Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.N>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(COc2ccncc2)cc1
Agent: N
Solvent: Cc1ccccc1
Product: C1=C(OCc2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1

Procedure:
Prepared from 4-benzyloxy pyridine and 2-(chloromethyl) benzimidazole in an analagous manner to that described previously. M.p. 170°-172° C. (PhMe); (Found: C, 75.19; H, 6.45; N, 13.02. C20H21N3O requires C, 75.21; H, 6.63; N, 13.16%). δH (CDCl3) 2.35 (2H, br s, tetrahydropyridinyl 3-CH2), 2.81 (2H, t, J 5.6 Hz, tetrahydropyridinyl 2-CH2), 3.21 (2H, br s, tetrahydropyridinyl 6-CH2), 3.98 (2H, s, NCH2Ar), 4.75 (1H, br s, tetrahydropyridinyl 5-CH), 4.81 (2H, s, PhCH2O), 7.22-7.27 (3H, m, ArH), 7.31-7.37 (6H, m, ArH), and 7.56 (1H, br s, NH); m/z (CI+, NH3), 336 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[C:24]([C:29](O)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([N:12]2[CH2:13][CH:14]3[CH:10]([CH2:9][N:8]([C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[CH2:15]3)[CH2:11]2)=[O:30])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccccc1-c1cccc(F)c1
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccc(F)c4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 3′-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C24H23FN4O, 402.46; m/z found, 403.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:26]([S-:28])#[N:27].[K+].BrBr>C(O)(=O)C>[OH:11][CH2:10][CH:9]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH:8]([OH:25])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:26]([NH2:27])[S:28][C:3]=2[CH:4]=1
Reactant: Nc1ccc(C(O)C(CO)N2CCC(Cc3ccccc3)CC2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(O)C(CO)N3CCC(Cc4ccccc4)CC3)cc2s1

Procedure:
To a stirred solution of 5 g of (+) three 1-p-aminophenyl-2-(4-benzylpiperidin-1-yl)-1,3 propandiol and 5.7 g of KSCN in 30 ml of glacial acetic acid was added dropwise a solution of 2.36 g of Br2 in 25 ml of glacial acetic acid at room temperature.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:34]=1[N:42]=[C:43]=[O:44])([CH3:32])[CH3:31]>>[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:40])[CH3:41])[C:34]=1[NH:42][C:43](=[O:44])[N:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)([CH3:31])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc(Oc3ccccc3)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(Oc3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 23.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-octylphenyl)[(4-phenoxyphenyl)methyl]amine (1.53 g) and 2,6-diisopropylphenyl isocyanate (0.88 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)-N-[(4-phenoxyphenyl)methyl]urea (0.55 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1
Reactant: Oc1cc(F)cc(F)c1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.), tetrahydro-2H-pyran-4-ol (1.2 equiv.), and triphenylphosphine (2.0 equiv.) in THF (0.33 M) at 0° C. was added DIAD (2.0 equiv.) dropwise. The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by flash chromatography over silica gel (heptanes:ethyl acetate gradient) to give 4-(3,5-difluorophenoxy)tetrahydro-2H-pyran in 90% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.72-1.84 (m, 2H), 1.96-2.09 (m, 2H), 3.59 (ddd, J=11.64, 8.31, 3.52 Hz, 2H), 3.90-4.04 (m, 2H), 4.44 (tt, J=7.78, 3.77 Hz, 1H), 6.32-6.53 (m, 3H).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].I[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:3]#[C:2][C:1]([NH2:5])=[O:4]
Reactant: Ic1cccs1
Reactant: C#CC(N)=O
Product: NC(=O)C#Cc1cccs1
Yield: 54.5 %

Procedure:
According to preparation 4, propiolamide (1.68 g, 24.45 mmol) was coupled with 2-iodothiophene (3.2 g, 15.67 mmol) to provide 1.29 g (55%) of product. NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[O:21]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1>C(#N)C>[O:21]1[C:25]2([CH2:30][CH2:29][N:28]([C:7]3[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=3[F:1])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)c(F)c1

