Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58.8 %

Procedure:
To a solution of 0.73 g (1.5 mmol) of (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 6) in ˜25 mL dry toluene was added 0.166 g (1.7 mmol) cyclopentane-1,3-dione and 0.03 g (0.15 mmol) of PTSA. The resulting mixture was heated at reflux for 2 hr. The solvent was removed under vacuum and the residue was purified by prep TLC eluting with CHCl3/2N NH3 in MeOH (9/1) to afford 0.49 g the title compound. The compound could be further purified by chiral HLPC on CHIRACEL AD column eluting with hexanes/EtOH (9/1). The compound could be crystallized (mp=216.5-217.5° C.) from hexanes/EtOAc or hexanes/EtOH. 1H-NMR (CDCl3): δ: 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2H, m), 6.93 (2 H, t, J=8.2 Hz), 4.89, 4.48 (1 H, s), 4.47 (1 H, m), 3.71, 3.48 (1 H, m), 3.35 (1 H, m), 3.28-3.17 (1 H, m), 2.95 (1 H, m), 2.95, 2.81 (1 H, m), 2.68 (2 H, m), 2.45 (2 H, m), 2.37 (2 H, m), 2.15 (1 H, m), 1.93 (2 H, m), 1.60 (1 H, m), 1.38 (1 H, m), 1.36 (3 H, t, J=6.0 Hz). MS: (MH)+ 556.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.C(Cl)(=O)C(Cl)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:14])[CH:8]=[CH:7]2
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2cccc(Br)c2n1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(c1ccc2cccc(Br)c2n1)N1CCCC1
Yield: 94.2 %

Procedure:
This compound (365 mg, 94% yield) as a tan crystalline solid was prepared similarly to that described in Example 167a, using 8-bromoquinoline-2-carboxylic acid (Princeton BioMolecular Research, Monmouth Junction, N.J.; 320 mg, 1.27 mmol), oxalyl chloride (2.54 mmol), and pyrrolidine (0.10 mL, 1.27 mmol) as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (1H, d, J=8.4 Hz), 8.23 (1H, dd, J=7.6, 1.2 Hz), 8.11 (1H, dd, J=8.2, 1.0 Hz), 8.01 (1H, d, J=8.6 Hz), 7.63 (1H, t, J=7.8 Hz), 3.98 (2H, t, J=6.5 Hz), 3.61 (2H, t, J=6.5 Hz), 1.95 (4H, m). m/z (ESI, +ve) 307/307 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2Br)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:26][C:27]1([CH3:38])[C:31](C)(C)OB(C=C(C)C)O1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH:26]=[C:27]([CH3:38])[CH3:31])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2Br)Cc2ccccc2C1
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccc(C)cc2C=C(C)C)Cc2ccccc2C1
Temperature: 110 °C
Yield: 92 %

Procedure:
A mixture of 2-(2-bromo-4-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (880 mg, 2.2 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-propenyl)-[1,3,2]dioxaborolane (903 μL, 4.4 mmol) and saturated NaHCO3 solution (4.4 mL) in anhydrous DMF (20 mL) is degassed with N2. While under N2 atmosphere, tetrakis(triphenylphosphine)palladium (196 mg, 10 mol %) is added and the reaction is heated in a 110° C. oil bath for 2 h. The reaction is cooled to room temperature, poured into water (40 mL) and extracted with EtOAc (2×30 mL). The combined organic layers are washed with water (15 mL) and brine (20 mL) then concentrated in vacuo. The residue is purified by flash column chromatography (24 g silica gel, gradient elution: 0-50% EtOAc in heptane) to give product (278) as a reddish-brown viscous oil (764 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[OH:18]O.[NH4+].[OH-]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]([NH2:17])=[O:18])[CH2:9][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:11]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Compound [XXXIII] (13.0 g, 44.2 mmol, 1.0 eq.) in MeOH (520 mL) was added H2O2 (13.7 mL, 33% in water, 133 mmol, 3.00 eq.), and NH4OH (52 mL). The resulting mixture was stirred for 16 hours at room temperature, then diluted with additional water and extracted with ethyl acetate (×3). The combined organics were washed with Na2S2O3 (10% in water), dried, and concentrated. The residue was purified by silica gel chromatography by eluting with heptane and ethyl acetate (gradient of 0% to 100% EtOAc) to give Compound [XXXIV]: LCMS (m/e) 312, 314 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.78-2.87 (m, 2H) 3.22-3.29 (m, 2H) 3.84-3.91 (m, 2H) 3.91-3.99 (m, 2H) 5.42 (br. s., 2H) 7.19-7.25 (m, 2H) 7.48-7.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH2:24]O)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH2:24][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Reactant: C1CCNCC1
Agent: [Cl-]
Product: COc1ccc(-c2cc(=O)n(CCN3CCCCC3)nc2-c2ccc(OC)cc2)cc1
Yield: 38.1 %

