Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](OC)=[CH2:4].[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH3:32])[CH:27]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]2=[O:41])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH:32]=[C:3]([N:2]([CH3:7])[CH3:1])[CH3:4])[CH:27]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]2=[O:41])=[O:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=C(OC)N(C)C
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Solvent: CN(C)C=O
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)N(C)C

Procedure:
1-Dimethylamino-1-methoxyethylene (218 g) is added dropwise, in the course of 55 minutes, to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (345 g) in anhydrous dimethylformamide (1,600 cc) at 80° C. This yields a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylaminoprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, which is poured into a stirred mixture of distilled water (2 liters), ice (2 kg) and ethyl acetate (2.5 liters). The organic phase is decanted, washed with distilled water (3×1 liter), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 30° C. The residue is divided into 2 equal parts which are each chromatographed separately on a column of Merck silica gel (0.06-0.2) (1,500 g) (diameter of the column: 8.5 cm; height: 70 cm). Each column is eluted with a 23/77 (by volume) ethyl acetate/cyclohexane mixture (20 liters), 1 liter fractions being collected. Fractions 7 to 15 from each column are concentrated to dryness at 30° C. under reduced pressure (20 mm Hg; 2.7 kPa). This yields 3-acetonyl-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (149 g) in the form of a hard yellow foam.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:18])[CH2:10][CH2:9]3)[CH2:6]1)=[N+]=[N-].[H][H]>O1CCCC1.[C].[Pd]>[NH2:1][CH2:4][CH:5]1[O:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:18])[CH2:10][CH2:9]3)[CH2:6]1
Reactant: [N-]=[N+]=NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Yield: 81.3 %

Procedure:
The compound obtained in Example 161 (0.53 g, 2.17 mmol) dissolved in tetrahydrofuran (26 ml) was combined with 10% palladium-carbon (0.32 g), then stirred in the stream of hydrogen at ambient temperature for 1.5 hour. After completion of the reaction, palladium-carbon was filtered off from the reaction mixture. The palladium-carbon was washed with tetrahydrofuran and then methanol. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ammonia/methanol=20:1). 0.385 g of the tile compound was obtained as colorless crystals (87.9%, mp.: 162°-163° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]1[O:28][C:27]2[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][C:17]=2[O:16]1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:27]4[O:28][CH2:15][O:16][C:17]=4[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(CC)c1=O
Yield: 37.4 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.33 g (12.1 mmol) of 3,4-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 1.34 g (yield 38%) of Compound 78 as a yellowish green powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1cccc(F)c1
Yield: 91.6 %

Procedure:
Step AO (1): 2-(3-Fluorophenyl)acetic acid (5 g, 32.4 mmol) was deprotonated with NaHMDS (2.0 M in THF, 32.4 mL, 64.9 mmol) and reacted with 1-chloro-4-iodobutane (3.97 mL, 32.4 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(3-fluorophenyl)hexanoic acid (7.26 g, 91% yield). LC-MS (M−H)− 243.2. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:27]=[C:25]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:18][CH:17]=[C:16]([C:24]=23)[CH2:15][N:14]1[CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNCc2c[nH]c3nccc(C(=O)O)c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2Cc3c[nH]c4nccc(c34)C2=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(((1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid was dissolved in DMF (3 mL). HATU (158 mg, 0.417 mmol) and DMAP (40 mg, 0.278 mmol) were added, and the reaction was stirred at rt for 2 h, concentrated in vacuo, and purified by preparative HPLC eluting with a gradient of 30% to 50% Solvent B in Solvent A to give 14.5 mg of the title compound as a light brown oil. 1H NMR (400 MHz, CD3OD) δ 1.46 (br. s., 9 H) 1.70-1.81 (m, 1 H) 1.99-2.11 (m, 1 H) 2.78 (dt, J=14.34, 7.11 Hz, 1 H) 3.11-3.22 (m, 1 H) 3.32-3.36 (m, 1 H) 3.47-3.57 (m, 2 H) 3.72 (d, J=7.33 Hz, 1 H) 3.76-3.89 (m, 1 H) 5.09 (s, 2 H) 7.38 (s, 1 H) 7.51 (d, J=5.31 Hz, 1 H) 8.42 (d, J=5.56 Hz, 1 H). [M+H] found 357.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1.Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[N:10]=[C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[N:8]=1
Reactant: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(C3CCCCN3)n2)c1
Yield: 5.9 %

