Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:24][C@H:25]1[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)[CH2:26]1)(=[O:3])[NH2:2].[OH-].[Na+].CO>O1CCCC1>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:24][C@H:25]1[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)[CH2:26]1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)Cn1cc(-c2cc3c(N[C@@H]4CN(c5ccc(C#N)cn5)C[C@@H]4C)c(C(N)=O)cnn3c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(=O)O)c3)cc12

Procedure:
A mixture of the crude ethyl 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetate from Step 1, a 2 N aqueous solution of NaOH (0.5 mL), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was stirred at room temperature for 1 h. The organic solvents were evaporated in vacuo. The aqueous residue was treated with 1 N HCl (1 mL) and water (1 mL) and filtered. The filter cake was washed with water and dried under vacuum to give crude 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid as dark brown solid (66.3 mg). This material was used in the next step without further purification. MS (ES+) m/z: 486.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[CH3:17])=[CH:6]/[C@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])[CH3:2]>C(OCC)(=O)C.[Pt]>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH3:17])[CH2:6][C@H:7]([NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:8])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)C[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
Next, a solution of (E)-(R)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoic acid ethyl ester (1.83 g, 7.11 mmol) in ethyl acetate (75 mL) is hydrogenated over 10% Pt/C (183 mg) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by chiral HPLC to afford (2R,4R)-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid ethyl ester, 1H-NMR (400 MHz, CDCl3); δ ppm 1.13 (t, 3H), 1.18 (m, 3H), 1.26 (t, 3H), 1.43 (s, 9H), 1.81 (s, 1H), 2.50 (m, 1H), 3.72 (m broad, 1H), 4.14 (m, 2H), 4.33 (m broad, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH2:28][O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:33][CH2:34]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(COCCC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(COCCC2CCN(c3cncc(OC[C@@H]4CCCN4C(=O)OC(C)(C)C)c3)CC2)cc1
Temperature: 99 °C
Yield: 84.1 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (112 mg, 0.31 mmol) and 4-[2-(4-methoxybenzyloxy)ethyl]piperidine (86 mg, 0.34 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (45 mg, 0.47 mmol, 1.5 equiv.), Pd2dba3 (5.7 mg, 6.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 10.8 mg, 19 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2, then 1:2. The product (137 mg, 84%) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.23-7.30 (m, 3H), 7.24 (d, 2H, J=8.4 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.41 (s, 2H), 4.10 (m, 2H), 3.90-3.80 (m, 1H), 3.78 (s, 3H), 3.65 (m, 2H), 3.49 (t, 2H, J=6.0 Hz), 3.39 (m, 2H), 2.72 (m, 2H), 2.02 (m, 3H), 1.84 (m, 1H), 1.75 (d, 2H, J=12.4 Hz), 1.55 (m, 3H), 1.45 (s, 9H), 1.31 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9](=[O:12])[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:9]([OH:12])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 0 °C
Yield: 55.6 %