Procedure:
After 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one was reacted with paratoluenesulfonyl chloride in a similar manner as in Example 116-(2), a further reaction was conducted with piperidine, whereby the title compound was obtained in a yield of 38.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:18]4[N:17]5[CH:19]=[CH:20][CH:21]=[C:16]5[C:15](=O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:23]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:18]4[N:17]5[CH:19]=[CH:20][CH:21]=[C:16]5[C:15](=[N:25][OH:26])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:23]=1
Reactant: NO
Reactant: O=C1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21
Yield: 154 %

Procedure:
In a 20 ml round-bottomed flask, a mixture of 60 mg of 5-(6-fluoro-1H-benzimidazol-2-yl)pyrrolo[1,2-a]indol-9-one obtained according to the preceding stage and 42 mg of hydroxylamine hydrochloride in 5 ml of pyridine is brought to reflux for 6 hours. The reaction medium is evaporated to dryness under vacuum and the residue taken up with 25 ml of a saturated solution of sodium bicarbonate is extracted with 3 times 25 ml of ethyl acetate. The combined organic phases are washed with 25 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, and evaporated to dryness under vacuum. 97 mg of 5-(6-fluoro-1H-benzimidazol-2-yl)pyrrolo[1,2-a]indol-9-one oxime are obtained in the form of a yellowish oil, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[N:15](C3CCCCO3)[CH:16]=[N:17][C:13]=2[C:12]=1[CH3:26])C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[NH:15][CH:16]=[N:17][C:13]=2[C:12]=1[CH3:26]
Reactant: Cc1c(CN(C)C(=O)OC(C)(C)C)ccc2c1ncn2C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc2[nH]cnc2c1C
Yield: 81.5 %

Procedure:
A solution of 262 (100 mg, 0.28 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at RT for 30 min. The solvent was removed and the residue was dissolved in EtOAc and neutralized with ammonia. The organic layers were separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 40 mg (82%) of N-methyl(4-methyl-1H-benzo[d]imidazol-5-yl)methanamine (264): MS (ESI) m/z=176.3 [M+l]+.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:81][C:82](=[O:89])[NH:83][CH:84]1[CH2:88][CH2:87][NH:86][CH2:85]1)[CH2:78][CH2:79][CH3:80]>CN(C=O)C.C(OCC)(=O)C>[CH2:77]([O:81][C:82]([NH:83][CH:84]1[CH2:88][CH2:87][N:86]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:85]1)=[O:89])[CH2:78][CH2:79][CH3:80]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCCCOC(=O)NC1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCOC(=O)NC1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C1
Reaction time: 12 h

