Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:36]([CH2:38][NH2:39])[OH:37]>CN(C=O)C.C(OCC)(=O)C>[OH:37][CH2:36][CH2:38][NH:39][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: NCCO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of quinaldic acid (5.0 g, 28.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g, 28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60 mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and 4-methylmorpholihne (4.76 mL, 43.31 mmol). The reaction was stirred at 0° C. for an additional 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed 3 times with H2O, once with NaHCO3 (sat), once with brine, dried over MgSO4, and concentrated in vacuo to provide 1.5 g (24% yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH3:19])[C:14]4[CH2:20][CH:21]5[NH:25][CH:24]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:33]CCl.Cl>CO.C(OCC)C>[ClH:33].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[CH2:20][CH:21]4[NH:25][CH:24]([C:13]3=2)[CH2:23][CH2:22]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
The product from step C (1.22 g, 2.7 mmol) was dissolved in methanol (7 mL) and dichloromethane (5 mL) and 2N HCl in diethylether (70 mL) was added. The reaction was stirred at room temperature for 12 h, after which a precipitate formed. The mixture was diluted with diethylether and filtered providing 2-phenylsulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (900 mg, 86%) as an off-white solid: Mpt 238-244° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 9.69 (brs, 1H), 9.15 (brs, 1H), 8.38 (s, 1H), 7.92 (dd, J=8.0, 1.7 Hz, 2H), 7.60 (m, 5H), 5.36 (d, J=4.8 Hz, 1H), 4.47 (brs, 1H), 3.68 (s, 3H), 3.34 (dd, 1H, partially masked by solvent), 3.00 (d, J=17.2 Hz, 1H), 2.25 (m, 2H), 2.08 (t, J=9.6 Hz, 1H), 1.80 (m, 1H); ESI MS m/z 353 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.02 min.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]#[N:14])=[CH:9][CH:10]=2)[NH:5]1.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl.C(OCC)C>CN1CCCC1=O.CO>[ClH:15].[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)(=[O:24])=[O:23])=[CH:20][N:21]=1)=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[CH:7]=2
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc2c(-c3ccc(S(=O)(=O)N4CCNCC4)cn3)c(O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
To a suspension of sodium hydride (97%, 0.024 g, 1.0 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added 2-oxoindoline-6-carbonitrile (0.119 g, 0.75 mmol). The formed mixture was stirred for 5 min at room temperature and tert-butyl 4-[(6-chloropyridin-3-yl)sulfonyl]piperazine-1-carboxylate (0.181 g, 0.5 mmol) was added. The resulting reaction mixture was set under an N2 atmosphere and stirred for 1 h at 90° C. Methanol (0.5 mL) was added to the mixture and the solvents were removed in vacuo. The crude product was dissolved in methanol (5 mL) and HCl in diethyl ether (4 M, 2.5 mL, 10 mmol) was added followed by reflux for 3 h. From the cooled solution the formed yellow precipitate was collected by filtration and dried to give 0.209 g (92% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 11.08 (s, 1H), 9.10 (br s, 2H), 8.67 (s, 1H), 7.89 (s, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.0, 1.2 Hz, 1H), 7.28 (d, J=1.2 Hz, 1H) 3.31 (br s, 4H), 3.25 (br s, 4H); MS (EI) m/z 384 (M++1).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.Cl.[CH3:70][CH:71]([CH3:116])[C@H:72]([NH:111][C:112](=[O:115])[O:113][CH3:114])[C:73](=[O:110])[N:74]1[CH2:78][CH2:77][CH2:76][C@H:75]1[C:79]1[NH:80][C:81]([C:84]2[CH:93]=[CH:92][C:91]3[C:86](=[CH:87][CH:88]=[C:89]([C:94]4[CH:99]=[CH:98][C:97]([C:100]5[NH:104][C:103]([C@H:105]6[NH:109][CH2:108][CH2:107][S:106]6)=[N:102][CH:101]=5)=[CH:96][CH:95]=4)[CH:90]=3)[CH:85]=2)=[CH:82][N:83]=1>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:109]1[CH2:108][CH2:107][S:106][C@H:105]1[C:103]1[NH:104][C:100]([C:97]2[CH:96]=[CH:95][C:94]([C:89]3[CH:88]=[CH:87][C:86]4[C:91](=[CH:92][CH:93]=[C:84]([C:81]5[NH:80][C:79]([C@@H:75]6[CH2:76][CH2:77][CH2:78][N:74]6[C:73](=[O:110])[C@@H:72]([NH:111][C:112]([O:113][CH3:114])=[O:115])[CH:71]([CH3:116])[CH3:70])=[N:83][CH:82]=5)[CH:85]=4)[CH:90]=3)=[CH:99][CH:98]=2)=[CH:101][N:102]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@H]6NCCS6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6SCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-thiazolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate 4HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 841.83 [M+H]+. (25 mg, 12%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:22]=1.N1C=CC=CC=1>C(Cl)Cl>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[O:11])[CH:28]=2)[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:22]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)Nc1ccc(F)cc1F
