Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1C=CC3N=C(C)OC=3C=1)C=2)=O)CCC.P(Cl)(Cl)([Cl:63])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:63])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Agent: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4nc(C)oc4c3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Temperature: 120 °C

Procedure:
A solution of the regiosomeric mixture of 1,4-dihydroxy-6-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester synthesized as described above (2.5 g, 6.12 mmol), and phosphorus oxychloride (685 μL, 7.35 mmol) in dichloroethane (30 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was stirred at ambient temperature with a saturated sodium bicarbonate solution for thirty minutes. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give a solid (1.72 g). It was recrystallized from ethyl acetate (130 mL) to give the title compound as a white solid (844 mg): MS: (+) m/z 427.16 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2([OH:26])[CH2:16][O:15][C:14]3[CH:17]=[CH:18][C:19]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:20][C:13]=3[O:12][CH2:11]2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].C(C1C=CC(OCC2OC3C=CC(CC(OC)=O)=CC=3C2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2([OH:26])[CH2:16][O:15][C:14]3[CH:17]=[CH:18][C:19]([CH2:21][C:22]([OH:24])=[O:23])=[CH:20][C:13]=3[O:12][CH2:11]2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC2(O)COc3ccc(CC(=O)OC)cc3OC2)ccc(C(C)=O)c1O
Agent: CCCc1c(OCC2Cc3cc(CC(=O)OC)ccc3O2)ccc(C(C)=O)c1O
Product: CCCc1c(OCC2(O)COc3ccc(CC(=O)O)cc3OC2)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 26, but substituting the compound of Example 38 for the compound of Example 25, there was obtained the title compound as a white foam.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#N)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(O)=[O:15]>[Ni]>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=CO
Reactant: N#Cc1ccc(-n2cccn2)cc1
Agent: [Ni]
Product: O=Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-pyrazol-1-yl-benzonitrile (1.6 g, 9.47 mmol), prepared in Step A of Preparation 42, in 75% aqueous formic acid (36 mL) was added Raney nickel alloy (1.6 g). The reaction was heated at reflux for 1.25 h and was cooled to room temperature. The solids were removed by filtration through Celite with the aid of hot EtOH. The solution was diluted with water and CHCl3. The aqueous layer was washed with CHCl3 (3×). To the organic solution was carefully added aqueous NaHCO3 until a pH of about 8 was achieved. The organic layer was dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography (2:1 hexanes:EtOAc) provided the title compound (1.44 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.01 (d, 1H), 7.96 (d, 2H), 7.87 (d, 2H), 7.76 (d, 1H), 6.51 (m, 1H); MS 173 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2([OH:61])[CH2:60][CH2:59][NH:58][CH2:57]2)[CH:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:58]3[CH2:59][CH2:60][C:56]([C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)([OH:61])[CH2:57]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2cccnc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3cccnc3)C2)cc1
Yield: 54.7 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyridin-3-ylpyrrolidin-3-ol dihydrochloride (7 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z: calcd for C20H19N3O4: 365.1376, found 365.1375.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1cccc(C=O)c1
Reactant: CCOC(=O)CC(=O)[O-]
Product: CCOC(=O)C=Cc1cccc(C)c1
Yield: 87.8 %

Procedure:
3-Methylbenzaldehyde (12.0 g, 100 mmol) and mono-ethyl malonate (15.5 ml, 130 mmol) were reacted as described under General Procedure A to furnish the title compound (16.7 g, 88%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=16.0 Hz, 1H), 7.34-7.18 (m, 4H), 6.42 (d, J=16.0 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.37 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:16][C:17]([O:19]CC)=[O:18])[C:4]=2[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:16][C:17]([OH:19])=[O:18])[C:4]=2[CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CCN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)O)CN(C)CC1
Temperature: 75 °C
Yield: 21 %

