Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:8][CH2:9][C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:23][C:6]2=3)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1N(c1ccc(Cl)cc1)CC2
Yield: 32.3 %

Procedure:
A solution of 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.08 mmol), phenylboronic acid (20 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (60 mg, 0.16 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=12:1) to afford 6-(4-chlorophenyl)-1-methyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (10 mg, yield 33%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.Cl.[CH3:32][O:33][C:34](=[O:47])[C@H:35]([CH2:37][NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:36].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:39]([NH:38][CH2:37][C@@H:35]([C:34]([O:33][CH3:32])=[O:47])[NH:36][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:19][C:11]=1[Cl:10])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Diisopropylethylamine (27 mL, 147.2 mmol) was added dropwise to a cooled (˜0° C.) solution of 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 9.00 g, 29.4 mmol), 3-benzoylamino-L-alanine methyl ester hydrochloride (Example 300; 11.4 g, 44.2 mmol), HTBU (13.4 g, 35.3 mmol) and HOBT (4.8 g, 35.3 mmol) in N,N-dimethylformamide (125 mL). The reaction was allowed to warm to room temperature and to stir for 18 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. Ethyl acetate was added and the solution was washed with water (2×150 mL). 1 M HCl (3×100 mL) and brine. The solution was dried (MgSO4), filtered, evaporated, and chromatographed (0-50% acetone/dichloromethane) to give 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (10.7 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[Br:17][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:12]
Reactant: CCOc1cccc(C(C)=O)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOc1cccc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
While a mixture of 3′-ethoxyacetophenone (37 g, 0.225 mol), aluminum chloride (0.27 g, 2 m mol) and ether (100 ml) was stirred under cooling with ice, bromine (11.5 ml, 0.225 m mol) was added dropwise thereto over a period of 15 minutes. After this mixture was further stirred for 10 minutes, ice water (500 ml) was added thereto and this mixture was extracted with ether (2×100 ml). After the extract was washed with water and dried, the solvent was distilled off under reduced pressure. The resulting residue was distilled under reduced pressure (150-155° C./5 mmHg) to obtain the desired compound (45.7 g). Although this product contained a small amount of dibromo-substituted compounds, it was directly used in the following step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([CH2:15][CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:17][CH2:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1ccc(OCCc2ccccc2)nn1

Procedure:
3,6-Dichloropyridazine (1.0 g, 6.712 mmol), 2-phenylethanol (820 mg, 6.712 mmol) and sodium hydride (60 percent suspension in oil, 268 mg, 6.712 mmol) were stirred in 25 ml of N-methylpyrrolidin-2-one at room temperature for 30 minutes. After concentrating, water and ethyl acetate were added, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 878 mg (56%), M+H+: 235.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[OH2:17]>>[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
The same oxidation reaction of diphenyl methane as set forth in Example 19a was carried out using acetonitrile and water in place of acetone and water as the reaction solvents. All other reactants and processing conditions remained the same. Again, 0.7 g of starting material was recovered and 0.92 g of benzophenone was obtained, resulting in an identical yield of 86% based on 59% conversion.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1-bromo-3-methyl butane (0.715 mL, 5.96 mmol) in N,N-dimethylformamide (20 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.86 mL, 12.43 mmol) at 65° C. for 5 days. The mixture was cooled to 25° C. and partitioned between water and dichloromethane. The organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to give the title compound (0.57 g, 42%). MS (DCI/NH3) m/z 272 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 0.96 (d, J=6.25 Hz, 6 H) 1.61 (m, 3 H) 3.89 (m, 2 H) 4.99 (s, 2 H) 5.98 (dd, J=7.54, 2.76 Hz, 1 H) 6.06 (d, J=1.84 Hz, 1 H) 7.14 (d, J=7.72 Hz, 1 H) 7.39 (m, 5 H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:20]=2[CH3:27])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CC#N.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=2[CH3:27])[CH:25]=[O:26])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C=O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one (1.5 g, 3.33 mmol) was dissolved in 75% CH3CN/CH2Cl2 (20 ml) and cooled to 0° C. Dess-Martin Periodinane (2.8 g, 6.66 mmol) was added and the reaction stirred for four hours. At this time, the reaction was quenched with 5% sodium bisulfite (aq.). The product was extracted with ethyl acetate. The combined organic extracts were then washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The resulting residue was taken up in diethyl ether and the precipitate was collected on a filter pad and washed with more diethyl ether to yield a white solid (1.35 g, 91%). 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.91 (dd, J=7.65, 1.61 Hz, 1H), 7.65 (m, 2H), 7.57 (d, J=7.85 Hz, 1H), 7.03 (m, 1H), 6.95 (ddd, J=12.69, 8.86, 2.62 Hz, 1H), 6.19 (s, 1H), 5.31 (s, 2H), 2.20 (s, 3H), 1.96 (s, 3H); ES-MS m/z 448 (M+H). ES-HRMS m/z 448.0347 (M+H calcd for C21H17BrF2NO3 requires 448.0354).
Reaction SMILES: OCC(CO)O.C[C@@H]1O[C@@H](O[C@H:14]2[C@H:19](O)[C@@H:18](O)[C@H:17]([NH:22]C(N)=N)[C@@H:16]([OH:26])[C@@H:15]2[NH:27]C(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.[OH-:47].[K+]>O>[NH2:22][C@H:17]([C:16]([OH:26])=[O:47])[CH2:18][CH2:19][CH2:14][CH2:15][NH2:27]
Reactant: [OH-]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Solvent: O
Solvent: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 20 h