Reaction time: 24 h
Yield: 52 %

Procedure:
2,4-Difluorophenyl isocyanate (10 mg, 0.064 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) and pyridine (0.02 mL, 0.177 mmol) in CH2Cl2 (5 mL), and the mixture was stirred for 24 h. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (2% CH3OH/CH2Cl2) afforded the title compound (15 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.39 (s, 1H), 8.04 (m, 1H), 7.86 (m, 1H), 7.72 (m, 3H), 7.27 (m, 2H), 7.00 (m, 1H), 6.92 (m, 1H), 5.92 (dd, 1H, J=3.2 and 9.2 Hz), 4.02 (m, 1H), 3.85 (m, 1H), 2.67 (m, 1H), 2.14 (m, 1H), 1.71 (m, 1H), 1.28 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O:21][C:22]1[C:31]([CH2:32][CH:33]=O)=[C:30]2[C:25]([C:26](=[O:37])[CH2:27][C:28]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:20][O:21][C:22]1[C:31]([CH2:32][CH2:33][N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:13]=4)[CH:9]=[CH:10]3)[CH2:15][CH2:16]2)=[C:30]2[C:25]([C:26](=[O:37])[CH2:27][C:28]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Reactant: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
120 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 120 mg of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolved in 8 ml of methylene chloride. Thereafter, 0.05 ml of acetic acid and 0.15 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then filtered. The filtrate was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate), so as to obtain 210 mg of the subject compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12>C1COCC1>[N:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:46]2[C:45](=[O:47])[C:44]3=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]3[C:42]2=[O:52])=[CH:17][CH:18]=1
Reactant: OCCCc1ccncc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccncc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
Diethyl azodicarboxylate (4.4 g, 25.4 mmol) was dissolved in dry THF and added dropwise to a solution of 3-(4-pyridyl)propanol (3.18 g, 23.18 mmol), triphenylphosphine (12.3 g, 46.9 mmol) and phthalimide (3.6 g, 24.5 mmol) in dry THF (50 mL). The mixture was stirred at RT for 3.5 h, concentrated and the residue taken up in ether and filtered. The filter cake was taken up in hexane/ethyl acetate/chloroform (40:30:30) and flash chromatographed (silica gel, 30:35:35 hexane:ethyl acetate:chloroform) (3 L) to yield the title compound (3.3 g, 54%). 1H NMR (90 MHz, CDCl3) δ8.44 (m, 2H), 7.71 (m, 4H), 7.13 (d, 2H), 3.70 (t, 2H), 2.65 (t, 2H), 2.05 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)[O:32][CH2:31][CH2:30][O:29]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:35]=[CH:34][C:33]([C:28]2([CH3:27])[O:29][CH2:30][CH2:31][O:32]2)=[CH:40][CH:39]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC1(c2ccc(CN)cc2)OCCO1
Product: CC1(c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)OCCO1
Yield: 68 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with 4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamine (prepared by following the procedure described in J. Med. Chem. 1978, 21, 507) (182 mg, 0.94 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1 and 9:1) to obtain the desired intermediate as an oil (150 mg, 68%). GC-MS m/z: 468 (M+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([C:15](=[O:17])[CH3:16])[CH:4]=1.Cl.Cl[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]Cl.C(N(C(C)C)CC)(C)C.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:15](=[O:17])[CH3:16])[CH:4]=[C:3]2[N:2]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: COc1ccc2cc(C(C)=O)cc(N)c2c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(C)=O)cc(N3CCNCC3)c2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-(4-amino-6-methoxynaphthalen-2-yl)ethanone hydrochloride (3) (3.0 g) and bis(2-chloroethyl)amine hydrochloride (2.54 g) were charged in a flask and to them was added toluene (100 ml) and diisopropylethylamine (6.5 ml). The reaction was heated to 120° C. and allowed to stir overnight. Upon completion, 5 N aqueous potassium hydroxide (50 ml) and water (100 ml) were added and the reaction was allowed to stir for 2 hours at room temperature. The liquids were decanted and to them was added concentrated hydrochloric acid until the aqueous was made acidic. 1-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)ethanone (106) was an orange-brown solid that was filtered and used with no further purification (3.5 g) LCMS (m/z): 285 [M+H].