Procedure:
3,4-Difluoronitrobenzene (15.53 g, 0.098 M) was dissolved in acetonitrile (150 ml), and treated with N,N-diisopropylethylamine (31.5 g, 0.244 M) and 1,4-dioxa-8-aza-spiro[4,5]decane (15.36 g, 0.107 M). The mixture was stirred and heated to reflux for 18 hours. After cooling, product precipitated as a yellow solid, and was filtered off (16.1 g); further product could be obtained by concentrating the residues (8.43 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][C@H:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C@H:3]1[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[OH:1][C@H:2]1[CH2:6][O:5][C@H:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C@H:3]1[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC/C=C\CC[C@H]1[C@H](O)CO[C@@H]1c1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)CC/C=C\CC[C@@H]1[C@@H](c2cccnc2)OC[C@@H]1O
Temperature: 10 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 12.97 g (0.0425 mol) of methyl (Z)-(2S,3S,4S)-7-[4-hydroxy-2-(3-pyridyl)-tetrahydrofuran-3-yl]-4-heptenoate, 26.57 g (0.101 mol) of triphenylphosphine and 3.32 g (2.72 mL, 0.069 mol) of 95% formic acid in 130 ml of tetrahydrofurane is added dropwise with stirring under argon at 10° C. 17.63 g (15.94 ml, 0.101 mol) of diethyl azodicarboxylate over a period of 10 min. The mixture is stirred at room temperature for one h and evaporated. The residue is triturated with ether and the mixture is allowed to stand at 0° C. overnight. The precipitated triphenylphosphine oxide is filtered and washed with ether. The combined filtrates and washings axe evaporated to dryness. The residue is dissolved in 130 ml of methanol and hydrogen chloride gas is bubbled through the solution for 3 to 5 min. The mixture is stirred for 30 min and evaporated to dryness. The residue is dissolved in 56 ml of water and the solution is extracted with ethyl acetate (3×). The aqueous layer is mixed with 100 ml of methylene chloride and neutralized with solid sodium bicarbonate with vigorous stirring. The layers are separated and the aqueous layer is extracted with methylene chloride (3×). The combined methylene chloride extracts are washed with brine, dried (MgSO4) and evaporated to give 12.68 g of methyl (Z)-(2S,3S,4R)-7-[4-hydroxy-2-(3-pyridyl)-tetrahydrofuran-3-yl]-4-heptenoate as oil with elemental analysis: C,66.1; H,7.36; N,4.89 (theory: C,66.86; H,7.59; N,4.59) and mass spectrum m/z 306 (M+1) (Calcd. MW=305.38).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH3:21])=[C:15]([CH:18]=1)[CH:16]=O>>[S:9]1[C:8]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[O:19][CH2:20][CH3:21])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: c1ccc2sccc2c1
Product: CCOc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
Thianaphthene and 5-bromo-2-ethoxybenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:47]=[CH:48][CH:49]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:27][C:28]([C:30]2[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=2)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:29])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=3)[CH2:33][S:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:29])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:47]=[CH:48][CH:49]=[C:3]([C:2]([F:51])([F:1])[F:50])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoate (600 mg, 0.84 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2.5 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 96.2 mg (15%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.92 (s, 1H), 9.51 (t, J=11.7 Hz, 1H), 8.95 (d, J=5.4 Hz, 1H), 8.28 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.82 (d, J=5.4 Hz, 2H), 7.73 (t, J=12.3 Hz, 2H), 7.55 (m, 5H), 6.96 (d, J=2.4 Hz, 1H), 6.76 (m, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 3.33 (s, 4H), 2.62 (m, 2H), 2.50 (m, 2H), 1.99 (s, 4H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]1[CH:8]2[C:9]3[C:14]([CH:5]1[CH2:6][CH2:7]2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH2:15])([CH3:3])[CH3:2].C[Al](C)C.[F:20][C:21]([F:33])([F:32])[C:22]1[C:23]([C:28](OC)=[O:29])=[N:24][CH:25]=[CH:26][N:27]=1.Cl>ClCCl>[CH:1]([CH:4]1[CH:8]2[C:9]3[C:14]([CH:5]1[CH2:6][CH2:7]2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:28]([C:23]1[C:22]([C:21]([F:32])([F:20])[F:33])=[N:27][CH:26]=[CH:25][N:24]=1)=[O:29])([CH3:3])[CH3:2]
Reactant: CC(C)C1C2CCC1c1c(N)cccc12
Reactant: COC(=O)c1nccnc1C(F)(F)F
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)C1C2CCC1c1c(NC(=O)c3nccnc3C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a 1-ml vial containing 9-isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (6) (0.1 g, 0.497 mmol) and DCM (Volume: 2 mL) was added a 2.0 M solution of trimethylaluminum (0.017 g, 0.243 mmol). After evolution of gas ceased, methyl 3-(trifluoromethyl)pyrazine-2-carboxylate (8) (0.113 g, 0.546 mmol) was added as a solution in dichloromethane (0.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2N HCl (5 ml) and after bubbling ceased, was extracted with dichloromethane (2×5 ml) and was passed through a Biotage phase separator. The organic extracts were combined and the solvent was removed. The residue was loaded onto a silica column and was eluted using a ethyl acetate/hexanes gradient to afford the title compound (0.15 g, 80%) as a white solid with 4:1 syn:anti product: mp 173-177° C.; 1H NMR (600 MHz, CDCl3) δ 9.33 (s, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.86 (d, J=2.3 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.20-7.14 (m, 1H), 7.06 (d, J=7.2 Hz, 1H), 3.40 (s, 1H), 3.28 (s, 1H), 2.02-2.00 (m, 2H), 1.65 (d, J=10.0 Hz, 1H), 1.32-1.18 (m, 2H), 1.05-0.98 (m, 1H), 0.84 (d, J=6.6 Hz, 6H); ESIMS m/z 376.3 ([M+H]+), m/z 374.4 ([M−H])−).
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:30])[CH2:27][CH2:28][CH3:29]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCC(=O)N(C)OC
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -10° C. and then the bath replaced. After the temperature had cooled to -60° C., 4.3 g (32.5 mmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 mL of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 80 °C