Procedure:
Ethyl 2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate (0.35 g, 1.2 mmol) in THF (10 mL) was added to a solution of sodium hydroxide (0.146 g, 3.6 mmol) in water (3 mL) and heated at 75° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed; water (10 mL) was added to the residue and the aqueous layer was washed with ethyl acetate (2×10 mL). The pH of aqueous layer was adjusted to 2-3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was evaporated, the residue was extracted with methanol, filtered, the filtrate was concentrated under reduced pressure to yield 2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetic acid (65 mg). 1H NMR (CD3OD): 7.30 (s, 1H) 7.20 (d, 1H), 7.0 (d, 1H), 5.1 (d, 1H), 4.8 (d, 1H), 4.18 (m, 1H), 4.0 (s, 2H), 3.81 (m, 1H), 3.42 (s, 3H), 3.15 (bs, 2H), 2.4 (s, 3H).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[CH2:6]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:22]=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>C(Cl)(Cl)Cl>[CH2:6]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[S:5][CH2:1][CH2:2][CH2:3][S:4]2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: SCCCS
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCCCC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOc1ccc(C2SCCCS2)cc1OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
1,3-propanedithiol (4.7 mL, 46.8 mmol) was added to a solution of 3,4-bis(dodecyloxy)benzaldehyde (20.0 g, 42.1 mmol) in 100 mL of chloroform. The reaction mixture was stirred at room temperature for 2 h. Concentrated hydrochloric acid (1.5 mL) was added to the mixture and the mixture was stirred at room temperature for additional 2 h. The mixture was washed with water and a saturated aqueous NaCl solution several times. The organic phase was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the product was further dried under vacuum at 47° C. overnight to give an off-white solid (22.7 g, 95%). mp 73-75° C. 1H NMR (200 MHz, CDCl3, δ): 6.91-7.00 (m, 2H), 6.78 (d, J=7.8 Hz, 1H), 5.08 (s, 1H), 3.96 (q, J=6.2 Hz, 4H), 2.80-3.12 (m, 4H), 1.89-2.21 (m, 2H), 1.78 (m, 4H), 1.42 (m, 4H), 1.24 (s, 32H), 0.86 (t, J=6.2 Hz, 6H). 13C{1H} NMR (50 MHz, CDCl3, δ): 149.12, 131.56, 120.02, 113.52, 113.14, 69.12, 51.19, 32.15, 31.86, 29.57, 29.36, 29.30, 29.20, 25.97, 25.04, 22.63, 14.05. IR (cm−1): 2916, 2847, 1586, 1517, 1466, 1269, 1137. HRMS-FAB (m/z): [M+H]+ calcd for C34H61O2S2, 565.4113; found, 565.4087. Anal. Calcd for C34H60O2S2: C, 72.28; H, 10.70. Found: C, 72.47; H, 10.78.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.O.[OH-].[Na+]>CO>[CH2:11]1[C:10]2=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][O:12]1
Reactant: CCOC(=O)c1ccn2c1COCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn2c1COCC2
Yield: 100 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 2a) (3.2 g, 16.4 mmol) in methanol (64 ml) was added water (64 ml) and sodium hydroxide (3.3 g, 82 mmol) and the mixture was stirred at reflux until complete conversion according to LC/MC (about 4 h). Approximately half of the solvents were evaporated in vacuo and the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 2.7 g (100%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as white solid. LC/MS (method 4): Rt=0.77 min; m/z=168.02 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[NH:6][C:5]2([C:17]#[C:18][CH:19]1[CH2:21][CH2:20]1)[C:13]([F:16])([F:15])[F:14].C([O-])([O-])=O.[Na+].[Na+].NC(N)=[S:30]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:30])[NH:6][C:5]2([C:17]#[C:18][CH:19]1[CH2:21][CH2:20]1)[C:13]([F:16])([F:15])[F:14]
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)N1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)C1(C#CC2CC2)NC(=S)Nc2ccc(Cl)cc21
Temperature: 95 °C
Yield: 39 %

