Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[O:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=2)[N:38]([S:54]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)(=[O:56])=[O:55])[CH:37]=1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:42]2[CH:43]=[C:44]3[C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:37][N:38]([S:54]([C:57]4[CH:58]=[CH:59][C:60]([CH3:63])=[CH:61][CH:62]=4)(=[O:56])=[O:55])[C:39]3=[N:40][CH:41]=2)=[CH:17][C:16]=1[C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[O:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(Br)ccc1NC(=O)NCCN(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Yield: 67.5 %

Procedure:
A mixture of {2-[3-(4-bromo-2-dimethylcarbamoyl-phenyl)-ureido]-ethyl}-methyl-carbamic acid tert-butyl ester (75 mg, 0.17 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (85 mg, 0.168 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane adduct (13.7 mg) was dissolved in a mixture of acetonitrile (4 mL), 1 M aqueous sodium carbonate (4 mL) and tetrahydrofuran (1 mL). The mixture was irradiated in the microwave to 120° C. for 10 minutes. The reaction mixture was then concentrated and the residue was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 84 mg (66%) of [2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: m/z 741.5 (M+H+).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)C2C=CC=C[C:45]=2N=N1.C(C1C=C(O)C=CC=1)#N.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[Si:16]([O:15][C@@H:14]1[C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][CH:45]=[C:31]([C:32]#[N:35])[CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4cccc(C#N)c4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 82 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this 3-cyanophenyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and 3-cyanophenol (13.1 mg, 0.110 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at 85° C. over 2 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 47.5 mg (82% yield) of the title compound as a clear gum. Rf (50% EtOAc in hexanes)=0.58. 1H NMR (500 MHz, CDCl3): δ 8.49 (s, 1H, Ar—H), 8.45 (s, 1H, Ar—H), 7.62-7.54 (m, 4H, Ar—H), 6.54 (t, 1H, H-1′, J=6.4), 4.64 (m, 1H, H-3′), 4.05 (q, 1H, H-4′, J=3.4), 3.91 (dd, 1H, H-5′, J=11.2, 3.9), 3.80 (dd, 1H, H-5′, J=11.2, 3.9), 2.64 (app quint, 1H, H-2′, Japp˜6.3), 2.49 (ddd, 1H, H-2′, J=13.2, 6.3, 4.4), 0.92, 0.916 (2 s, 18H, tert-Bu), 0.11, 0.105 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 159.1, 153.0, 152.7, 151.6, 142.2, 130.4, 129.2, 126.7, 125.6, 122.1, 117.9, 113.6, 88.1, 84.8, 71.8, 62.7, 41.5, 25.9, 25.7, 18.4, 17.9, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C29H44N5O4Si2 (M++H) 582.2932. found 582.2927.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C@H:22]([NH2:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](=[O:37])[CH2:35][CH:34]([CH:38]=O)[CH2:33]2)=[CH:28][CH:27]=1>CC(O)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C@H:22]([NH:24][CH2:38][CH:34]2[CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[C:36](=[O:37])[CH2:35]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=CC1CC(=O)N(c2ccc(F)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H](NCC1CC(=O)N(c2ccc(F)cc2)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with sodium triacetoxyborohydride (1.0 g, 4.8 mmol), (R)-1-(3-chlorophenyl)ethanamine 55 (0.413 g, 2.7 mmol), 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carbaldehyde 54 (0.500 g, 2.4 mmol), 10 mL of DCE, and 5 drops of AcOH. This mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography on silica gel (3% to 7% MeOH in DCM) to give 4-({[(1R)-1-(3-chlorophenyl)ethyl]amino}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one 56 as a 1:1 mixture of diastereomers. Mass spectrum: calculated for C19H20ClFN2O 346.1; found 347.2 (M++1).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:59]([SH:67])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O1CCCC1.C(OCC)(=O)C>[C:59]([S:67][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[CH2:3]1)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(S)c1ccccc1
Reactant: Cn1nnnc1SC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1SC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.23 g) and triphenylphosphine (1.23 g) in tetrahydrofuran (25 ml) was added dropwise a solution of diethyl azodicarboxylate (0.74 ml) in tetrahydrofuran (2 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, to the solution was added thiobenzoic S-acid (0.55 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (19:1, V/V). The fractions containing the resired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(1-methyl-1H-tetrazol- 5-yl)thiomethyl-1(4-nitrobenzyloxycarbonyl)pyrrolidine (1.61 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([B:13]2[O:17][C:16]([CH3:19])(C)C(C)(C)[O:14]2)=[C:6]([C:9]([F:12])=[CH:10][CH:11]=1)C=O)[CH3:2].[OH-].[Na+].[N+:24](C)([O-:26])=[O:25].Cl>O>[CH2:1]([O:3][C:4]1[C:5]2[B:13]([OH:14])[O:17][CH:16]([CH2:19][N+:24]([O-:26])=[O:25])[C:6]=2[C:9]([F:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOc1ccc(F)c(C=O)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(F)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.8 %

