Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@H:2]([C:10](ON1C(=O)CCC1=O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:37][C@H:38]([C:65]([OH:67])=[O:66])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:45]1[CH:52]=[CH:51][C:48]([O:49][CH3:50])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@H:2]([C:10]([NH:37][C@H:38]([C:65]([OH:67])=[O:66])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:45]1[CH:52]=[CH:51][C:48]([O:49][CH3:50])=[CH:47][CH:46]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(C(NCCCC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(NCCCC[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a stirred suspension of Fmoc-Phe-OSu (2.0702 g, 4.2728 mmol, 1.0 eq) and Lys(MMT) (1.7995 g, 4.2995 mmol, 1.01 eq) in DMF (30 ml) was added DIEA (1.5 ml, 8.6112 mmol, 2.02 eq). The solid dissolved gradually and the solution was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 ml) and pH5 buffer (0.05M phthalic acid, adjusted with 10N KOH to pH 5.0, 200 ml). The aqueous solution was extracted with more ethyl acetate (50 ml×2). The combined organic phase was washed with brine (50 ml×3), dried over MgSO4. After removal of solvent and being dried in vacuo, 3.3014 g (98.1%) of pale-yellow foam was obtained. ES(+)-MS: 516(M-MMT+1), 273(MMT).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:28])=S.[Na+].[Na+].O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCOc1ccc(Sc2ccccc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 86 %

Procedure:
In 85 g of acetic acid was dissolved 12 g of 4-(2-methoxyethoxy)phenyl phenyl sulfide obtained in Synthesis Example 1-29. While the solution was maintained at an internal temperature of 30° C., 4.5 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 1.2 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 80 g of methylene chloride and 40 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum. On subsequent crystallization from ethyl acetate/hexane, 11 g of the target compound, 4-(2-methoxyethoxy)phenyl phenyl sulfoxide was obtained as white crystals. Yield 86%.
Reaction SMILES: C(N(CC)CC)C.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>C1COCC1>[F:20][C:21]([F:33])([F:34])[O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]2[O:28][C:8](=[O:9])[NH:30][N:29]=2)=[CH:25][CH:24]=1
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Triethylamine (3.52 ml, 25.28 mmol) and 1,1′-carbonyldiimidazole (4.84 g, 29.87 mmol) were added to a solution of 4-trifluoromethoxybenzoic hydrazide (5.06 g, 22.98 mmol) in THF (150 ml) while cooling in an ice-bath and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to which water was added. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated under reduced pressure to afford 5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (5.34 g, yield 94%) as a colorless crystalline powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([Br:18])=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[C:19]([C:21]1[CH:36]=[CH:35][C:24]2[C:25]([N:28]3[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]3)=[CH:26][S:27][C:23]=2[CH:22]=1)#[N:20]>>[Br:18][C:16]1[CH:15]=[CH:14][C:13]2[C@H:8]([CH2:7][CH2:6][N:31]3[CH2:32][CH2:33][N:28]([C:25]4[C:24]5[CH:35]=[CH:36][C:21]([C:19]#[N:20])=[CH:22][C:23]=5[S:27][CH:26]=4)[CH2:29][C@H:30]3[CH3:34])[O:9][CH2:10][CH2:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(Br)ccc21

Procedure:
The title compound was prepared from 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate and (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described for Example 1b).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:35][N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([NH:36][OH:35])=[O:34])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid (280 mg, 0.57 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (92 mg, 0.57 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol), and hydroxylamine (0.174 ml, 2.85 mmol), 180 mg (62%) of the product was isolated as a solid. HR-MS: m/z Calculated for C24H32N2O8S 531.1771; Found 531.1768.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[O:11][CH2:10]2)=[O:6].[N+:37]([CH3:40])([O-:39])=[O:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:36][C:2]([F:1])([F:35])[C:3]([CH2:40][N+:37]([O-:39])=[O:38])([C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([Cl:33])=[C:30]([Cl:32])[CH:31]=1)[CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)[O:11][CH2:10]2)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.4 %

Procedure:
To the stirred solution of tert-butyl 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 2, 8.6 g, 15.33mmol) in DMF (215 mL) was added nitro methane (8.20 mL, 153.29mmol) and DBU (2.22 mL, 14.87 mmol) at room temperature. Reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with addition of water (250 mL) and extracted with ethyl acetate (2×300 mL). Combined organic layer was washed with LiCl Solution (2×400 mL) and brine (500 mL). Organic layer was dried over sodium sulfate and concentrated to get crude compound sticky solid (11.23 g). Purification was done by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to afford light yellow sticky liquid (5.10 g, impure-used as such in next step). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 9H), 3.95 (d, J=18.72 Hz, 1H), 4.13-4.18 (m, 3H), 4.33-4.36 (m, 2H), 5.17-5.18 (m, 2H), 5.42 (d, J=12.2 Hz, 1H), 5.58 (d, J=12.16 Hz, 1H), 7.20 (s, 1H), 7.31 (s, 1H), 7.60-7.65 (m 1H), 7.78 (d, J=16.92 Hz, 1H), 7.98-8.00 (m, 1H). LC-MS (m/z): 622.9 (M−H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 515.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14]([F:17])([F:16])[F:15])=[C:7]2[C:12]=1[N:11]=[C:10](O)[N:9]=[CH:8]2.P(O[Cl:22])(=O)=O>>[Cl:22][C:10]1[N:9]=[CH:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: COc1ccc(C(F)(F)F)c2cnc(O)nc12
Reactant: O=P(=O)OCl
Product: COc1ccc(C(F)(F)F)c2cnc(Cl)nc12
Temperature: 25 °C
Yield: 70 %

