Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([N:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][O:36]C3CCCCO3)[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]>CO.O>[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([N:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][OH:36])[CH:28]=2)[N:26]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCO)c2)n1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Pyridinium p-toluenesulfonate (362 mg, 1.44 mmol) was added to a solution of Intermediate 39c (360 mg, 0.48 mmol) in MeOH (5 mL). The solution was stirred at 40° C. for 19 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH3 in MeOH] in DCM, to give the title compound as a white powder after freeze-drying (218 mg, 68%). LCMS (Method 5): Rt 4.22 min, m/z 665 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.60-1.63 (2H, m), 1.70-1.75 (4H, m), 1.86-1.92 (2H, m), 2.01-2.06 (1H, m), 2.10-2.16 (1H, m), 3.14 (4H, t, J 5.2), 3.71 (2H, q, J 5.1), 4.03 (2H, t, J 5.0), 4.79-4.82 (1H, m), 4.87 (1H, t, J 5.5), 5.54 (1H, t, J 4.3), 6.33 (1H, s), 6.96 (1H, m), 7.11-7.22 (4H, m), 7.34-7.46 (5H, m), 7.61-7.64 (2H, m), 8.11 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[N:25]1([CH2:31][CH2:32][C:33](O)=[O:34])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:33](=[O:34])[CH2:32][CH2:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)CCN1CCOCC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)CCN2CCOCC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(3-morpholin-4-yl-propionyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 3-morpholin-4-yl-propionic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a white solid. MS m/e: 490.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[F:14][C:15]([F:21])([F:20])[CH2:16][CH2:17][CH2:18][NH2:19]>>[F:14][C:15]([F:21])([F:20])[CH2:16][CH2:17][CH2:18][NH:19][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: NCCCC(F)(F)F
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: O=C(O)c1ccc(C(=O)NCCCC(F)(F)F)nc1

Procedure:
The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 4,4,4-trifluorobutan-1-amine, and the second as described for Intermediate example I-98 at 55° C., starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 34%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, 1 H), 9.09 (dd, 1 H), 8.44 (dd, 1 H), 8.14 (dd, 1 H), 3.38 (q, 2 H), 2.20-2.36 (m, 2 H), 1.71-1.81 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+];
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:9](=[O:27])[C:8]=3[CH:7]=[CH:6][N:5]2[CH:28]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:29]([N:12]1[C:13]2[C:4]3=[N:3][C:2]([CH3:1])=[CH:28][N:5]3[CH:6]=[CH:7][C:8]=2[C:9](=[O:27])[C@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C@H:11]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:31])[CH3:30]
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](OC(=O)C(C)(C)C)C3=O
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1c2c(ccn3cc(C)nc23)C(=O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 7.00 g (18.5 mmol) (8R,9R)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridin-7-one in toluene (70 ml) is added 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethylamine and the reaction mixture is stirred for 1 h at 0° C. Afterwards further 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethylamine are added to the reaction mixture and it is warmed up to 25° C. and stirred at this temperature for 1 h. Subsequently the reaction is quenched by adding of saturated aqueous ammonium chloride solution. This mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is crystallised from diethyl ether to provide 5.4 g (12.7 mmol/70%) of the title compound as a colourless solid with a melting point of 168–169° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[I:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[I:18])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cncn1-c1ccc(F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1

Procedure:
A solution of ethyl 1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (14) (5 g, 21.4 mmol), N-iodosuccinimide (12 g, 53.4 mmol), and THF (100 mL) was refluxed overnight. A solution of saturated sodium thiosulfate was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(OC)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-methoxyphenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([N+:14]([O-])=O)[CH:6]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]3[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=3)=[O:28])[CH:24]=2)[CH:19]=[CH:18]1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:33]([C:32]3[CH:31]=[CH:30][C:29]([C:27]([NH:26][C:23]4[CH:24]=[C:25]5[C:20]([CH:19]=[CH:18][NH:17]5)=[CH:21][CH:22]=4)=[O:28])=[CH:36][CH:35]=3)[NH:14][C:7]=2[CH:6]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc2cc[nH]c2c1)c1ccc(-c2nc3ccc(OCCO)cc3[nH]2)cc1