Procedure:
3-Ethoxy-6-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.65 g, 5.61 mmol) was added to a solution of NaOH (225 mg, 5.60 mmol) in H2O (10 mL) and stirred for 10 min at RT. Added nitromethane (1.03 g, 16.83 mmol) dropwise and stirred for 4 h at RT. The reaction mixture was acidified with 4N HCl and extracted with ethyl acetate. Organic layer was washed with water, brine and dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography with 10 to 40% EtOAc/hexanes afforded 1.7 g of a mixture of compounds by 1H NMR spectrum. This mixture was used in next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.13 (t, J=8.8 Hz, 1H), 6.79 (dd, J=8.8, 2.5 Hz, 1H), 5.95 (d, J=9.0 Hz, 1H), 5.14 (s, 1H), 5.01 (dd, J=13.3, 2.3 Hz, 1H), 4.44 (dd, J=13.3, 9.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 1.45 (t, J=6.8 Hz, 3H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −131.00-−130.97 (m, 1F).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Cl:18])=[CH:12][C:11]=1[F:19])[C:8]#[N:9].[OH2:20].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Cl:18])=[CH:12][C:11]=1[F:19])[C:8]([NH2:9])=[O:20]
Reactant: O
Reactant: COc1cc(C(N)C#N)c(F)cc1Cl
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc(C(N)C(N)=O)c(F)cc1Cl
Reaction time: 3 h
Yield: 68 %

Procedure:
Then, 3.6 g of concentrated sulfuric acid was added to 0.33 g of water, to which 3.6 g of 2-amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 15 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 2.45 g (yield, 68%) of 2-amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)acetamide, m.p. 161.7° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[C:15]#[C:16][Si](C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:15]([C:6]1[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=[CH:10][C:5]=1[C:4]([N:3]([O:2][CH3:1])[CH3:22])=[O:21])#[CH:16]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100.1 %

Procedure:
To a suspension of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethynyl-nicotinamide (148 g, 0.449 mmol) in THF (1 ml) and CH3OH (0.5 ml) was added a solution of 1N-NaOH (0.5 ml) and the mixture was stirred for 50 min at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 2-ethynyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (116 mg, 99%).
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:43]=[C:42]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]=[CH2:52])=[CH:47][CH:46]=3)[C:41]([Cl:53])=[C:40]3[C:35]=2[CH2:36][CH2:37][CH2:38][O:39]3)[O:22][C@@H:21]1[CH2:54][O:55][C:56](=[O:58])[CH3:57])(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:43]=[C:42]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:2][CH2:52]4)=[CH:47][CH:46]=3)[C:41]([Cl:53])=[C:40]3[C:35]=2[CH2:36][CH2:37][CH2:38][O:39]3)[O:22][C@@H:21]1[CH2:54][O:55][C:56](=[O:58])[CH3:57])(=[O:18])[CH3:17]
Reactant: C=Cc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3c(c2Cl)OCCC3)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C4CC4)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
The mixture of Et2Zn (1.1M in toluene, 4 mL, 4.39 mmol) and CH2Cl2 (8 mL) was cooled to 0° C. TFA ((0.34 mL, 4.39 mmol) in CH2Cl2 (4 mL)) was added to the mixture at 0° C. The mixture was stirred at 0° C. for 1 hr. CH2I2 ((0.36 mL, 4.39 mmol) in CH2Cl2 (4 mL)) was added to the mixture at 0° C. The mixture was stirred at 0° C. for 1 hr. The acetate 179 ((270 mg, 0.44 mmol) in CH2Cl2 (4 mL)) was added to the mixture at 0° C. The mixture was warmed up to rt slowly and stirred at room temperature for 15 hours. The mixture was extracted with EtOAc/aq. sat'd NH4Cl (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 180 (152 mg, 55%).
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:30][C:31]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:31]1([F:36])[CH2:35][CH2:34][N:33]([C:2]2[C:3]([F:28])=[C:4]([N:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]4[N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[CH:19][CH:18]=4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:32]1
Reactant: FC1(F)CCNC1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CCC(F)(F)C3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 50.9 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (221 mg, 0.5 mmol), 3,3-difluoropyrrolidine hydrochloride (86.1 mg, 0.6 mmol), NaOt-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 24 h under N2. The mixture was diluted with saturated. NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) to yield the title compound (119 mg, 51% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.42-2.50 (2H, m), 3.56 (2H, t, J=7.4 Hz), 3.71-3.88 (5H, m), 6.43-6.54 (1H, m), 6.84-7.13 (3H, m), 7.27-7.49 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=2.3 Hz). Anal. Calcd for C24H20F3N5O2.0.2H2O: C, 61.20; H, 4.37; N, 14.87. Found: C, 61.36; H, 4.45; N, 14.56.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=[O:24].CC(O)=O>CCO>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=1[F:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCC(=NNC(=O)c1cc(F)ccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.8 %

