Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:12])=[C:9](Br)[CH:10]=1)=[O:4].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:8]([Cl:12])=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Product: COC(=O)c1cnc(Cl)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5a, using 5-bromo-6-chloro-3-pyridinecarboxylic acid methyl ester and 4-fluorophenylboronic acid as starting materials, MS (ISP) 266.1 (M+H)+.
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(=O)NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)=CC=2C(O)=O)C=1C.[CH2:44]([N:48]([C:92]1[CH:101]=[CH:100][C:95]([C:96]([O:98]C)=[O:97])=[CH:94][CH:93]=1)[C:49]([C:51]1[C:55]([Cl:56])=[C:54]([CH3:57])[N:53]([C:58]2[CH:63]=[CH:62][C:61]([C:64](=[O:79])[NH:65][S:66]([C:69]3[CH:78]=[CH:77][C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=3)(=[O:68])=[O:67])=[CH:60][C:59]=2[C:80]([N:82]2[CH2:91][CH2:90][C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH2:83]2)=[O:81])[N:52]=1)=[O:50])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]([C:92]1[CH:93]=[CH:94][C:95]([C:96]([OH:98])=[O:97])=[CH:100][CH:101]=1)[C:49]([C:51]1[C:55]([Cl:56])=[C:54]([CH3:57])[N:53]([C:58]2[CH:63]=[CH:62][C:61]([C:64](=[O:79])[NH:65][S:66]([C:69]3[CH:78]=[CH:77][C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=3)(=[O:67])=[O:68])=[CH:60][C:59]=2[C:80]([N:82]2[CH2:91][CH2:90][C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH2:83]2)=[O:81])[N:52]=1)=[O:50])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(C(=O)OC)cc1
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(C(=O)O)cc1
Yield: 124.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 91F, methyl 4-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)benzoate (Example 154, 2 mg, 2.0 μmol) was converted to the title compound (2 mg, 94%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.71 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.06 (s, 2H), 8.04-7.97 (m, 2.5H), 7.93 (d, J=2.0 Hz, 0.5H), 7.87 (d, J=8.6 Hz, 1H), 7.75-7.64 (m, 3H), 7.54 (d, J=8.1 Hz, 0.5H), 7.41 (d, J=8.8 Hz, 0.5H), 7.22-7.18 (m, 3.5H), 7.01-6.99 (m, 1.5H), 6.73 (d, J=7.0 Hz, 1H), 4.97 (br s, 1H), 4.69 (br s, 1H), 4.52-4.31 (m, 2H), 4.17 (br s, 1H), 3.93 (br s, 1H), 3.64-3.43 (m, 1H), 2.94-2.78 (m, 1H), 2.21-2.17 (m, 1H), 2.16 (s, 2H), 2.14 (s, 1H), 2.06-2.00 (m, 1H), 1.64-1.56 (m, 1H), 1.44-1.20 (m, 3H), 0.93-0.81 (m, 3H); MS(ESI+) m/z 804.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C@H:13]([NH2:15])[CH3:14].C([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([C:47](O)=[O:48])=[CH:44][CH:45]=3)[C:40]([CH3:50])=[C:39]2[CH3:51])=[CH:33][CH:32]=1)=[O:24])(C)(C)C>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[C@H:13]([NH:15][C:47]([C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:26]3[C:25]([C:23]([OH:24])=[O:22])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1)[C:39]([CH3:51])=[C:40]2[CH3:50])=[O:48])[CH3:14]
Reactant: C[C@@H](N)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cc(C(F)(F)F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 639 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C1SCC(=O)Nc2c1c(-c1ccccn1)nn2C
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 4 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To a solution of 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (0.200 g, 0.52 mmol) in THF (6 mL) was added a solution of borane THF complex (4 mL, 1M in THF, 4 mmol, Acros) at rt. Subsequently, the mixture was heated under reflux for about 3 h. After cooling to about 4° C., HCl (5 M aqueous, 6 mL) was added dropwise and the mixture was stirred for about 2 h at about 4° C., then NaOH (1 M aqueous, 50 mL) and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Method a, Table 2) to give 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.0917 g, 0.25 mmol, 48%). LC-MS (Table 1, Method a) Rt=4.23 min, m/z 371 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.58 (3H, s) 2.68 (1H, ddd, J=15.0, 6.1, 2.5 Hz) 