Procedure:
To a solution of 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.144 mmol) in methanol (20 ml) was added concentrated hydrochloric acid (200 ul). The mixture was hydrogenated over palladium (5 wt % on activated carbon) at 50 psi for 6 h. The mixture was filtered through Celite. The filtrate was rotary evaporated to dryness and purified by column chromatography to give a brown oil (3 mg, 6%). 1H NMR (CDCl3): 7.83 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 6.90-6.85 (m, 3H), 6.77 (dd, J=1.8, 7.8 Hz, 1H), 3.90 (dd, J=3.0, 10.5 Hz, 1H), 3.81 (s, 3H), 3.29 (d, J=11.4 Hz, 1H), 2.88-2.80 (m, 2H), 2.25 (d, J=10.5 Hz, 1H), 1.92 (s, 1H), 1.69-1.56 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(C(F)(F)F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of dimethyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (4.94 g, 13.09 mmol) in acetonitrile (60 mL) and water (1.2 mL) was added lithium bromide (9.10 g, 104.74 mmol) and triethylamine (7.26 mL, 52.37 mmol). The resulting mixture was heated under reflux for 2 h, then cooled to room temperature. Water was added and acetonitrile removed by evaporation. The aqueous layer was further diluted with water, then washed with MTBE. The organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl, a colorless precipitate formed. The aqueous layer was extracted with DCM three times. The combined organic layers were dried over MgSO4 and evaporated. 2-(3-Fluoro-5-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.58 g, 96%) was isolated as a pale yellow viscous oil. MS m/z 364 (M+H)+
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[NH2:8].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>C(O)(C)C.[Pd]>[CH3:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[NH:8][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)C=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: Cc1ccc(NCC(C)C)c(C)c1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
An aqueous solution of ammonium formate (3.15 g, 50.0 mmol, 10 mL) was diluted with isopropanol (80 mL) and added to palladium on carbon 10% wet (1.064 g, 10.00 mmol) under nitrogen. A solution of 2,4-dimethylaniline (1.212 g, 10 mmol) and isobutyraldehyde (1.004 mL, 11.00 mmol) in isopropanol (3 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through celite, the celite cake washed with isopropanol and combined liquid phases concentrated in vacuo. The residue (1.8 g) was purified using a pre-conditioned aminopropyl solid phase extraction cartridge (NH2 SPE) (20 g) using methanol as an eluent. The methanolic organic phase was concentrated under vacuo to give a second residue which was further purified on a Biotage Flashmaster II using silica (Si) 10 g/mmol using a 0-100% dichloromethane-cyclohexane gradient over 40 mins. The fractions containing the expected product were combined and concentrated in vacuo to give the desired product 1.5 g as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:18]1([CH:21]=O)[CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH:18]1([CH2:21][N:10]2[CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=3[NH:7][C:8](=[O:12])[CH2:9]2)[CH2:20][CH2:19]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(CC1CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (450 mg, 1.90 mmol) and cyclopropanecarboxaldehyde (2.84 mL, 37.9 mmol) in dichloromethane (50 mL) and methanol (5 mL) was added acetic acid (0.22 mL, 3.8 mmol). After being stirred for two hours at room temperature, sodium triacetoxyborohydride (1.2 g, 5.7 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was washed with saturated aqueous sodium bicarbonate and brine before being dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (0-5% MeOH-DCM) gave 4-cyclopropylmethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (440 mg, 80%) as a yellow-orange solid; 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.59 (s, 1H), 7.33 (s, 1H), 3.91 (2s, 5H), 3.43 (s, 2H), 2.41 (d, J=6 Hz, 2H), 0.86 (m, 1H), 0.47 (m, 2H), 0.10 (m, 2H); MS (m/e) 292 (M+1); mp 178° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.O>C(O)(=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cn1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
Acetic anhydride (27.4 mL) was added to a stirred suspension of 2-amino-5-bromopyridine (10.0 g) in acetic acid (40 mL). The mixture was heated at reflux for 4 hours, then cooled to room temperature and then poured into water (200 mL). The resulting solid was collected, washed three times with water (300 ml) and then dried in vacuo at 70° C., affording the title compound as a white solid (10.9 g).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:36]([Cl:37])=[CH:35][C:8]([C:9]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)=[O:10])=[C:7]([O:38][CH3:39])[CH:6]=1>C(O)C>[NH2:4][C:5]1[C:36]([Cl:37])=[CH:35][C:8]([C:9]([NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:18]2)=[O:10])=[C:7]([O:38][CH3:39])[CH:6]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Yield: 82.6 %

Procedure:
Hydrazine monohydrate (11.3 ml) was added to a solution of 4-amino-5-chloro-N-(1-(5-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)pentyl)-piperidin-4-ylmethyl)-2-methoxybenzamide (60 g) in ethanol (0.6 L), and the mixture was refluxed under heating for 4 hr. The precipitated crystals were filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 37.0 g of 4-amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl) -5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl[CH2:13][CH2:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][CH2:13][CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: ClCCNCc1ccccc1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NCCNCc2ccccc2)cc(OC)c1

