.8 g, 0.0144 mol) in methanol (25 mL) was added 480 mg of 10% Pd/C and stirred at room temperature under H2 overnight. The resulting mixture was filtered and concentrated to give the title product (2.8 g, 97%) as colorless oil. LC-MS (ESI) m/z: 215 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.25 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.64 (s, 1H), 2.78-2.87 (m, 4H), 3.99-4.05 (m, 2H).
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH2:31][NH2:32])=[CH:23]1>>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH2:31][NH:32][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)=[CH:23]1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1csc2ccccc12
Product: CCCCCCCCc1noc(-c2ccc(CNCc3csc4ccccc34)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 434.3. HPLC (Condition A), Rt: 4.30 min (HPLC purity: 89.9%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:4]([C:2]([O:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COC(=O)Oc1ccccc1
Yield: 92.8 %

Procedure:
13.5 ml (105.6 mmol) of phenyl chloroformate are added, dropwise, at ambient temperature to a solution of 10 g (96.15 mmol) of ethyl glycolate and 27 ml (192.3 mmol) of triethylamine in 20 ml of toluene and the mixture is stirred at ambient temperature for 2 h. The salt formed is separated and the filtrate is concentrated under reduced pressure to obtain 20 g of oily product, which are used without modification in the following step.
Reaction SMILES: [OH-].[K+].[SH:3][CH2:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][O:8][C:6]1=[O:7].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:20]([S:3][CH2:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][O:8][C:6]1=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OCC(c2ccc([N+](=O)[O-])cc2)C1CS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1OCC(c2ccc([N+](=O)[O-])cc2)C1CSCc1ccccc1
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a solution of 71 mg of potassium hydroxide in 6 ml of ethanol were added 253 mg of α-mercaptomethyl-β-(p-nitrophenyl)-γ-butyrolactone and 239 mg of benzyl bromide and the resulting mixture was kept at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with 60 ml of ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The resulting crude product was purified by a silica gel column chromatography to give 218 mg (yield 50%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1cc(CCOc2ccc(N)c3ccccc23)ccn1

Procedure:
A solution of N-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide (570 mg, 1.62 mmol) in a mixture of AcOH: MeOH (6:1 v/v, 54 mL) was subjected to hydrogenation by passage through a Thales H-cube (1 mLmin−1, 30 mm, 10% Pt/C Cat-Cart, full H2, 45° C.). The solvent was removed by evaporation in vacuo, and, the residue was subjected to SCX capture and release to furnish the title compound, Intermediate B, (550 mg, 100%): m/z 322 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][S:12]([CH3:14])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1>CO>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][S:12]([CH3:14])=[O:13])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CS(=O)COc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CS(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 91.3 %

Procedure:
In a manner similar to the method described in Example 9b, 5-chloro-2-methanesulfinylmethoxy-benzaldehyde (0.4 g, 1.72 mmol) was reacted with 6-chlorooxindole (0.31 g, 1.86 mmol) and pyrrolidine (0.13 g, 1.86 mmol) in methanol (10 mL) to give the title compound as a yellow solid (0.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[K+].[K+]>C(#N)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]([C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)=[O:16]
Reactant: COC(=O)CCOc1ccc(C)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CCOc1ccc(C=O)cc1
Reaction time: 3.5 h
Yield: 92.5 %