Procedure:
A solution of (+/-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (0.33 g, 1.0 mmol) in phosphorous oxychloride (5 mL) containing Na2CO3 (160 mg, 1.5 mmol) was heated at 95° C. overnight. After cooling to room temperature, the phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in ethanol (5 mL) and thiourea (0.35 g, 4.6 mmol) was added. The resulting mixture was heated at reflux for 24 hours, cooled to room temperature and concentrated. The material was dissolved in EtOAc (75 mL) and washed sequentially with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL). The organic extract was dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (25% EtOAc/hexanes) to afford the title compound as a white solid (129 mg, 37%): mp 259-260; 1H NMR (300 MHz, acetone-d6) δ 10.3 (br s, 1H), 8.95 (br s, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.48 (dd, J=8.4, 2.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 1.49-1.44 (m, 1H), 0.93-0.85 (m, 2H), 0.80-0.76 (m, 2H); 19F NMR (282 MHz, acetone-d6) δ -82; MS (CI) calc'd for C14H10ClF3N2S: m/z 330.020533, found 330.019821; 331 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][C@H:29]([C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][C@@H:29]([OH:30])[C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNC[C@@H](O)c1cnccn1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C[C@@H](O)c2cnccn2)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.7 %

Procedure:
A mixture of N-(4-fluorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (104 mg, 0.275 mmol), (1R)-2-(methylamino)-1-pyrazin-2-ylethanol (Preparation 80, 65 mg, 0.0.42 mmol) and diisopropylethylamine (72 μL, 0.0.41 mmol) in dry DMF (5.5 mL) was stirred at room temperature for 17 hours. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo, providing a white solid. Attempted recrystallization from acetonitrile (20 mL, dissolved with warming and then cooled to room temperature) gave the title compound (31 mg) as a white solid upon concentrating the filtrate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[CH3:35][NH:36][CH3:37]>C1COCC1>[CH3:35][N:36]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N:11]2[C:10](=[S:30])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:31]([F:32])([F:34])[F:33])[CH:5]=3)[C:16](=[O:17])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=1)[CH3:37]
Reactant: CS(=O)(=O)OCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of Methanesulfonic acid 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]phenylmethyl ester (50a) (0.02 g, 0.039 mmol) and dimethylamine (0.5 ml; distilled from its 40% aqueous solution) in THF (1 ml) was stirred for 2 hours at −78° C. The mixture was concentrated and chromatographed (dichloromethane:acetone, 95:5; acetone) to yield 4-[5-(4-dimethylaminomethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-7-yl]-2-trifluoromethylbenzonitrile (50c) [RD156] (0.017 g, 0.037 mmol, 95%), the structure of which is illustrated in Formula 24, as a white powder.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:11]1[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[CH2:7][CH2:8][CH2:9][C:10]2=1
Reactant: O=C1CCCCc2ccccc21
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c3c(c2c1)CCCc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using 6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.10 g, 6.87 mmoL) and 4-methoxy-phenylhydrazine HCl salt (1.20 g, 6.87 mmoL) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.[Cl-].[NH4+]>CS(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14](=[C:5]([C:3]#[N:4])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C(C#N)=C1C=CC(Br)=CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (66.4 g, 60% oil dispersion) in dry DMSO (1.5 L) was added t-butyl cyanoacetate (243 mL) at 18-25° C. for 1 hour, the mixture was stirred at room temperature for 2 hours. 2,5-Dibromopyridine (150 g) was added to the resulting mixture, the mixture was stirred at 120° C. for 6.5 hours. After cooling, the mixture was poured into saturated ammonium chloride solution, the resulting precipitates were collected by filtration, washed with water and cooled EtOH to give t-butyl (5-bromo-2(1H)-pyridinylidene)cyanoacetate (166 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:5][CH:6]=[N:7][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[C:4]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)=[N:5][CH:6]=[N:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][N:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2ncncc2CCl)cc(OC)c1OC
Product: COc1cc(-c2ncncc2CN2CCN(Cc3cncnc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC

Procedure:
5-Chloromethyl-4-(3,4,5-trimethoxyphenyl)pyrimidine (250 mg) and piperazine (37 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[Si:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Hydroxybenzaldehyde (70 g, 0.57 mol), tert-butyldimethylsilyl chloride (92 g, 0.61 mol), and imidazole (92 g, 1.35 mol) were combined in dimethylformamide (250 mL). The mixture was stirred at room temperature, under nitrogen, for 1 hour. The solution was poured into water (1.5 L) and extracted with 2×500 mL petroleum ether (35°-60° C. boiling range). The organic solution was washed with saturated sodium chloride solution (100 mL), dried over magnesium sulfate, treated with silica gel (20 g), filtered, and concentrated in vacuo. The residue was dried further under high vacuum to yield (126.6 g (94%) of the air and light-sensitive 3-((tert-butyldimethylsilyl)oxy)benzaldehyde as an amber oil.
Reaction SMILES: [O-]CCCC.[K+].C1COCC1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:21]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[C:34]=1[C:43](Cl)=[O:44]>O>[F:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[C:14]=1[C:20]1[CH:24]=[CH:23][N:22]([C:25](=[C:43]([C:34]2[C:35]([C:39]([F:42])([F:41])[F:40])=[N:36][N:37]([CH3:38])[C:33]=2[Cl:32])[OH:44])[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:21]=1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1Cl
Reactant: C=CCOC(=O)Cn1ccc(-c2c(F)cccc2F)n1
Agent: CCCC[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=C(O)c1c(C(F)(F)F)nn(C)c1Cl)n1ccc(-c2c(F)cccc2F)n1
Reaction time: 0.08 h

Procedure:
Potassium butoxide (0.5 g) was added to a THF (10 mL) solution of allyl 2-{3-(2,6-difluorophenyl)pyrazol-1-yl}acetate (0.5 g) and 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carbonyl chloride (0.44 g) at 0° C. and stirred for 5 minutes. Water (5 ml) was added thereto, and then extracted with diluted hydrochloric acid and ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, and then concentrated, and the resulting concentrate was purified through silica gel column chromatography (chloroform) to obtain the intended product, Compound No. I-133 (0.89 g).
Reaction SMILES: [F:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([C:8]#[C:9][Si](C)(C)C)=[N:6][CH:7]=1.C(C1N=C(OC)C=CN=1)#C>>[C:8]([C:5]1[N:4]=[C:3]([O:14][CH3:15])[C:2]([F:1])=[CH:7][N:6]=1)#[CH:9]
Reactant: COc1nc(C#C[Si](C)(C)C)ncc1F
Agent: C#Cc1nccc(OC)n1
Product: C#Cc1ncc(F)c(OC)n1

Procedure:
Obtained (82%) from 5-fluoro-4-methoxy-2-((trimethylsilyl)ethynyl)pyrimidine (Preparation 16b) following the experimental procedure as described in Preparation 1b followed by purification by flash chromatography (99:1 dichloromethane/methanol).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(Cl)cc1

Procedure:
Following the general method as outlined in Example 1, starting from tert-butyl(2-bromo-4-chlorophenoxy)acetate (Intermediate 1) and 4-chlorophenylacetylene (Apollo), the title compound was obtained as a beige solid after purification by preparative HPLC
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[N:32]O)[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C1(C)C(S(Cl)(=O)=[O:41])=CC=CC=1>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@H:24]3[C@H:25]4[O:31][CH2:30][C:29](=[O:41])[NH:32][C@H:26]4[O:27][CH2:28]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: ON=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: c1ccncc1
Solvent: CO
Product: O=C1CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,3aS,6aR)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one oxime (20 mg, 0.043 mmol) was dissolved in pyridine and was cooled in an ice bath. Toluene sulfonyl chloride (21.2 mg, 0.11 mmol) was added in one portion and the mixture was stirred in an ice bath for 1 hour. The mixture was warmed to room temperature and additional toluene sulfonyl chloride (17 mg, 0.09 mmol) was added. After 2 hours, the solution was placed in a 60 degree oil bath for 1.5 hours and then cooled to room temperature. The reaction mixture was evaporated to give a foam, which was dissolved in methanol (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water to give the title compound. LC-MS: calculated for C24H19ClN4O4 462.11 observed m/e: 463.95 (M+14)+ (Rt 1.25/2 min); 1H NMR δ (ppm) (CD3OD): 7.93 (s, 1H), 7.78 and 7.73 (ABq, 4H), 7.70 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 6.44 (d, 1H), 5.48 (t, 1H), 4.83 (t, 1H), 4.63 (ABq, 2H), 4.50 (dd, 2H) and 4.45 (dd, 1H).