Procedure:
To a stirred solution of (R)-1-Benzyl-3-chloro-2-oxopropylcarbamic acid tert-butyl ester (8.0 g, 27 mmol) in THF/water (200 mL, 9/1, v/v) at 0° C. is added NaBH4 (1.23 g, 32 mmol). After 30 min the mixture is concentrated under reduced pressure and the residue is suspended in a mixture of water and ethyl acetate (1:1, v/v). This mixture is cooled to 0° C. and the pH is adjusted to ˜2 by the slow addition of 2M NaHSO4. The phases are separated and the organic layer is washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford a white solid as a mixture of diastereomers (7.92 g, 27 mmol, ˜5:2 R,R:R,S), which is purified using General Purification Procedure C to afford the title compound as a white solid (4.45 g, 15 mmol).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH3:16])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[F:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH3:16])([CH3:1])[CH2:3][C:4]([O:6][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)=[O:5]
Reactant: CSSc1ccccc1C(C)(C)CC(=O)O
Reactant: Oc1ccc(F)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSSc1ccccc1C(C)(C)CC(=O)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of 3-methyl-3-(2-methyldisulfanylphenyl)butanoic acid, 4-fluorophenol (1.1 eq) and 4-(N,N-dimethylamino)pyridine (0.5 eq) in CH2Cl2 was added diisopropylcarbodiimide (1.5-2.0 eq) at 0° C. The mixture was stirred overnight at ambient temperature. The precipitate was filtered off and the filtrate concentrated by rotary evaporation. The crude product was purified on a silica gel column to afford 4-fluorophenyl 3-methyl-3-(2-methyldisulfanylphenyl)butanoate as a colorless oil in 62% yield: 1H NMR (CDCl3, 300 MHz) δ (ppm): 1.76 (s, 6H), 2.52 (s, 3H), 3.44 (s, 2H), 6.70 (dd, J=9.0, 4.2 Hz, 2H), 7.00 (t, J=9.0 Hz, 2H), 7.2-7.3 (m, 2H), 7.36 (dd, J=7.8, 1.5 Hz, 1H), 7.96 (dd, J=7.8, 1.2 Hz, 1H). 19F NMR (CD3CN, 282 MHz) δ (ppm): −119.2.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([C:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=2)[CH:9]=1.C(O)(C(F)(F)F)=O>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:16]2[CH:15]=[N:14][N:13]3[C:8]([NH2:7])=[CH:9][C:10]([C:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=4)=[N:11][C:12]=23)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.057 mmol, 40 mg) was charged to a 20 mL scintillation vial containing 1 mL TFA. The reaction mixture was stirred at room temperature. The reaction mixture was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield 3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (m+H=343.31, retention time=2.05 min)
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH3:16])[CH2:11]2.[CH3:17][O:18]C(Cl)Cl.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([CH:17]=[O:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH3:16])[CH2:11]2
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1CCN(C)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1CCN(C)C2
Temperature: 0 °C
Yield: 74.5 %

Procedure:
Into a flask equipped with a mechanical stirrer, an equilibrium addition funnel, and a condenser fitted with a calcium chloride drying tube, were placed methylene chloride (150 ml) and 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (15.0 g, 0.085 mole). The solution was cooled to 0°C and stirred. Titanium tetrachloride (51.6 g, 0.272 mole) was added gradually, followed by the rapid dropwise addition of α,α-dichloromethyl methyl ether (9.8 g, 0.085 mole). After the reaction mixture was allowed to warm to room temperature, it was refluxed for 7 hours. The titanium chloride complex of the product was decomposed with water and ice, and the resulting solution kept cool as it was made basic with excess sodium hydroxide (20%). The resulting suspension was extracted with chloroform. The extract was dried over sodium sulfate and the solvent removed, affording the crude product which was vacuum distilled (b.p. 122°C/0.1 mm) to yield 13.0 g (74%) of 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde. The hydrochloride salt melted at 244°- 245°C after recrystallization from absolute ethanol. Anal. Calcd. for C12H13NO2Cl: C, 59.6; H, 6.7; N, 5.8; Cl, 14.7. Found: C, 59.8; H, 6.8; N, 5.8; Cl, 14.4.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=501, obsd.=501).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[N:25]=[C:24]([NH:26][CH2:27][CH2:28][NH:29][CH3:30])[CH:23]=[CH:22][C:21]=1[N+:31]([O-:33])=[O:32].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([N:29]([CH3:30])[CH2:28][CH2:27][NH:26][C:24]2[N:25]=[C:20]([NH2:19])[C:21]([N+:31]([O-:33])=[O:32])=[CH:22][CH:23]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Reactant: CNCCNc1ccc([N+](=O)[O-])c(N)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNc1ccc([N+](=O)[O-])c(N)n1)c1ccc([N+](=O)[O-])c(-c2ccc(Cl)cc2Cl)c1
Temperature: 85 °C
Yield: 36 %