Procedure:
To a solution of 303 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 34 μl DIPEA, 193 mg HATU and 103 mg pyrrolidin-3-yl-carbamic acid butyl ester. After stirring for 12 h the reaction mixture was diluted with ethyl acetate, washed with aqueous LiCl (4%) and saturated aqueous NaHCO3 solution. The solution was concentrated, dissolved in 2 ml dichloromethane and stirred in the presence of 384 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 229 mg MS (ES+): m/e=710.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=O)=O.[C-:32]#[N:33].[K+]>CN(C)C=O>[CH2:18]([N:15]1[C:10]2[C:11](=[O:14])[N:12]([CH3:13])[C:7]([CH2:6][C:32]#[N:33])=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:9]=2[CH:17]=[CH:16]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [C-]#N
Reactant: Cn1c(COS(C)(=O)=O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(CC#N)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A suspension of 1-benzyl-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4 g, 10.6 mmol) in Dichloromethane (DCM) (50 mL) was treated with Et3N (4.38 mL, 31.5 mmol) and MsCl (1.839 mL, 23.60 mmol) at 0° C. and then stirred for 30 min. The mixture was diluted with Dichloromethane, washed with 0.1N HCl and NaHCO3, dried over Na2SO4, filtered and concentrated to afford (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate as a pale yellow solid (4.8 g, 10.5 mmol, 95% yield) which was used for in next step without any further purification. A solution of (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate (4.8 g, 10.5 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was treated with KCN (6.15 g, 94 mmol) and the resultant was stirred at ambient temperature overnight. The mixture was quenched with water and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetonitrile (2.7 g, 7.0 mmol, 67% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.47-7.52 (m, 2H) 7.31-7.35 (m, 3H) 7.27-7.30 (m, 4H) 7.04-7.09 (m, 1H) 5.94-5.98 (m, 1H) 5.83-5.88 (s, 2H) 3.81 (s, 3H) 3.64 (s, 2H); LCMS (m/z) ES+=388 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:20]O>>[CH3:20][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)CCCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCc1ccc(O)cc1
Yield: 99 %

Procedure:
The 4-(4-hydroxyphenyl)butanoic acid (1) (4.6 g) from the previous step was dissolved in methanol (60 mL), concentrated sulfuric acid (1 mL) was added, and refluxed by heating for two days. The reaction solution was poured into water, and extracted with ethyl acetate (200 mL). The organic layer was washed with water (50 mL), saturated aqueous solution of sodium hydrogen carbonate (50 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration and vacuum concentration, the above-identified compound (4.9 g, yield 99%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]1([NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Cc1cccc(O)c1)Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1cccc2ccccc12
Yield: 47.9 %

Procedure:
A mixture of 2-(3-hydroxyphenyl)-N-naphthylacetamide (5.00 g, 18.03 mmol), benzyl bromide (3.76 g, 22.0 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in acetone (50 mL) was heated to reflux overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (3.176 g, 48% yield): 1H NMR (DMSO-d6) 10.13 (br, 1H), 8.06 (m, 1H),7.94 (m, 1H), 7.77 (d, 1H), 7.67 (d, 1H), 7.26-7.56 (m, 9H), 6.92-7.11 (m, 3H), 5.11 (s, 2H), 3.79 (s, 2H); ES−MS (m/z) 368 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([OH:13])[C:7]([CH3:11])([CH3:12])[S:8](=[O:9])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)C(O)c2ccc(Br)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A cooled (0° C.) solution of 6-bromo-2,2-dimethyl-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 241; 652 mg; 2.25 mmol) in MeOH (15 ml) and DCM (7 ml) was treated with NaBH4 (43 mg; 1.13 mmol) portionwise. The resulting solution was stirred at RT for 1.5 h, before being cooled to 0° C. and carefully quenched with water. The mixture was concentrated under reduced pressure, water was added to the residue and the aqueous phase was extracted three times with DCM. The combined organic phases were washed with brine, dried with MgSO4, filtered and concentrated to dryness to give the title compound as a white solid (637 mg, 97%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[N:38]([C:42]3[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=3[CH:51]([CH3:53])[CH3:52])[CH:39]=[CH:40][N:41]=2)[CH:34]=[CH:35][CH:36]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:51]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH:48]([CH3:50])[CH3:49])[C:42]=1[N:38]1[CH:39]=[CH:40][N:41]=[C:37]1[C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:9]=1)([CH3:53])[CH3:52]
Reactant: c1ccc(Nc2cccc(-c3ccc4ccccc4n3)c2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(N(c2ccccc2)c2cccc(-c3ccc4ccccc4n3)c2)c1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
N-phenyl-3-(quinolin-2-yl)aniline (3 g, 10.12 mmol), sodium tert-butoxide (1.555 g, 16.20 mmol), 2-(3-bromophenyl)-1-(2,6-diisopropylphenyl)-1H-imidazole (4.07 g, 10.63 mmol), Pd2dba3 (0.232 g, 0.253 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (0.415 g, 1.012 mmol) were charged into the reaction vessel with 250 mL of toluene. This mixture was evacuated and back-filled with nitrogen. The reaction mixture was then heated at reflux for 20 h. The reaction mixture was cooled to room temperature then was diluted with 200 mL of water. The toluene layer was separated and the aqueous was extracted with 100 mL of toluene. The organic extracts were combined and removed under vacuum. The crude residue was passed through a silica gel column using 5-25% ethyl acetate/DCM yielding 3-(1-(2,6-diisopropylphenyl)-1H-imidazol-2-yl)-N-phenyl-N-(3-(quinolin-2-yl)phenyl)aniline (5.5 g, 91% yield) as a yellow foamy solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[CH2:42]([S:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])=[O:45])[CH3:43]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([N:50]2[CH2:49][CH2:48][N:47]([S:44]([CH2:42][CH3:43])(=[O:45])=[O:46])[CH2:52][CH2:51]2)=[O:40])[CH:34]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCS(=O)(=O)N1CCN(C(=O)c2cccc(-c3cc(-c4nnnn4CCCOC)c(O)cc3O)c2)CC1