Procedure:
A solution of methyl 3-(4-methylphenoxy)-propanoate, (15.0 g, 0.077 moles) in acetonitrile, (270 ml), was added to a solution of potassium peroxydisulphate, (41.60 g, 0.154 moles) and copper (II) sulphate (3.85 g, 0.015 moles) in water, (270 ml). The resulting mixture was stirred at 65°-70° C. for 3.5 h, then cooled and extracted with diethyl ether. The organic extract was washed with water, saturated brine and dried, (MgSO4). Evaporation of the solvent gave 14.83 g of an orange oil which was distilled at 0.1 mm/Hg to yield 7.40 g (47%) of the title compound as an oil which crystallized, mp 48°-50° C., υmax (mull) 1735, 1680, (shoulder at 1685), 1605, 1580, 1515 cm-1 δ(CDCl3) 2.81 (2H, t, J 6 Hz, CH2CO2) 3.72 (3H, S, CH3) 4.30 (2H, t, J6 Hz OCH2) 7.39 (4H, ABq, Δυ75 Hz, J9 Hz C6H4) 9.90 (1H, s, CHO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][C:25]1[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][C:25]1[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ncccc1CCl
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ncccc1Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 100 °C
Yield: 30.3 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 476 mg, 1.56 mmol), 3-chloromethyl-2-methoxy-pyridine (Intermediate 51; 989 mg, 6.3 mmol) and tetrabutylammonium iodide (580 mg, 1.6 mmol) in dimethylformamide (16 mL) was heated at 100° C. for 48 h. The solvent was evaporated and dichloromethane (250 mL) was added. The solution was washed with concentrated aqueous sodium thiosulfate (2×100 mL), saturated aqueous sodium hydrogen carbonate (100 mL), water (6×500 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated and purified using a Biotage 40L system, eluting with 1-2% methanol/dichcloromethane to give an oily material. This material was dried on a vacuum pump, co-evaporated three times with ethanol, and finally held again under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(2-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (201 mg, 30%) as an off-white solid. ES(+)-MS (M+H) 426.
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>C(#N)C>[Cl:15][CH:2]([Cl:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1)=[O:14])(=[O:11])=[O:10]
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(Cl)Cl
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(Dichloromethyl)benzenesulfonyl isocyanate, prepared from 10 mmol of sulfonamide as described in the synthesis of Example 1, was treated with acetonitrile and 2-amino-4,6-dimethylpyrimidine (1.23 g). The mixture was stirred at room temperature for 18 hrs, cooled, and filtered to provide 1.08 g of white solid, mp 195°-197° (Dec).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH3:22])[NH:11][C:12](=O)[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCCl>[C:1]1([S:7]([N:10]([CH3:22])[N:11]=[C:12]([Cl:24])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CN(NC(=O)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Solvent: ClCCCl
Product: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Into a 1 L three necked round bottom flask equipped with a magnetic stirrer and condenser under an atmosphere of nitrogen was added N-benzenesulfonyl-N-methyl-2,6-dichlorobenzoyl hydrazine (35.9 g, 0.10 mol), 1,2-dichloroethane (500 mL), and phosphorus pentachloride (31.2 g, 0.15 mol). The temperature of the mixture was raised to the point of reflux and was allowed to stir for 30 min. The solvent was removed in vacuo and the residue dissolved in methylene chloride and carefully diluted with water. The organic phase was washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo to give an oil which solidified when triturated with ethyl acetate/hexanes mixture to give 36.1 g (95.7% yield) N-benzenesulfonyl-N-methyl-2,6-dichlorobenzhydrazonoyl chloride as a white crystalline solid: mp 103-104° C.; 1H NMR (CDCl3) δ7.9 (m, 2H), 7.4-7.7 (m, 3H), 7.2-7.4 (m, 3H), 3.1 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][N:13]=1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1
Yield: 22 %

Procedure:
Compound I (13 mg, 0.027 mmol, preparation of which is outlined above in Example 12), Pd(PPh3)4 (3.5 mg, 0.003 mmol), 4-fluorophenylboronic acid (7.6 mg, 0.055 mmol) and potassium carbonate (15 mg, 0.108 mmol) were stirred in toluene (1.5 mL) and water (0.7 mL) at 120° C. under microwave irradiation (300 W) for 20 min. The reaction mixture was then poured onto brine (5 mL) and extracted with EtOAc (3×5 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 85:15) to furnish II as a colourless oil (2.5 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:26])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([OH:20])=O)[N:10]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([NH:48][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([C:14]3[C:13](=[O:26])[CH:12]=[CH:11][N:9]4[C:8]=3[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:2]=3[F:1])=[N:10]4)[CH:16]=2)[CH2:47][CH2:46]1
Reactant: NC1CC1
Reactant: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC2CC2)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 1 in CH2Cl2 was added triethyl amine and ethylchloroformate at 0° C. The mixture was warmed to ambient temperature and stirred for 10 min. The reaction was complete by LCMS analysis and concentrated in vacuo to yield crude residue. To the crude residue was added CH2Cl2 and cyclopropyl amine, followed by stirring for ½ hr. LCMS indicated the reaction was complete. The reaction was diluted with CH2Cl2, washed with 0.5 N NaOH, H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2/MeOH).
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][N:5]([CH3:16])[C:6]1[N:15]=[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][N:8]2[N:7]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:26]=[N:25][N:24]([CH3:27])[C:23]=1[C:28](O)=[O:29])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[CH:26]=[N:25][N:24]([CH3:27])[C:23]=1[C:28](=[O:29])[NH:14][C:11]1[CH:12]=[CH:13][N:8]2[N:7]=[C:6]([N:5]([CH2:4][CH2:3][F:2])[CH3:16])[N:15]=[C:9]2[CH:10]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: CN(CCF)c1nc2cc(N)ccn2n1
Agent: Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)CCF)nc2c1
Yield: 76.1 %

Procedure:
The product was prepared in the same manner as described in example 65c) using N2-(2-fluoro-ethyl)-N2-methyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine hydrochloride (1.3 g, 5.3 mmol) and 2-methyl-2H-pyrazole-3,4-dicarboxylic acid-4-ethyl ester (1.08 g, 5.45 mmol) as starting materials. The solvent was evaporated and the resulting yellowish oil was triturated with sat. sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water 4 times and dried in vacuo affording 5-{2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl}-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.57 g, 76.2%) as a light yellow solid. MS: m/z=390.5 (M+H+).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:27][CH:28]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (20 mL) was added a solution of 4-(trifluoromethyl)phenyl isocyanate (0.41 g, 2.2 mmole) in dry dichloromethane (3 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. The resulting mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and 2N aqueous HCl. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield the title compound as an orange solid (0.36 g, 49% yield), mp=81–83° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−25.6° (c=1, EtOH).