2.85 (1H, ddd, J=15.0., 9.6, 2.5 Hz) 3.21-3.29 (1H, m) 3.56-3.65 (1H, m) 3.79 (1H, br s) 3.83 (3H, s) 6.66 (1H, s) 6.99 (1H, dd J=8.3, 2.1 Hz) 7.07 (1H, ddd J=8.0, 5.0, 1.0 Hz) 7.12 (1H, d J=8.0 Hz) 7.15 (1H, d, J=2.0 Hz) 7.59 (1H, td, J=7.5, 2.0 Hz) 7.79 (1H, d, J=8.0 Hz) 8.46 (1H, d, J=4.5 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:29])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:30]S(C1C=CC(N2C=CC(O[C@H]3CC[C@H](C(OCC)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH:27]([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]3)=[CH:13][C:12]2=[O:29])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)[C@H]1CC[C@@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 65 was prepared according to procedures described in Example 66 substituting cis-ethyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)cyclohexanecarboxylate for trans-ethyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)cyclohexanecarboxylate. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.05 (d, J=7.5 Hz, 1H), 5.96 (s, 1H), 5.00 (sept, J=6.2 Hz, 1H), 4.44-4.48 (m, 1H), 3.08 (s, 3H), 2.36-2.41 (m, 1H), 1.99-2.08 (m, 2H), 1.83-1.95 (m, 2H), 1.63-1.79 (m, 4H), 1.21 (d, J=6.2 Hz, 6H). MS (ESI) 434 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][S:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([S:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CSc1ccc(C(=O)Cl)cc1
Product: CSc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-(methylthio)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 450/452 (M+H). 1H-NMR (DMSO-d6) δ 2.43 (s, 3H), 3.24 (td, J=9.0, 5.6 Hz, 1H), 3.39 (td, J=8.7, 5.2 Hz, 1H), 3.43-3.48 (m, 2H), 3.62-3.69 (m, 2H), 4.23 (s, 2H), 4.53 (t, J=5.4 Hz, 1H), 5.09 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.6 Hz, 1H), 5.40 (d, J=9.1 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.9 Hz, 1H), 7.17 (s, 4H), 7.27 (s, 1H), 7.54 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([CH3:15])([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:4]#[N:5].[C:17]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[NH2:5][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([N:2]([CH3:16])[CH3:1])([CH2:6][O:7][Si:8]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:10])[CH3:9])[CH3:15]
Reactant: [Li]c1ccccc1
Reactant: CN(C)C(C)(C#N)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(C)(CO[Si](C)(C)C(C)(C)C)C(N)c1ccccc1
Yield: 33 %

Procedure:
The title compound (930 mg, 33%) was prepared from 2-(dimethylamino)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methylpropanenitrile D47 (2.1 g, 8.67 mmol), phenyl lithium (10.0 ml of a 1.8M solution in dibutyl ether, 18.0 mmol) in THF (30 ml) followed by sodium borohydride (830 mg, 26.0 mmol) in methanol (50 ml) in a similar manner to that described in D2. Chromatography (Biotage Horizon) to isolate the title compound was carried out using (i) 0 to 100% ethyl acetate/pentane, (ii) 100% ethyl acetate and (iii) 0 to 20% methanol/ethyl acetate. The product containing fractions were combined and evaporated. Mass spectrum (Electrospray LC/MS), API+: Found 323 (MH+), 306 (M−16). C18H34N2OSi requires 322. Ret. time 2.35-2.39 min. (broad peak).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH3:14].[CH3:15][Mg]Br>O1CCCC1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([CH3:15])([OH:13])[CH3:12])=[CH:4][C:3]=1[CH3:14]
Reactant: C[Mg]Br