Procedure:
200 gm of succinic anhydride and 800 gm of aluminum chloride were added to 250 ml of 2-fluorotoluene, and the mixture was heated at 80° C. for 1 hour. Upon the addition of 5 l of 1% cold hydrochloric acid aqueous solution, the reaction mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 345 gm of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:13][C:14](OC(C)=O)=[O:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:15])[CH3:13]
Reactant: CC(C)c1cc(O)cc(C=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C=O)cc(C(C)C)c1
Yield: 113.8 %

Procedure:
A solution of 33.2 mg (0.202 mmol) of 3-hydroxy-5-isopropylbenzaldehyde and 50 μL (0.53 mmol) of Ac2O in 3 mL of pyridine was stirred at r.t. for 70 min. The solution was concentrated, water and EtOAc were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash silica gel chromatography (20% EtOAc/hexanes) (neutral silica gel) to provide 47.4 mg of 3-formyl-5-isopropylphenyl acetate as a yellow oil with some impurity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2)([O-:3])=[O:2].[F-].[Cs+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9](=[O:14])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCc1ccccc1
Reactant: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=c1ccc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
Compound 46B (50 mg, 0.26 mmol) was dissolved in DMF (1 mL), CsF (120 mg, 0.79 mmol) and benzyl chloride (0.09 mL, 0.79 mmol) were added, and the reaction was stirred at rt for 16 h. The reaction mixture was then concentrated under reduced pressure and subsequently purified by silica gel flash chromatography eluting with 0-5% EtOAc/CH2Cl2 (gradient) to give the title compound (57 mg, 77%). LC/MS m/z 281 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[C:14]([C:15](OC)=[O:16])=[CH:13][N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:22][CH:21]=2)[N:11]=1)([CH3:9])[CH3:8].O>O1CCCC1>[CH:7]([C:10]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)[N:11]=1)([CH3:9])[CH3:8]
Reactant: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(C(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Lithium aluminium hydride (0.58 g) was added to a solution of methyl 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carboxylate (9.02 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and [3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]methanol (8.20 g, yield: 97%) was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:4]([C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2cccc(Cl)c2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(CN(C)C)n2c1CN=C(c1cccc(Cl)c1)c1cc(F)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-fluoro-2-(m-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-fluoro-6-(m-chlorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20]([CH3:29])([CH3:28])[O:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C@@H:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:20]([CH3:28])([CH3:29])[O:19][C:18]4=[O:30])=[CH:15][CH:16]=3)=[N:9][N:8]=2)[N:7]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3ccc(Cl)nn3)cc2)[C@H]1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4ccc(Cl)nn34)cc2)[C@H]1c1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
(S)—N′-(6-Chloropyridazin-3-yl)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzohydrazide (100 mg, 0.228 mmol) was dissolved in MeOH (2.284 mL). To the reaction mixture was added 4-methylbenzenesulfonic acid hydrate (43.4 mg, 0.228 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.). The mixture was heated at 55° C. and was stirred overnight. LC-MS indicated incomplete conversion. The mixture was then heated at 100° C. in a microwave for 1 hour. LC-MS indicated complete and clean conversion to the desired product. The reaction mixture was then concentrated under reduced pressure and providing a yellow residue. The residue was dissolved in 2 mL of MeOH and 1 mL of NH4OH, and the mixture was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 20% to 90% over 20 minutes. The pure fractions were combined and diluted with 30% ammonium hydroxide, and the aqueous layer was extracted with DCM (3×20 mL) to provide (S)-3-(4-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (30 mg, 0.071 mmol, 31.3% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J=9.40 Hz, 1H), 8.20 (d, J=8.33 Hz, 2H), 7.74 (d, J=9.19 Hz, 2H), 7.52 (d, J=9.62 Hz, 1H), 7.36-7.42 (m, 2H), 7.26-7.35 (m, 3H), 5.55 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 420.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[N:3]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:3]=[C:4]([CH2:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1CS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)nc1CS(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
A stirred mixture of 2-chloro-5-nitro-6-[(phenylsulfonyl)methyl]pyridine (1.41 g, 4.50 mmol), 1-benzylpiperazine (0.873 g, 4.95 mmol), and K2CO3 (0.683 g, 4.95 mmol) in ethanol is heated at reflux temperature for 1.5 h, cooled, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, EtOAc as eluent) to afford the title compound as an orange-yellow solid, 1.96 g (96% yield), mp 175-176° C., identified by NMR and mass spectral analyses.