Procedure:
To a solution of (4-oxo-4-phenylbutyl)-carbamic acid tert-butyl ester (3.2 g, 12.2 mmol) and 2,5-difluorobenzoic acid hydrazide (2.1 g, 12 mmol) in EtOH (40 mL) was added HOAc (0.5 mL). The reaction was then heated to reflux and stirred for 3 days. The reaction mixture was then cooled to room temperature and concentrated to give desired product (5.1 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (26 g, 0.12 mol) was suspended in a solution of triethylamine (85 mL) in dichloromethane (125 mL) and the mixture was cooled to 0-5° C. A solution of trans-4-isopropylcyclohexane carbonyl chloride (25 g, 0.13 mol) in dichloromethane (75 mL) was added dropwise over a period of 10 minutes while maintaining the temperature at 0-5° C. The resulting mixture was stirred for 12 hours at ambient temperature then washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 38 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][N:28]([CH3:49])[CH2:29][CH2:30][N:31](CCN(C)C)[S:32]([C:35]1[S:36][C:37]([Cl:43])=[C:38]([N+:40]([O-])=O)[CH:39]=1)(=[O:34])=[O:33]>>[Cl:43][C:37]1[S:36][C:35]([S:32](=[O:34])(=[O:33])[NH:31][CH2:30][CH2:29][N:28]([CH3:49])[CH3:27])=[CH:39][C:38]=1[NH:40][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:25])[F:26])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCN(CCN(C)C)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CN(C)CCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.14) according to general procedure II.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[N:7]=1.[OH-].[Na+].B(Br)(Br)Br>CO>[NH2:1][C:2]1[N:3]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCOC(=O)Cn1nnc2c(-c3ccco3)nc(N)nc21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-c2ccco2)c2nnn(CC(=O)O)c2n1
Yield: 84.8 %

Procedure:
A solution of ethyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylacetate (547 mg, 1.89 mmol) in MeOH (5 mL) was treated with aqueous NaOH (2 mL, 2-M, 4 mmol), refluxed for 10 min, cooled, acidified with aqueous HCl (1-M), filtered and dried to give the title compound (417 mg, 85%) as a white solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].C1COCC1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:26].Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][N:31]=[C:30]2[N:36]=[C:37]([S:39][CH3:40])[S:38][C:29]=12>CN(C=O)C.O>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:26][C:28]1[C:33]([C:34]#[N:35])=[CH:32][N:31]=[C:30]2[N:36]=[C:37]([S:39][CH3:40])[S:38][C:29]=12
Reactant: CSc1nc2ncc(C#N)c(Cl)c2s1
Reactant: Nc1c(Cl)ccc2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ncc(C#N)c(Nc3c(Cl)ccc4c3OCO4)c2s1
Reaction time: 0.25 h

Procedure:
1M sodium hexamethyldisilazane in THF (1.42 mL, 1.42 mmol) was added to 5-chloro-benzo[1,3]dioxol-4-ylamine Compound 31a (as described in PCT Application WO03/008409) (221 mg, 1.29 mmol) in DMF at 0° C. and the mixture was stirred for 15 min. 7-chloro-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile Compound 1g (312 mg, 1.29 mmol) in DMF (1 mL) was added and the reaction mixture stirred for an additional 2 hr at ambient temperature. The mixture was then diluted with water and filtered through Celite 545 to form a plug. The celite plug was rinsed with EtOAc and the organic layer was isolated and washed with brine. The organic layer was dried over MgSO4, then filtered and evaporated onto silica gel. Isolation by flash chromatography (eluted with a 20 to 40% EtOAc/hexane gradient) gave 7-(5-chloro-benzo[1,3]dioxol-4-ylamino)-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile Compound 31b (30 mg) as a yellow oil. MS 377, 379 (MH+).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH:3]([C:10](Cl)=[O:11])[CH:2]2[CH3:13].[CH3:14][OH:15]>N1C=CC=CC=1>[CH3:14][O:15][C:10]([CH:3]1[CH2:4][CH:5]2[CH2:9][CH:1]([C:6]2([CH3:8])[CH3:7])[CH:2]1[CH3:13])=[O:11]
Reactant: CC1C(C(=O)Cl)CC2CC1C2(C)C
Reactant: CO
Solvent: c1ccncc1
Product: COC(=O)C1CC2CC(C1C)C2(C)C

Procedure:
4 g of (+)-pinane-3-carboxylic acid chloride are mixed with methanol and the solution is boiled under reflux in the presence of pyridine, then concentrated to a small volume, mixed with water and extracted with ether. Fractional distillation of the dried ether solution gives (+)-pinane-3-carboxylic acid methyl ester boiling at from 55 to 56° C/0.2 mm Hg and having an optical rotation of [α]D24 = +18.9° (pure).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH:24]([C:26]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH2:25]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:25][CH2:24][C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: C=CC1(O)CCCCC1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(CCC3(O)CCCCC3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 1-vinyl-cyclohexanol analogous to Example 44: (M−1)−=353; HPLC retention time=1.35 min (method A).