Reactant: CC(=O)CCc1cc(C)c(Br)c(C)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(CCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenyl)butan-2-one (100 mg) in tetrahydrofurane (2 mL) is added at 0° C. methylmagnesium bromide (840 μL of a 1.4 M solution in tetrahydrofurane/toluene 1:3). The mixture is stirred for 2 hours while warming to room temperature and then partitioned between saturated aqueous NH4Cl solution and diethylether. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 105 mg; LC (method 8): tR=0.47 min; Mass spectrum (ESI+): m/z=271 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:24]([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:14]=2[CH3:24])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(F)cc(F)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc(F)cc(F)c1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.607 mmol) was dissolved in 10 mL THF and cooled to −75° C. Lithium diisopropylamide (0.45 ml, 0.91 mmol) was added and the mixture stirred for 15 min at −75° C. lodomethane (0.05 ml, 0.85 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3— solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10->20:80 gradient) and by recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40 mg, 19%), MS: m/e=344.5 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:22])([F:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([F:22])([F:21])[F:5])=[CH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform are added to a solution of 5.0 g (19.82 mmol) of (4′-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is separated off, dried over sodium sulphate and evaporated after filtration. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% yield) of a colourless solid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:20])[CH2:18][CH3:19])=[C:14]([CH3:21])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:20])[CH2:18][CH3:19])=[C:14]([CH3:21])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]propan-1-one (0.88 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (15 mL) and methanol (1 mL), and sodium borohydride (90%, 0.25 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (2 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.85 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1OC.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>>[CH3:15][C:13]1[CH2:12][C:11](=[O:16])[C:4]2[C:5](=[CH:7][CH:8]=[CH:2][CH:3]=2)[N:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(N)ccc1Cl
Product: CC1=Nc2ccccc2C(=O)C1

Procedure:
Condensation of 4-chloro-3-methoxy aniline and ethyl acetoacetate followed by thermal cyclization provided 2-methyl-4-quinolone 1 via Conrad-Limpach synthesis. Iodination of 1 with iodine in saturated aqueous potassium iodide solution and n-butylamine provided the 3-iodo-4-quinolone 2. Copper-mediated coupling of 4-bromophenol and 4-trifluoromethoxyphenyl boronic acid with Hunig's base and pyridine afforded the diaryl ether 4. Reaction of the lithium anion of 4 with boron triisopropoxide followed by acidic hydrolysis of the resulting boronic ester provided the boronic acid 5. Suzuki-Miyaura reaction of the 3-iodo-4-quinolone 2 with the boronic acid 5 resulted in difficult to separate mixtures of quinolone starting material and product. This difficulty in separation was likely the result of a combination of pi-stacking and intermolecular hydrogen bonding typical of 4-quinolones. A functional group protection strategy involving the 4-position alcohol was devised that would alleviate this problem by mitigating intermolecular hydrogen bonding. To this end 4-O-carbonates and 4-O-acetates were prepared, but these were found to be labile under Suzuki-Miyaura reaction conditions. A more robust protecting group, a 4-O-ethyl ether, was shown to be stable under these reaction conditions, yet reactive enough to be selectively removed in the presence of an aryl methoxy moiety. The 3-iodo-quinolone 2 was reacted with ethyl iodide and potassium carbonate to give the corresponding ethyl ether 3. Suzuki-Miyaura coupling of 3 with 4-phenoxyphenylboronic acid using palladium tetrakis triphenylphosphine and aqueous potassium carbonate provided 3 in very good yield. ELQ-300 was obtained in quantitative yield by heating the ethyl ether 3 in 30% hydrobromic acid in acetic acid.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cnc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