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and 1-ethylsulfonyl piperazine as described in general procedure D. LCMS: 531 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.P(OC)(OC)(O[CH3:14])=O>C(Cl)Cl>[CH3:14][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: COP(=O)(OC)OC
Reactant: Oc1ccc2c(c1)NCC2
Solvent: ClCCl
Product: CN1CCc2ccc(O)cc21
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
To 37.78 g (0.286 mol) of 6-hydroxyindoline 5 in a 100 ml round-bottom flask fitted with a magnetic stirrer, thermometer and condenser connected to a source of nitrogen was added 13.38 ml (16.02 g, 0.114 mol) of trimethyl phosphate. It was then placed in an oil bath and heating was commenced. The bath temperature reached 105° in 10 min. Then the reaction mixture became homogeneous and shortly thereafter an exotherm occurred. The flask was removed periodically from the oil bath to keep the internal temperature below 150°. The reaction was heated at 140°-150° for 2 hr. Thin layer chromatography on silica gel plates eluted with 50% Ethyl acetate/hexane or 4% methanol/methylene chloride showed that starting material was still present and 3 ml (3.59 g, 25.6 mmol) more of trimethyl phosphate was added. Heating was continued at 155° for 1.5 hr. The reaction mixture was allowed to cool and then dissolved in 100 ml of saturated sodium carbonate solution and 100 ml of methylene chloride with warming in portions. The aqueous phase was separated and washed with 2×100 ml of methylene chloride. The organic phases were combined, washed with 200 ml of half-saturated brine, dried over sodium sulfate and concentrated in vacuo to leave 28.6 g (67%) of dark tar. This was dissolved in methylene chloride and filtered through 300 ml of silica gel in methylene chloride. A total of 800 ml of methylene chloride eluate and then 400 ml of ethyl acetate was collected. Concentration and collection of the residue from hexane gave 18.29 g (43%) of crude product 7 as a brown solid which was used for the preparation of 9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([CH2:23][N:24]([CH2:26][C:27]([OH:29])=O)[CH3:25])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH2:32]>>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][N:24]([CH3:25])[CH2:26][C:27]([NH:32][CH3:31])=[O:29])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CN(CC(=O)O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN
Product: CNC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 56 using [({5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazol-3-yl}methyl)(methyl)amino]acetic acid (preparation 133) (618 mg, 1.46 mmol) and methylamine (2M in THF) (1.4 ml, 2.80 mmol) as starting materials.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:10]=1>>[CH3:22][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)[N:10]=[C:9]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: Oc1ccccc1
Product: COc1ccc2c(Oc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5,6-dimethoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH2:29])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:30][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH:29][C:31](=[O:33])[CH3:32])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)c(N)c1
Product: CC(=O)Nc1cc(C)ccc1-c1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)o1

Procedure:
5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with acetyl chloride by method Q. This resulted in the product with the molecular weight of 446.23 (C26H30N4O3); MS (ESI): 447 (M+H+).