Procedure:
The glycerol stocks of the Escherichia coli WC196LC/pCABD2 strain were thawed, 100 μL of each was uniformly applied to an L-plate containing 25 mg/L of streptomycin, and culture was performed at 37° C. for 20 hours. The cells in an amount of about ⅛ of the cells obtained on one plate were inoculated in 20 mL of the fermentation medium described below containing 25 mg/L of streptomycin, which was contained in a Sakaguchi flask, and cultured at 37° C. for 16 hours or 20 hours on a reciprocally shaking culture apparatus. Each of the samples derived from the alga obtained in Example 8 (1) serving as the carbon source was suspended in distilled water, Tween 80 was added to the suspension at a concentration of 1%, and the mixture was adjusted to pH 7.0 with 3 N KOH, autoclaved at 120° C. for 20 minutes, and used as the carbon source solution. The medium composition used for the culture is shown below. The total of the measured aliphatic acid and glycerol concentrations of the hydrolysate of the crude extract derived from the alga is indicated.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[I:9]I.CCCCCC>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: CCO
Product: Nc1ccc(Br)nc1I
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1×100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65%) of the title compound as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): δ 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH:14]=[CH:20][N:21]([CH3:23])[CH3:22])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1
Reactant: Cc1cc(-c2ccccc2F)ncc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(-c2ccccc2F)ncc1[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-fluoro-phenyl)-4-methyl-5-nitro-pyridine (5.4 g, 23 mmol) in DMF (30 mL) was treated with N,N-dimethylformamide dimethyl acetal (3.6 g, 30 mmol), and the mixture was stirred at 115° C. for 1 h, cooled, and concentrated in vacuo to yield crude {2-[2-(2-fluoro-phenyl)-5-nitro-pyridin-4-yl]-vinyl}-dimethyl-amine as a brown solid. The solid was dissolved in THF (100 mL), and water (100 mL), and then sodium periodate (14.06 g, 66 mmol) was added. The suspension was stirred at room temperature for 24 h. The reaction mixture was filtered, and the filtrate was concentrated, and then diluted with EtOAc. The organic extract washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), and concentrated in vacuo to yield crude title compound as a solid. The crude solid was purified by column chromatography (4:2:0.5; CHCl3:hexanes:EtOAc) to yield 2-(2-fluoro-phenyl)-5-nitro-pyridine-4-carbaldehyde, the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Yield: 53 %

Procedure:
tert-Butyl 4-(2-fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate was dissolved in DCM (5 mL). TFA, 10 eq, was added and the reaction was heated to reflux for 2 h. The mixture was neutralized with sat NaHCO3 and the phases were separated. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure to yield 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (186 mg, 53%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:13][N:23]=[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:15]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Cn1cnc2cc(-c3nc(-c4cccnc4)no3)ccc21