Procedure:
To 10 mgs of 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene in acetonitrile was added 10 mgs of (6-amino-5-nitro(2-pyridyl))[2-(methylamino)ethyl]amine and 7 μl of N,N-diisopropylethylamine, and the mixture was heated to 85° C. over-night. After an aqueous work up the crude was purified on a silica gel column with 30% acetone in hexane as the eluent to give 6 mgs of N˜6˜-{2-[(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)(methyl)amino]ethyl}-3-nitropyridine-2,6-diamine.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][CH2:16][CH:17]([OH:30])[CH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(N(CC)CC)C.C1COCC1.CS(C)=O>[CH3:14][O:15][CH2:16][C:17](=[O:30])[CH2:18][C:19]1[N:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:22]=[CH:21][CH:20]=1
Reactant: COCC(O)Cc1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCC(=O)Cc1ccnn1-c1ccccc1
Temperature: -42 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a THF solution (100 ml) of DMSO (14.2 ml) was added dropwise trifluoroacetic anhydride over 15 min at −42° C., and the mixture was stirred at −42° C. for 15 min. To the reaction mixture was added dropwise an THF solution (66 ml) of 1-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-ol (9.3 g) over 1 hr at −42° C., and the mixture was stirred at 0° C. for 15 min. To the reaction mixture was added dropwise triethylamine (22.3 ml) over 15 min at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 10% aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.11 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[CH:5][CH:4]=1.[N:14]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[K+]>O>[CH3:12][CH:9]1[CH2:8][C:7]2[C:6]([CH3:13])=[CH:5][CH:4]=[C:3]([NH:2][NH2:14])[C:11]=2[O:10]1
Reactant: Cc1ccc(N)c2c1CC(C)O2
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1ccc(NN)c2c1CC(C)O2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 50 ml of concentrated hydrochloric acid and 19.8 g of 1D was stirred, warmed to 80° C. and then allowed to stand at room temperature for 18 hours. Then 50 ml of ice water was added, the mixture was cooled to 0° C. and stirred while a solution of 9.6 g of sodium nitrite in 20 ml of water was added drop-by-drop over 15 minutes. The cold mixture was stirred for an additional hour and then added to a cold stirred mixture of 100 g of sodium sulfite in 180 ml of water. The resulting mixture was stirred at room temperature for six hours, then 21.9 g of sodium dithionite was added, in portions. The resulting mixture was stirred at room temperature for 18 hours, then at 75° C. while 150 g of potassium chloride was added. The resulting mixture was stirred at 75° C. for 30 minutes, at room temperature for two hours, then was cooled to 5° C. and filtered. The filter cake was air dried, then mixed with 400 ml of methanol, the mixture was chilled to 0° C. and an excess of anhydrous hydrogen chloride was added. The methanol was evaporated under reduced pressure, the residue was taken up in water, 50% aqueous sodium hydroxide solution was added, and the resulting mixture was extracted with ether. The extract was dried (MgSO4) and the solvent was evaporated to give 2,3-dihydro-2,4-dimethyl-7-hydrazinobenzofuran (1E), as an amber syrup.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.C[NH:18]N>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH:5]=[N:18]1
Reactant: CNN
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccccc2[N+](=O)[O-])cn1
Yield: 92.1 %