4-Hydroxymethylimidazole hydrochloride (10 g) was suspended in dichloromethane (200 ml). ρ-Toluenesulfonyl chloride (15.58 g) was added and triethylamine (25.8 ml) was added dropwise to the stirred reaction mixture which was allowed to stir at room temperature overnight. The mixture was washed with water (2×100 ml) and brine (1×100 ml) and the organic layer was dried and evaporated to leave a clear oil which was recrystallised from ethyl acetate/hexane to afford a white crystalline solid (15 g, 80%). 1H NMR (360 MHz, CDCl3) δ2.44 (3H, s), 4.55 (2H, s), 7.21 (1H, s), 7.35 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz), 7.98 (1H, s). MS (CI+) m/z 253 (M+H, 100%).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:5](OCC)=[O:6].[CH2:17]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[N:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:17]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([OH:6])=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:3]=[N:33]2)=[N:28][CH:27]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccncc1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NCc1ccccc1)c1ccc(-n2ncc(-c3ccncc3)c2O)nc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
Combined ethyl 3-(dimethylamino)-2-(pyridin-4-yl)acrylate (40.0 mg, 0.182 mmol) and N-benzyl-6-hydrazinylnicotinamide (33.8 mg, 0.140 mmol) in 2-propanol (0.698 mL) and stirred for 18 hours at room temperature. Hunig's base (0.219 mL, 1.257 mmol) was then added and the reaction was stirred for 24 hours at 50° C. The reaction mixture was then purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) eluting with ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (18.5 mg, 35.7%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.58 (d, J=5.8 Hz, 2 H) 7.33 (dq, J=8.5, 4.3 Hz, 1 H) 7.37-7.45 (m, 4 H) 8.28 (d, J=6.3 Hz, 2 H) 8.45 (d, J=7.1 Hz, 2 H) 8.49-8.58 (m, 2 H) 8.63 (s, 1 H) 8.99 (s, 1 H) 9.33 (t, J=5.9 Hz, 1 H). MS m/z [M+H]+ 372.4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].F[C:23](F)(F)[C:24]([OH:26])=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[C:24]([N:57]1[CH2:58][CH2:59][CH:54]([CH2:53][CH2:52][NH:51][C:43]2[CH:44]=[CH:45][C:46]3[NH:47][C:48]4[N:49]=[C:33]([NH:34][C:35]5[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=5)[CH2:40][CH2:41][C:42]=2[CH:50]=3)[N:32]=[CH:31][C:30]=4[Cl:29])[CH2:55][CH2:56]1)(=[O:26])[CH3:23]
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and acetyl chloride as the starting materials in 50% yield. LCMS for C26H31ClN7O (M+H)+: m/z=492.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(NC(C)C)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:26][CH2:27][CH2:28][C:29]4=[O:30])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1nnc2ccc(-c3cccc(N4CCCC4=O)c3)nn12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 2 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 400 ml of dichloromethane was added 1.7 ml of diisopropylamine and 1 ml of 4-chlorobutyryl chloride. This solution was stirred for 12 hours, then poured onto 200 ml of saturated aqueous sodium bicarbonate and extracted with 150 ml portions of dichloromethane. The combined extracts were dried and concentrated in vacuo. The residue was dissolved in 200 ml of dimethylformamide and 2.0 g of potassium carbonate was added. This solution was heated to 80° C. for 12 hours, then poured onto 200 ml of water and extracted with 150 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing the desired product were combined, concentrated in vacuo and the solid recrystallized from dichloromethane-hexane to give 1.67 g of white crystals, mp 235°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>FC1C=CC=CN=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Fc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccccn2)CC1
Yield: 147.1 %

Procedure:
1-tert-Butyloxycarbonyl-4-(aminomethyl)piperidine (3 g; 14 mmol) and 10 ml of 2-fluoropyridine were heated to reflux for 4 h. Concentration and stirring of the crude product in n-pentane afforded 3 g of a white solid, melting point: 126–130° C.;