Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH3:27]>>[CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:34]3[CH2:33][CH2:32][N:31]([S:28]([CH2:26][CH3:27])(=[O:29])=[O:30])[CH2:36][CH2:35]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Reactant: CCS(=O)(=O)N1CCNCC1
Agent: Cl
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 60% (307 mg) yield as described in general procedure (B) from trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (349 mg, 1.0 mmol) and 1-ethanesulfonyl-piperazine hydrochloride (215 mg, 1.0 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C.[CH2:46]([OH:51])[CH2:47][CH2:48][C:49]#[CH:50]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.O.O1CCOCC1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:50]#[C:49][CH2:48][CH2:47][CH2:46][OH:51])[CH:20]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: C#CCCCO
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCCCO)c2)N=C1N
Temperature: 80 °C
Reaction time: 5 h
Yield: 73.3 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (1.15 g, 2.8 mmol), dioxane, bis(benzonitrile)dichloropalladium(II) (32.2 mg, 0.084 mmol), tri-tert-butyl phosphine (10% w/w in hexane, 339 mg, 0.17 mmol) and diisopropyl amine (340 mg, 3.36 mmol) was degassed under argon for 5 minutes, treated with pent-4-yn-1-ol (236 mg, 2.8 mmol), stirred at 80° C. for 5 hours, poured into water and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by ICSO (EtOAc/MeOH 10/1) gave the title compound as a white solid (849 mg), identified by NMR and mass spectral analyses. MS m/e [M+H]+ 414.2
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13]([C:16]3[N:17](COCC[Si](C)(C)C)[N:18]=[CH:19][CH:20]=3)=[CH:14][N:15]=[C:8]1[C:7]([NH:29][CH2:30][CH2:31][CH2:32][O:33][P:34](=[O:51])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N:6]2.Cl.[Na]>C(O)C.C(O)(C)C>[N:18]1[NH:17][C:16]([C:13]2[N:9]3[C:10]4[C:5]([N:6]=[C:7]([NH:29][CH2:30][CH2:31][CH2:32][O:33][P:34](=[O:51])([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:8]3=[N:15][CH:14]=2)=[CH:4][C:3]([C:2]([F:1])([F:53])[F:52])=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1cnc2c(NCCCOP(=O)(OCc3ccccc3)OCc3ccccc3)nc3cc(C(F)(F)F)ccc3n12
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: CCO
Product: O=P(OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3ccn[nH]3)cnc12)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a stirred solution of phosphoric acid dibenzyl ester 3-{7-trifluoromethyl-1-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-imidazo[1,2-a]quinoxalin-4-ylamino}-propyl ester (966 mg; 1.26 mmol; 1.0 eq) in absolute ethanol (7 mL) at 0° C., is added a 4N solution of hydrogen chloride in isopropanol (3.5 mL). The solution is stirred for 5 minutes at 0° C., warmed-up to room temperature and stirred for two additional hours. The reaction mixture is basified with an aqueous solution saturated with sodium hydrogenocarbonate (35 mL). The aqueous layer is extracted three times with ethyl acetate (3×40 mL). The combined organic phases are dried over sodium sulphate, filtered and concentrated under vacuum. Purification by two successive silica gel chromatography (elution with ethyl acetate) afforded the title compound (392 mg; 0.61 mmol; 48%) as a colourless oil.
Reaction SMILES: C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC([C:12]([F:15])([F:14])[F:13])=CC=2)C)CC1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([CH:37]2[CH2:39][CH2:38]2)[CH3:36])=[CH:31][CH:30]=1>>[CH:37]1([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([C:32]2[CH:33]=[CH:34][C:29]([C:12]([F:15])([F:14])[F:13])=[CH:30][CH:31]=2)[CH3:36])[CH2:39][CH2:38]1
Reactant: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3)C3CC3)c[nH]c12
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CC(c1ccc(C(F)(F)F)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 153 mg (0.39 mmol) of the compound from Example 185 in analogy to the synthesis of the compound from Example 209. 63 mg (38% of theory) of the target compound were obtained.