Procedure:
A solution of 60 g of 3-(dimethylamino)-2-(2-nitrophenyl)acrolein (see Example 10) and 16.1 g of methylhydrazine in 200 ml of toluene was refluxed for 10 hours, then concentrated to dryness in vacuo. The residue was recrystallized from 1-chlorobutane/hexane (about 1:1) to yield 51 g of the title compound; m.p. 41°-44° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C#N)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.4 g, 0.9 mmol), 4-cyanophenylboronic acid (0.2 g, 1.35 mmol), Na2CO3 (2 M, 2.0 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta [a]pentalen-6-yl]-biphenyl-4-carbonitrile as brown solid in 50% yield.
Reaction SMILES: C[N:2]([CH3:20])[CH:3]=[C:4]([C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:21][CH:22]([F:25])CN.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[F:21][CH:22]([F:25])[CH2:20][N:2]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(I)ccc1F
Reactant: NCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(CC(F)F)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (335 mg, 0.86 mmol) and 2,2-difluoroethylamine (76 mg, 0.94 mmol) in ethanol (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in DMF (3 mL). Potassium carbonate (178 mg, 1.28 mmol) was added to the reaction mixture and the reaction was heated to 70° C. for 3 h, then cooled to room temperature and poured into water. The title compound formed a precipitate which was collected by filtration and placed upon lyophilizer overnight to remove residual water. MS (ESP): 408 (M+H+) for C14H12F2INO3; NMR: 1.29 (t, J=7 Hz, 3H), 4.25 (q, J=7 Hz, 2H), 4.96 (m, 2H), 6.50 (t, J=20 Hz, 1H), 7.73 (m, 1H), 8.08 (m, 1H), 8.50 (m, 1H), 8.70 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Yield: 63.7 %

Procedure:
30.0 g of 2-aminobiphenyl, 23.4 g of ethyl diisopropylamine and 35.4 g of ethyl 4-bromobutyrate are heated together to 150° for 3 hours while stirring. After cooling, the reaction product is stirred with diethyl ether, the precipitated salt is filtered off, and the residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 32.0 g (63.7% of theory) of ethyl 4-(biphenyl-2-yl)aminobutyrate, MP 60° to 62°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1)#[N:2].C(Cl)[Cl:13].CO.N>CO.Cl.[Pd]>[ClH:13].[ClH:13].[C:9]([C:6]1[N:7]=[CH:8][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1)(=[O:10])[NH2:11]
Reactant: ClCCl
Reactant: N#Cc1ccc(C(N)=O)nc1
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: CO
Product: NCc1ccc(C(N)=O)nc1
Reaction time: 5 h

Procedure:
67 g (0.46 mol) of 5-cyanopyridine-2-carboxamide (Chem. Ber. 117 (1984) 1259) were suspended in 1 l aqueous methanol (1/1) and 84.7 ml (1.9 equivs.) of conc. HCl, 21,4 g of 10% strength Pd/C were added and hydrogenation was carried out in a shaken vessel at room temperature for 5 h (H2 uptake: 23.2; l theory: 22.3 l). The product dissolved during the hydrogenation (and the catalyst changed from gray to black). TLC (CH2Cl2/MeOH 9/1, NH3-saturated) revealed only traces of starting material.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:20])[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][N:23]1[C:27]([CH2:28]Cl)=[N:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:18][C:16]([C:14]1[CH:15]=[C:10]2[N:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]2=[N:12][C:13]=1[O:20][CH2:28][C:27]1[N:23]([CH3:22])[N:24]=[CH:25][N:26]=1)([CH3:17])[CH3:19]
Reactant: CC(C)(C)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(cc1C(C)(C)C)nnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of 3-phenyl-6-(tert-butyl)-3,4-dihydro-1,2,3-triazolo[4,5-b]pyridin-5-one (0.025 g, 0.093 g), 2-methyl-3-chloromethyl-1,2,4-triazole hydrochloride (0.15 g, 1.1 mmol) and cesium carbonate (0.65 g, 2.0 mmol) in dry DMF (4 ml) was stirred at r.t. for 20 h. The mixture was diluted with water (50 ml) and 1M citric acid (5 ml), and extracted with dichloromethane (2×25 ml). The extracts were dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography, eluting with 5% methanol-dichloromethane, gave 6-(1,1-dimethylethyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-b]pyridine (0.028 g, 83%) as a white solid, m.p. 165-167° C. δH (360 MHz; CDCl3) 1.43 (9H, s), 3.94 (3H, s), 5.69 (2H, s), 7.46 (1H, t, J=7), 7.60 (2H, dd, J=7 and 7), 7.93 (1H, s), 8.20 (2H, d, J=7) and 8.31 (1H, s); m/z (ES+) 364 (M+H+).