Procedure:
Compound 672 was prepared according to the procedure similar to that described in Scheme III from 1-(2-hydroxyethoxy)-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C24H20N4O3: 413.15; found: 412.96.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4](=[N:6][OH:7])[CH3:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C.[Cl-].[Na+].O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:7][N:6]=[C:4]([CH3:5])[CH3:3])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)=NO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOc1ccc([N+](=O)[O-])cc1
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
To a 0° C. slurry of sodium hydroxide (82 g, 2 mol) in DMF (1.5 L) was added acetone oxime (125 g, 1.7 mol). After stirring 45 min, 1-fluoro-4-nitrobenzene (218 g, 1.55 mol) was added over 45 min. After stirring at room temperature for 2.5 h, the reaction was poured into cold brine (4.5 L). The mixture was stirred at 0° C. for 2 h. The solid was collected by filtration, washed with water (4×1.5 L) and dried to provide 300 g (99%) of 2-propanone O-(4-nitrophenyl)oxime.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C[CH2:15][N:16]=[C:17]=NCCCN(C)C.Cl.CNC.C1COCC1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:16]([CH3:17])[CH3:15])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-bromo-1H-indazole-3-carboxylic acid (1 g, 4.15 mmol) and EDC.HCl (1.2 g, 6.2 mmol) in DMF (5 mL) was added 2 M dimethylamine in THF (3.45 mL, 10.3 mmol). Mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo to remove the volatiles, then diluted with EtOAc (30 mL) and washed with water. The aqueous layer was extracted with more EtOAc (20 mL). The combined organics were washed with water (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid: 1H NMR (250 MHz, DMSO) delta 3.06 (3H, s), 7.34 (1H, dd, J=8.68, 1.52 Hz), 7.84 (1H, d, J=1.07 Hz), 7.92 (1H, d, J=8.68 Hz), 13.62 (1H, br. s.); LC-MS: m/z=+269.75 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16](=O)[CH3:17])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21].Cl.[CH3:27][O:28][NH2:29]>CO>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:16][CH:17]=[N:29][O:28][CH3:27])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CON
Reactant: CC=C(C(=O)OC)c1ccc(C(C)=O)c(COc2ccccc2)c1C
Agent: Cl
Solvent: CO
Product: CC=C(C(=O)OC)c1ccc(CC=NOC)c(COc2ccccc2)c1C
Temperature: 25 °C
Yield: 72.7 %

Procedure:
22 g (67.4 mmol) of methyl α-[2-methyl-4-acetylphenyloxymethylphenyl]-β-methylacrylate and 11.3 g (0.135 mol) of O-methylhydroxylamine hydrochloride were refluxed in 600 ml of methanol for 6 hours. The mixture was allowed to cool to about 25° C., was hydrolyzed and extracted with ice water. The organic phases were washed with water, dried and evaporated down. There was obtained 18 g of the title compound in the form of pale yellow crystals (m.p.: 55°-60° C.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:30][CH2:31][CH2:32][CH2:33][CH2:34]I>O1CCCC1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C@H:11]([CH2:34][CH2:33][CH2:32][CH2:31][I:30])[C:12]([O:14][CH3:15])=[O:13])[C:16]([O:18][CH3:19])=[O:17])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: ICCCCI
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCCI)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -70 °C
Reaction time: 1 h

Procedure:
5.51 g (20 mmol) of dimethyl Boc-glutamate were dissolved in 60 ml of tetrahydrofuran and cooled to −70° C. Over a period of one hour, 44 ml (44 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise at this temperature, and the mixture was stirred at −70° C. for 2 hours. 18.60 g (60 mmol) of 1,4-diiodobutane were then added dropwise, and after 2 h at this temperature the cooling bath is removed and 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6]([CH3:41])([CH3:40])[C:7](=[O:39])[N:8]([CH2:16][CH2:17][CH2:18][N:19]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2=[O:15])=[CH:4][CH:3]=1>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([CH3:41])([CH3:40])[C:7](=[O:39])[N:8]([CH2:16][CH2:17][CH2:18][N:19]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN(CCCN2C(=O)c3c(ccc(N)c3[N+](=O)[O-])C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCN(CCCN2C(=O)c3c(ccc(N)c3N)C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A mixture of tert-butyl [3-(7-amino-4,4-dimethyl-8-nitro-1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl)propyl]-[2-(3,4-dimethoxyphenyl)ethyl]carbamate (3.60 g, 6.31 mmol) and 20% Pd(OH)2/C (0.72 g) in EtOH (100 mL) and THF (10 mL) was stirred under H2 (balloon) for 16 h. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40-63μ silica gel, hexane:EtOAc 1:1 to 1:2) to give the title compound (2.85 g, 83% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:25]=2[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[CH3:47])=[O:23])[CH2:18][C@@H:17]1[CH2:48][C:49](O)=[O:50])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:25]=2[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[CH3:47])=[O:23])[CH2:18][C@@H:17]1[CH2:48][C:49](=[O:50])[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
To a stirred, ice-cold solution of 4-aminomethyl-tetrahydropyran (0.047 g, 0.40 mmol), EDIA (0.19 ml, 1.08 mmol) and the compound of step 2 (0.190 g, 0.27 mmol) was added TBTU (0.259 g, 0.81 mmol) in small portions. The solution was stirred at room temperature for 18 h. Then water (8 ml) was added and the mixture was extracted 3 times with EA. The combined organic phases were washed with 1 N hydrochloric acid, water, a saturated solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 50:50) to give 0.117 g of the title compound as an orange gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH3:10])=[CH:5][CH:4]=1.[H][H]>[C].[Pd].O1CCCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH3:10])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(C)(c2ccc(OC)cc2)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(c2ccc(N)cc2)c2ccc(OC)cc2)cc1