Reaction SMILES: Cl.C(O[C:7](=[O:28])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:21]3[N:22]=[C:23]([NH2:25])[S:24][C:20]=3[CH2:19]2)[CH2:11][CH2:10]1)(C)(C)C.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1C(O)=O.C(N=C=N[CH2:46][CH2:47][CH2:48]N(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O1CCCC1>[NH2:25][C:23]1[S:24][C:20]2[CH2:19][C@@H:18]([N:17]([CH2:46][CH2:47][CH3:48])[CH2:16][CH2:15][C@H:12]3[CH2:11][CH2:10][C@H:9]([NH:8][C:7]([C:30]4[O:29][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[CH:31]=4)=[O:28])[CH2:14][CH2:13]3)[CH2:27][CH2:26][C:21]=2[N:22]=1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN[C@H]2CCc3nc(N)sc3C2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC[C@H]1CC[C@H](NC(=O)c2cc3ccccc3o2)CC1)[C@H]1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 M HCl solution in dioxane (1.0 mL, 4.0 mmol) was added to a solution of compound 20 (87 mg, 0.2 mmol) in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. Solvent was evaporated in vacuo and the residue was used directly for the next step without further purification. To a solution of the residue in tetrahydrofuran (THF) (20 mL), were added benzofuran-2-carboxylic acid (32 mg, 0.2 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDCI) (38 mg, 0.2 mmol), 1-hydroxybenzotriazole (HOBT) (27 mg, 0.2 mmol), and diisopropylethylamine (DIPEA) (103 mg, 0.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. Solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, and dried over anhydrous Na2SO4. Flash column chromatography (MeOH/EtOAc, 1:6) gave compound 11 as a colorless oil (60 mg, 63%). 1H NMR (CDCl3, 300 MHz) δ 7.68 (d, 7.6 Hz, 1H), 7.52-7.28 (m, 4H), 6.49 (d, J=8.2 Hz, 1H), 4.82 (s, broad, 2H), 3.98-3.85 (m, 1H), 3.50-2.25 (m, 8H), 2.20-1.10 (m, 16H), 0.94 (t, J=6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 158.50, 155.06, 149.22, 128.06, 127.22, 124.08, 123.11, 112.08, 110.71, 52.80, 48.68, 35.63, 33.04, 31.74, 19.26, 11.97, 11.77; HRMS-Electrospray (m/z): [M+H]+ calcd 481.2637. found 481.2637; purity HPLC 99.2%, tR=29.761 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>ClCCl>[Cl:24][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([NH:13][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:23]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(OC)c1
Yield: 90.5 %

Procedure:
3-Methoxyphenylacetyl chloride (1.11 g, 6 mmol) was added to methyl 2-amino-4-chlorobenzoate (0.93 g, 5 mmol) in dichloromethane (30 ml) and the solution stirred under reflux for 18 h. The oily residue remaining on evaporation of the solvent was triturated with diethyl ether to afford methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate as a colourless solid (1.51 g), m.p. 144°-146° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][C@@H:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([F:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH:26]=O>>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][C:10]1[C:11]2[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([F:17])=[CH:15][C:16]=2[N:8]2[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([OH:2])=[O:22])[C:9]=12
Reactant: COC(=O)C[C@H]1CCn2c1cc1c(S(C)(=O)=O)cc(F)cc12
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: CS(=O)(=O)c1cc(F)cc2c1c(Cc1ccc(Cl)cc1Cl)c1n2CC[C@@H]1CC(=O)O

Procedure:
Starting from methyl[(1R)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 62A, Step 2, 120 mg, 0.37 mmol) and 2,4-dichlorobenzaldehyde (71 mg, 0.51 mmol), the title compound was synthesized following the procedures as described in Step 1 of Example 60 and Step 10 of Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=NC(C)C)=[C:4]([CH3:19])[CH:3]=1.[OH:20]S(O)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=[O:20])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(F)ccc1-c1ccccc1C=NC(C)C
Product: Cc1cc(F)ccc1-c1ccccc1C=O
Temperature: 25 °C

Procedure:
A solution of 20.36 g (79.8 mmol) (4′-fluoro-2′-methyl-biphenyl-2-ylmethylene)-isopropyl-amine in 110 ml 4N H2SO4 was heated at reflux for 6 h. After cooling to RT, the solution was extracted twice with 150 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/hexane 1:1) to give 4′-fluoro-2′-methyl-biphenyl-2-carbaldehyde as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH:11](=[C:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: c1cnc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: C(=C1CCCc2cccnc21)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (18.2 g, 137 mmol), benzaldehyde (17.67 g, 166.0 mmol), and acetic anhydride (24.5 mL, 254 mmol) was heated under a nitrogen environment at 165° C. for 16 hours. The reaction mixture was cooled to room temperature. Crushed ice was added, and the mixture was slowly basified with NaOH (solid then 2 N NaOH) to pH around 7. The aqueous layer was extracted with hexane/ethyl acetate (1:1 solution) 3 times. The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum to give 8-benzylidene-5,6,7,8-tetrahydro-quinoline (Intermediate 1) as a brown solid. A solution of Intermediate 1 in dichoromethane (100 mL) and methanol (500 mL) was cooled to −78° C. (dry ice/acetone bath), and charged with ozone/oxygen (3 psi, 1.5 ampere). The dark brown solution turned yellow after several hours. When Intermediate 1 was consumed (TLC), ozone/oxygen flow was stopped. The reaction mixture was purged with nitrogen for 10 minutes. Methyl sulfide (6 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The solvents were removed under vacuum. The residue was dissolved in 1 N HCl (500 mL), and washed with diethyl ether (4×150 mL). The aqueous layer was basified to pH˜7 with NaOH (s), and extracted with ethyl acetate (2×200 mL). The pooled ethyl acetate layers were dried over magnesium sulfate. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 90% EtOAc:hexane to give a clean product. The aqueous layer was extracted with chloroform/isopropanol (3:1) several times. The pooled chloroform/isopropanol layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum to give 6,7-dihydro-5H-quinolin-8-one (Intermediate 2), 17.89 g (122.0 mmol, 89% over 2 steps).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:27])[C:7]=2[N:6]=[C:5]1[CH2:28][CH2:29][CH3:30].[H][H].[CH2:34](O)[CH3:35]>[Pt]>[CH2:34]([NH:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[C:5]([CH2:28][CH2:29][CH3:30])=[N:6][C:7]=3[C:8]([NH2:27])=[N:9][C:10]=2[CH:11]=1)[CH3:35]
Reactant: CCCc1nc2c(N)nc3cc(Oc4cccc([N+](=O)[O-])c4)ccc3c2n1CC(C)C
Reactant: [H][H]
Reactant: CCO
Agent: [Pt]
Product: CCCc1nc2c(N)nc3cc(Oc4cccc(NCC)c4)ccc3c2n1CC(C)C
Reaction time: 1 h

Procedure:
1-(2-Methylpropyl)-7-(3-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.254 g, 0.606 mmol), prepared as described in Example 37, was stirred in ethanol (10 mL), and 5% platinum on carbon (0.025 g) was added. The reaction was placed under a positive pressure of hydrogen and stirred for one hour. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 98:2 to 95:5). The product was recrystallized from acetonitrile to provide 0.032 g of 7-(3-ethylaminophenoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as square, orange crystals, mp 168-174° C.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[S:21](Cl)(=[O:23])=[O:22].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1>C(#N)C>[Br:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[S:21](=[O:23])(=[O:22])[NH:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c(Br)c1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Br)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
Pyridine (1.5 equiv) was added dropwise to the cooled suspension of the crude 2-bromo-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (24 g, 0.06 mol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1.2 eq) in acetonitrile (300 ml) at 0° C. over 10 min. The r×n mix was stirred overnight. The solid was filtered and washed with EtOAc. The filtrate was washed with, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness to give crude N-(3-bromo-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide which was purified by flash chromatography on silica gel. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.6 (s, 1H), 10.56 (s, 1H), 9.20 (s, 1H), 8.12 (d, J=1.9 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.79 (dd, J=2.0, 8.6 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.20 (dd, J=1.9, 8.3 Hz, 1H), 4.85 (s, 2H). MS (ESI) m/z=479 (M+1).