Reaction SMILES: CO[C:3](=[O:17])[C@H:4]([CH2:13][CH:14]([CH3:16])C)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:18]1(C)C=CC=CC=1>>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][CH2:14][CH2:16][CH3:18])[CH:3]=[O:17])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: Cc1ccccc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Product: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Under an argon gas stream, N-(tert-butoxycarbonyl)-(L)-leucine methyl ester (9.8 g, 40 mmol) as dissolved in toluene (70 ml), and cooled to -78° C. To the solution, while keeping the temperature at -60 to -70° C., was added gradually aluminum diisobutyl hydride (toluene 1.0 M solution, 52 ml). After stirring at -78° C. for 40 minutes, the cooling bath was removed, and methanol (2.1 ml) and 20% aqueous citric acid solution (30 ml) were added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with 20% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (S)-2-(tert-butoxycarbonylamino)-5-methylpentanal (8.5 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:20])[C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[N+:17]([O-:19])=[O:18])[C@@H:4]([C:21]([OH:23])=O)[CH2:3]1.C([N:26](CC)CC)C.ClC(OCC)=O>C(#N)C>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:20])[C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[N+:17]([O-:19])=[O:18])[CH:4]([C:21]([NH2:26])=[O:23])[CH2:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1C[C@H](O)CN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: CCOC(=O)Cl
Solvent: CC#N
Product: NC(=O)C1CC(O)CN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5 g (0.015 mole) of trans-4-hydroxy-1-(4,5-methylenedioxy-2-nitrobenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 1 are suspended in 130 ml of acetonitrile at room temperature and then 2.25 ml (0.015 mole) of triethylamine are added. After 30 minutes of stirring starting from the end of the addition, 1.5 ml (0.015 mol) of ethyl chloroformate are added into the suspension previously cooled at 5° C. The reaction mixture is again stirred for 30 minutes. Ammonia is bubbled through this solution, the temperature of which is maintained between 0° C. and 5° C. A precipitate appears. It is spun, washed with ether and recrystallized in acetonitrile.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Product: O=[N+]([O-])c1ccc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluoro-5 nitrobenzaldehyde. MS (ESI) m/z 532.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:33]3[CH:34]=[N:35][C:30]([C:29]([F:38])([F:28])[F:37])=[CH:31][CH:32]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)nc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 9.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-137 by using methyl 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.256 mmol), 6-(trifluoromethyl)pyridin-3-amine (0.062 g, 0.387 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.013 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 3.33 (s, 2H), 7.33-7.41 (m, 4H), 7.89 (d, J=9.0 Hz, 1H), 8.47 (d, J=6.6 Hz, 1H), 9.00 (s, 1H), 10.09 (s, 1H), 11.20 (br s, 2H); MS [M+H]+: 520.11
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH:50]([CH:54]=O)[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][C:24]([C:11]2[C:12]([CH3:22])([CH3:23])[C@H:13]3[C@:8]([CH3:34])([CH2:9][CH:10]=2)[C@@H:7]2[C@:16]([CH3:21])([C@@:17]4([CH3:20])[C@H:4]([CH2:5][CH2:6]2)[C@H:3]2[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]2([NH:1][CH2:54][CH:50]2[CH2:51][CH2:52][CH2:53][N:48]([C:46]([O:45][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:47])[CH2:49]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:33][CH:32]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CCCN(C(=O)OC(C)(C)C)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.055 mmol) in DCE (0.5 mL) was added 3-formyl-piperidine-1-carboxylic acid tert-butyl ester (14.71 mg, 0.069 mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg, 0.110 mmol) was added. After stirring the mixture for 16.5 h, the mixture was diluted with 3 mL of sat. NaHCO3 and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was adsorbed to silica gel and was purified by silica gel flash chromatography using a 0-10% EtOAc in hexanes gradient and a Thomson 12 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound (29 mg, 0.039 mmol, 70.9% yield) as an off-white film. The product was used in the next step with no additional purification. LCMS: m/e 741.7 (M+H)+, 3.76 min (method 2).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[N:16]=[C:17]([C:21](=[O:38])[NH:22][C:23]2[C:24]([C:28](=[O:37])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:25][NH:26][CH:27]=2)[N:18]([CH3:20])[CH:19]=1)(C)(C)C>ClCCl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:28]([C:24]2[C:23]([NH:22][C:21]([C:17]3[N:18]([CH3:20])[CH:19]=[C:15]([NH2:14])[N:16]=3)=[O:38])=[CH:27][NH:26][N:25]=2)=[O:37])=[CH:31][CH:32]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(N)nc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Trifluoroacetic acid (200 μl) was added to a stirred suspension of {2-[3-(4-fluoro-phenylcarbamoyl)-1H-pyrazol-4-ylcarbamoyl]-1-methyl-1H-imidazol-4-yl}-carbamic acid tert-butyl ester (30 mg) in dichloromethane (5 ml), then stirred at room temperature for 2 hours. The solvent was evaporated then re-evaporated with toluene (2×10 ml). The residue was triturated with diethyl ether and the resultant solid collected by filtration. The solid was washed with diethyl ether then dried under vacuum to give 15 mg of 4-[(4-amino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide as an off-white solid. (LC/MS: [M+H]+ 343.72).