Procedure:
The title compound was prepared according to Method C using 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ7.65 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 7.68-7.88 (m, J=8.8 Hz, 1 H), 7.87-8.10 (m, 2 H), 8.14-8.37 (m, 1 H), 8.46 (dt, J=8.1, 1.9 Hz, 1 H), 8.82 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.0, 0.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2].[F:22][C:23]([F:39])([F:38])[C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:24]([C:23]([F:38])([F:22])[F:39])[CH:25]=2)[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N)C[C@@H]1C
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NC(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (150 mg, 0.50 mmol) and 3,5-bis-trifluoromethylphenylacetic acid (138 mg, 0.51 mmol) in 1.5 ml anhydrous dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg, 0.66 mmol) and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml ethyl acetate and was washed with 0.1N HCl (2×10 mL), 0.1N NaOH (2×10 mL) and brine (1×10 mL). The organic phase was dried (MgSO4), filtered and concentrated, and the the residue was chromatographed using 20:1 hexanes:ethyl acetate. The title compound crystallized out of the combined fractions (129 mg, 46%). Me 157-9° C.; MS m/z 549 (M+ +1); 1H NMR (CDCl3) δ 1.07 (d, 3H), 7.70-7.78 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].N[C:11]1N=C(O)C=CC=1.BrBr>C(O)(=O)C.O>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:11])=[CH:5][CH:4]=1
Reactant: Nc1nc(O)ccc1Br
Reactant: Nc1cccc(O)n1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(N)n1
Reaction time: 0.25 h

Procedure:
In accordance with scheme 1, the compound of formula V (6-amino-5-bromo-pyridin-2-ol) may be prepared as described in Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Letters 1991, 32, 4263-4266) as follows: To a solution of 6-amino-pyridin-2-ol in acetic acid at room temperature is added bromine and stirred for 15 min. The mixture is diluted with water and the precipitate is filtered off. The filtrate is extracted and the combined organic layers are dried and evaporated to dryness. Then a suspension of 6-amino-5-bromo-pyridin-2-ol is treated with KOH pellets and dimethylsulfate. The mixture is stirred for 4 h at room temperature and evaporated to dryness. The residue is purified and 3-bromo-6-methoxy-pyridin-2-yl-amine (IV) is obtained. Furthermore, a mixture of 3-bromo-6-methoxy-pyridin-2-yl-amine, phenylboronic acid (wherein the phenyl ring may be substituted by R1), Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium II) dichloromethane adduct in dioxane is heated to 110° C. for 2 h. The mixture is concentrated, diluted Na2CO3 aq. is added and extracted. The combined organic phases are dried and evaporated. The residue is purified to yield the corresponding compound of formula II, for example 6-methoxy-3-phenyl-pyridin-2-yl-amine. A mixture 6-methoxy-3-phenyl-pyridin-2-yl-amine (II) and ethoxycarbonyl isothiocyanate is stirred at room temperature for 2 h and afterwards evaporated to dryness. The obtained compound of formula III is then treated with a mixture of hydroxylamine hydrochloride and N-ethyldiisopropylamine (DIPEA). The mixture is heated to 80° C. for 16 h, evaporate to dryness, taken up in water and extracted with diethyl ether. The combined organic phases are dried and evaporated to yield, for example, 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine (Ia). A mixture of 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and a compound of formula R2Cl, for example 3-fluorophenyl carboxylic acid chloride, and NEt3 in dioxane is heated to 90° C. for 16 h. The mixture is purified to give a compound of formula I, for example 3-fluoro-N-(5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide.
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[NH:9][CH2:10][CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NCCC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Cn2nccc2-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 65D (3.1 g) in dichloromethane (10 mL) was added TFA (10 mL) and the mixture was stirred overnight. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (300 mL) and washed with 2N aqueous NaOH, water and brine. The combined organic layers were concentrated, and the residue was dissolved in dichloroethane (30 mL) and MnO2 (2.5 g) was added. The mixture was stirred overnight. Filtration and evaporation of the solvent provided the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20]B(O)O.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH3:20][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1Cl
Reactant: CB(O)O
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: C1COCCO1
Solvent: O
Product: Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
In a sealed tube, dissolve 6-chloro-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carbonitrile (242 mg, 0.853 mmol), CH3B(OH)2 (300 mg, 5.10 mmol), K2CO3 (1.6 g, 12 mmol), and Pd(PPh3)4 in a solution of dioxane (10 mL) and H2O (2 mL). Bubble argon through the mixture for 30 minutes and seal. Heat the mixture at 115° C. overnight. Cool the mixture to room temperature. Add H2O (20 mL) and extract with EtOAc (3×20 mL). Combine the organic extracts and wash with brine (60 mL). Dry the organic layer over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with EtOAc/hexane (1:1) to yield the title compound. MS 264.07 (M+1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]1([NH:6][C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1cc(Cl)nc(NC2CCCC2)n1
Reactant: C1CCNC1
Product: Clc1cc(N2CCCC2)nc(NC2CCCC2)n1
Yield: 72.4 %

Procedure:
2-Cyclopentylamino-4,6-dichloropyrimidine is reacted with pyrrolidine as described in Example 12 to give the title compound as an oily product in a yield of 72.4%.