Procedure:
70 g (0.19 mol) of the above synthesized 1,1-bis(4-methoxyphenyl)-1-(4-nitro-phenyl)ethane, 200 ml of tetrahydrofuran and 3.5 g of palladium carbon were placed in an Erlenmeyer flask, and the 1,1-bis(4-methoxyphenyl)-1-(4-nitro-phenyl)ethane was reduced by 13.65 l of hydrogen. After this reduction reaction, the tetrahydrofuran was distilled away from the reaction mixture under reduced pressure, whereby 1,1-bis(4-methoxyphenyl)-1-(4-amino-phenyl)ethane was obtained in the form of a white solid in a yield of 64.2 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:24]=[C:25]([NH2:27])[S:26][CH:2]=3)=[C:6]([CH3:23])[CH:7]=2)=[CH:14][CH:15]=1)([CH3:22])[CH3:21]
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(N)n1
Yield: 61.4 %

Procedure:
A mixture of 2-bromo-1-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)ethanone (16-5, 2.57 g, 6.8 mmol) and thiourea (0.60 g, 7.8 mmol) in 95% EtOH (30.0 mL) was heated at reflux for 4.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (16-6, 1.48 g) as yellow solids in 61% yield: 1H NMR (500 MHz, DMSO-d6) 6.94 (m, 6 H), 6.62 (s, 2 H), 6.33 (s, 1 H), 4.54 (t, J=6.0 Hz, 1 H), 2.05 (s, 6 H), 1.26 (s, 3 H), 1.25 (s, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14].Cl>O>[CH3:12][S:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])=[O:14]
Reactant: NCCCCCC(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
6-aminohexanoic acid (904 mg, 6.89 mmol) and NaOH (415 mg, 10.34 mmol) were dissolved in H2O (30 mL) and cooled to 0–5° C. Methanesulfonyl chloride (0.586 mL, 7.58 mmol) was added dropwise and the reaction mixture stirred for 2 h, then warmed to ambient temperature and stirred for an additional 2 h. The mixture was acidified with HCl (1 N) and extracted with EtOAc (3×15 mL). The extracts were combined, washed with H2O, then brine, dried over MgSO4, and filtered. Evaporation under reduced pressure gave 69 as a white crystalline solid (207 mg, 0.99 mmol, 14%). 1H-NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 6.91 (t, 1H), 2.90 (dt, 2H), 2.87 (s, 3H), 2.20 (t, 2H), 2.48 (m, 2H), 2.43 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([C:16]2[C:28]([Cl:29])=[CH:27][C:19]3[NH:20][C:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[N:22][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:10]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:15]=[CH:14][C:13]([C:16]2[C:28]([Cl:29])=[CH:27][C:19]3[N:20]([CH2:8][O:7][CH2:6][CH2:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[N:22][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
SEMCl (2.28 mL, 12.87 mmol) was added to a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (3.79 g, 9.9 mmol) and Hunig's base (2.08 mL, 11.88 mmol) in THF (20 mL) at 0° C. The reaction was stirred at rt for 3 h then partitioned between EtOAc and saturated aqueous NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 5-25% EtOAc/hexanes afforded the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCNCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
tert-butyl 10-bromo-6-(2-isobutoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0412 g, 0.0859 mmol) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (1.0 mL, 1.48 g, 13.0 mmol, 151 equiv.) was added. The resulting solution was stirred at rt for 2.5 h. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (2 mL), then treated with 1N HCl in Et2O. Hydrochloride salt formation did not occur and the resulting solution were concentrated to dryness. The residue was partitioned between EtOAc and 1N NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude isobutyl (10-bromo-2,3,4,5-tetrahydroazepino[4, 5-b]indol-6(1H)-yl)acetate (0.0260 g) was obtained in 80% yield. 1H NMR (300 MHz, CD3OD) δ 0.85, 1.86, 2.98-3.03, 3.11-3.14, 3.53-3.56, 3.91, 5.02, 6.94, 7.18, 7.25; MS (ESI+) for C18H23BrN2O2 m/z 379.0 (M+H)+.