Procedure:
In a manner similar to Preparation 29, react 3,5-dimethoxybenzenamine with N-(2-chloroethyl)benzenemethanamine to obtain the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[N:9]=[C:8]([C:15]#[N:16])[CH:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:13][N:12]([CH3:14])[C:10]1[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=1
Reactant: CC(=O)OCc1cc(C#N)nc(N(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)c1cc(CO)cc(C#N)n1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirring solution of 364 mg (1.66 mmol) of (2-cyano-6-(dimethylamino)pyridin-4-yl)methyl acetate in 7 mL of MeOH was added 365 mg (2.64 mmol) of K2CO3. After 1 h, the mixture was filtered through Celite with MeOH and EtOAc. More EtOAc and H2O (30 mL) were added; the aqueous layer was extracted with EtOAc (4×). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) provided 253 mg of 6-(dimethylamino)-4-(hydroxymethyl)picolinonitrile as a pale yellow solid in 86% yield.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:43]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:16]([C:39]([F:42])([F:41])[F:40])=[N:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:43]2[CH2:47][CH2:46][C:45]([F:48])([F:49])[CH2:44]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:16]([C:39]([F:40])([F:41])[F:42])=[N:17][NH:18][CH:19]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)c2n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c[nH]nc3C(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of crude 5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, triethylsilane in TFA was stirred at room temperature for 3 h, concentrated and subjected to purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions the title compound was isolated as white solid. MS(m/e): 431.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C[Al](C)C.[N:22]1([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:38])[C:32]=2[C:33](OCC)=[O:34])=[O:27])[CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[N:22]1([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:38])[C:32]=2[C:33]([NH:8][C:7]2[CH:6]=[CH:5][N:4]3[N:9]=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:11]=[C:3]3[C:2]=2[CH3:1])=[O:34])=[O:27])[CH2:23][CH2:24][CH2:25]1
Reactant: Cc1c(N)ccn2nc(-c3ccccc3)nc12
Reactant: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2c(C(=O)N3CCC3)cnn2C)ccn2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To an argon purged solution of 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (60 mg, 268 μmol) in dioxane (5 ml) is added trimethylaluminum (2M solution in toluene, 401 μl, 803 μmol). The resulting mixture is stirred for 1 hour at 25° C., then ethyl 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylate (63.5 mg, 268 μmol) is added, the mixture is heated to 100° C. and stirred for 72 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 50-100% as eluent affording 4-(azetidine-1-carbonyl)-1-methyl-N-(8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (77 mg, 69.3%) as a white solid. mp.: 243-5° C. MS: m/z=416.2 (M+H+).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].S(=O)(=O)(O)O>>[F:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:4](=[O:5])[CH:3]([CH3:13])[CH2:2]2
Reactant: CC(CCl)C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ten grams (0.05 mole) of 3-chloro-4'-fluoro-2-methylpropiophenone is added to 20 ml. of concentrated sulfuric acid at 20°-25°C and the mixture is warmed to 50°C. After stirring for 3 hours at 50°C, the reaction is quenched in ice. The product is extracted into hexane. The hexane layer is concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:22])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]#[N:21]
Reactant: c1cc2[nH]ccc2cn1
Reactant: N#Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Product: N#Cc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzonitrile (Compound No. 95) was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-cyanobenzoic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].[OH-].[Na+]>N1C=CC=CC=1.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1cccc(Br)c1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A solution of imidazole (2.66 g, 39.1 mmol) and triethylamine (Et3N) 8.03 g, 79.4 mmol) in pyridine at 0° C. is treated with 3-bromobenzoyl chloride (17.5 g, 79.9 mmol), stirred for 5 min, allowed to warm to room temperature for 45 min, treated with an aqueous sodium hydroxide solution (7.5 N, 20 mL, 150 mmol), heated at reflux temperature for 2 h, cooled to room temperature, diluted with water, further cooled with an ice bath for 1 h and filtered. The filtercake is washed with water and dried under vacuum at 50° C. overnight to afford the title compound as a light tan solid, 4.89 g (50% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 10.58 (br s, 1H), 8.73 (t, J=1.8 Hz, 1H), 8.61 (dt, J=7.8, 1.2 Hz, 1H), 7.75-7.72 (m, 1H), 7.42-7.38 (m, 2H), 7.32 (s, 1H); ESI MS m/z 250 [C10H7BrN2O+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 0.51 g (3.54 mmol) of 4-(methoxymethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.66 g of 4-methoxymethoxy-but-2-ynoic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: ma of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile: mass spectrum (electrospray, m/e,): M+H 465.1, 467.0.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[CH2:29]([N:31]([CH2:35][CH3:36])[C:32](Cl)=[O:33])[CH3:30].[Cl-].[Ca+2].[Cl-]>O1CCCC1.O>[CH2:29]([N:31]([CH2:35][CH3:36])[C:32]([N:15]1[CH2:16][CH:13]([O:12][C:11]2[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)[CH2:14]1)=[O:33])[CH3:30]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 15 h
Yield: 60.1 %

Procedure:
A stirred slurry of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 50 ml of tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 2.5 g (0.018 mole) of diethylcarbamoyl chloride was added. After stirring an additional 15 hr, the reaction was treated with 10 ml of water and saturated with calcium chloride. The tetrahydrofuran was decanted from the solid residue and concentrated in vacuo to an oil. The crude oil was chromatographed on a Water's Prep-LC using 50% ethyl acetate/toluene as the eluent. After concentration of the main fractions 3.1 g (60.1%) of pale yellow oil was obtained.