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:4]2=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[N:20]1([CH2:26][CH2:27][C:28]2[N:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]3=[C:30]([C:37](Cl)=[O:38])[N:29]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[C:10]1([NH:11][C:37]([C:30]2[N:29]=[C:28]([CH2:27][CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=23)=[O:38])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2ccccc12)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of 1-naphylamine (0.077 g, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (58 mg, 32%). 1H NMR (DMSO-d6) δ 10.0 (1H), 8.45 (1H), 8.10 (1H), 7.98 (3H), 7.78 (1H), 7.55 (3H), 7.18 (1H), 6.93 (1H), 3.59 (4H), 3.30 (2H), 2.85 (2H), 2.57 (4H); m/z (M+H)=401.13.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4C(OC(C)(C)C)=O)=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:61][O:62][C:63]([NH:65][C@H:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([OH:69])=O)=[O:64].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:61][O:62][C:63]([NH:65][C@H:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:42]1[C:40]1[NH:41][C:37]([C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=2)[C:17]2[NH:18][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]5[CH2:55][CH2:56][O:57][CH2:58][CH2:59]5)=[N:15][C:16]=2[CH2:26][CH2:25]4)[CH:36]=[CH:35]3)=[CH:38][N:39]=1)=[O:69])=[O:64]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
(S)-tert-butyl 2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (136 mg, 0.17 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane, 1 mL) was added. After stirring for 1 h, the reaction mixture was concentrated and the residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (36 mg, 0.170 mmol), COMU (73 mg, 0.170 mmol) and DMF (3 mL). DIPEA (0.12 mL, 0.68 mmol) was added dropwise. After 20 min, the reaction was quenched by addition of H2O and the crude mixture was purified by HPLC to afford the title compound (57 mg, 38%). MS: (ESI) m/z 891 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCC(O)CC1)C(=O)O

Procedure:
0.74 g (7.17 mmol) of rhodium was added to a solution of 7.00 g (24.88 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxyphenyl)propionic acid in 50 ml of methanol, and hydrogenation was carried out at 50 C/6 bar pressure of hydrogen. After conversion was complete, the catalyst was filtered off and the filtrate was concentrated. The product was pure enough for further reactions.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1.[OH-].[Na+]>O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: NNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 1,681 g of ethyl 4-chloro-quinoline-3-carboxylate, 1,017 g of p-chlorophenylhydrazine and 25 L of xylene is heated to 105° for 24 hours while stirring under nitrogen. The resulting suspension is cooled to 20°, combined with 14 L of 2 N aqueous sodium hydroxide, stirred for 15 minutes and diluted with 30 L of water. Stirring is continued for 1 hour, the aqueous phase separated, washed five times with 8 L of diethyl ether each, filtered and the filtrate treated with the solution of 1,600 g of ammonium chloride in 8 L of water while stirring under nitrogen. The resulting suspension is stirred overnight at room temperature, filtered and the residue washed 5 times with 12 L of hot water. This residue is dried at 5 mmHg and 90° and 1,665 g thereof are dissolved in 8.4 L of dimethylformamide at 130°. The solution is filtered and allowed to cool to room temperature while stirring. The resulting suspension is filtered, washed twice with 500 ml of cold dimethylformamide each, four times with 1 L of diethyl ether and the residue is dried at 0.1 mmHg and 100°, to yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one of the formula ##STR9## melting at 324°-327° with decomposition.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]3[CH3:29])[N:18]=2)=[C:11]([O:30][CH3:31])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[CH3:29][C:24]1[N:23]([C:19]2[N:18]=[C:17]([C:12]3[CH:13]=[C:14]([CH2:15][CH3:16])[C:9]([OH:8])=[CH:10][C:11]=3[O:30][CH3:31])[CH:22]=[CH:21][CH:20]=2)[C:27]([CH3:28])=[CH:26][CH:25]=1
Reactant: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1O
Temperature: 25 °C
Yield: 98 %

Procedure:
Under a nitrogen atmosphere, 5.90 g (14.30 mmol) of 2-(4-benzyloxy-5-ethyl-2-methoxy-phenyl)-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (6) and 27.06 g (429.1 mmol) of ammonium formate were combined in 125 mL of methanol and 500 mg of 20% Pd(OH)2 on carbon. The resultant slurry was allowed to reflux for 45 minutes. 500 mg of 20% Pd(OH)2 on carbon was added twice more, and the resultant slurry was allowed to reflux for 45 minutes. The reaction mixture was then allowed to cool to ambient temperature and passed through a pad of celite to remove the catalyst. The filtrate was concentrated in vacuo and the resultant yellow residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted again with ethyl acetate (200 mL). The combined organic extracts were washed with brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.52 g (98%) of 4-[6-(2,5-Dimethyl-pyrrol-1-yl)-pyridin-2-yl]-6-ethyl-3-methoxyphenol (7) as a tan solid.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:19].ClCl>B(Br)(Br)Br>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:19]
Reactant: COc1cccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Agent: ClCl
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 54.8 %

Procedure:
By the method used in Example 1, Part D, 1.6 g (4.9 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 20 mL of 1M BBr3 /CH2 Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 841 mg (55% yield) of 1-([1,1'-biPhenyl]-2-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1F>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:8][CH:6]1[CH2:7][N:2]([CH3:1])[CH2:3][C:4]2[CH:11]=[CH:10][S:9][C:5]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CN1Cc2ccsc2C(O)C1
Product: CN1Cc2ccsc2C(Oc2cccc(Cl)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.