Procedure:
The crude 8-methoxy-5-(trifluoromethyl) quinazolin-2-ol was heated in neat phosphooxychloride (POCl3) at 110° C. for 2 h. The resulted mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and precipitate was filtered, washed and dried to provide 2-chloro-8-methoxy-5-(trifluoromethyl) quinazoline as a light pink solid in 70% yield. ES/MS m/z 263.0 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[C:21]2[NH:22][CH2:23][CH2:24][O:25][C:20]=2[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=1>>[Br:15][C:16]1[C:21]2[N:22]([C:2]3[C:3](=[O:14])[N:4]([C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:23][CH2:24][O:25][C:20]=2[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: COC[C@H](C)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)OCCN2
Product: COC[C@H](C)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 6.74 (d, J=3.0 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.24–5.10 (m, 1H), 4.52–3.86 (m, 4H), 3.76 (s, 3H), 3.57 (d, J=3.7 Hz, 2H), 3.35 (s, 3H), 1.41 (d, J=6.9 Hz, 3H); HRMS (ESI) m/z 444.0339 [(M+H)+, calcd for C17H20N3O4BrCl 444.0326].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][C:28]1[O:37][C:36]2[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[NH:33][CH2:32][CH2:31][C:30]=2[N:29]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:33]2[CH2:32][CH2:31][C:30]3[N:29]=[C:28]([CH3:27])[O:37][C:36]=3[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)ccc1CNC(=O)OC(C)(C)C
Reactant: Cc1nc2c(o1)-c1ccccc1NCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-methyl-benzoic acid from Example E2h (400 mg, 1.5 mmol) in dichloromethane (20 ml) and triethylamine (to pH9) was treated with WSCD (573 mg, 3.0 mmol) and DMAP (183 mg, 1.5 mmol). The solution was stirred for 30 min at room temperature then 2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene from Example E6 (300 mg, 1.5 mmol) was added and the mixture was heated at reflux for 3 days. WSCD (287 mg, 1.5 mmol) was added and the mixture was heated at reflux for another 24h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (62 mg, 9%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])=[O:11].[OH-].[Na+]>CO.O>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:10](=[O:11])[CH:9]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(OC)c1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(38) To a solution of benzaldehyde (295 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hour at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 371 mg (49.9%) of white flakes: mp 125.5-126.6° C. (lit. mp 123-124° C., Kuck and Grutzmacher, Org. Mass. Spect., 1978, 13, 90-102). 1H NMR (250 MHz) δ 7.55-7.51 (m, 2 H), 7.39-7.30 (m, 5H), 7.00-6.94 (d, 1 H), 6.64-6.61 (d, 2 H), 3.79 (s, 6 H); 13C NMR (62.7 MHz) 213.8, 176.1, 163.9, 153.4, 149.4, 149.0, 147.4, 147.3, 147.0, 122.6, 74.5 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](OCC)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)Cc3ccccn3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (3.5 g, 10 mmol) and 2-methylpyridine (1.9 g, 2.0 mmol) in 50 mL of THF was stirred at 0° C. as LiHMDS (1.0M, 22 mL) was added dropwise. The reaction was stirred at 45° C. overnight, then quenched with ice-water and the solvent evaporated. The residue was extracted with CH2Cl2 (3×30 mL), and the combined CH2Cl2 layers were washed with saturated NaHCO3, saturated NaCl solution, dried over Na2SO4, and concentrated to give the product; Mp 138-140° C.; MS m/z 397 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[O:10][CH:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:12]2[CH:16]([OH:17])[CH2:15][N:14]([C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:13]2)=[CH:5][CH:4]=1.[C:50]1(=[O:56])[O:55][C:53](=[O:54])[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:12]2[CH2:13][N:14]([C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:15][CH:16]2[O:17][C:50](=[O:56])[CH2:51][CH2:52][C:53]([OH:55])=[O:54])=[CH:43][CH:44]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2O)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2OC(=O)CCC(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Referring to scheme 19, Compound 77 (2 g, 3 mmol) was mixed with succinic anhydride (0.600 g, 6 mmol) and DMAP (0.366 g, 3 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.913 g, 1.25 mL, 9 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 4 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography using 6% MeOH/DCM to afford compound 79 as white solid (2.05 g, 89% yield; Rf=0.4 in 10% MeOH/CHCl3).
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH:15]([CH3:16])[CH2:14][C:5]2=3)[CH:24]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CC(C)N(C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6.6 %

Procedure:
2,3,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (214 mg, 1 mmol) was dissolved in DMF (3 mL) and NaH (80 mg, 3.33 mmol) was added portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The solution of 3-(2-methyloxiran-2-yl)pyridine (270 mg, 2 mmol) in DMF (2 mL) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 10 min and at RT for 16 h. Completion of reaction was monitored by LCMS. The reaction mixture was poured onto crushed ice slowly and extracted with EtOAc (3×30 mL). The organic layer was washed with water (7×40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product that was purified by reverse HPLC to give 23 mg of 2-(pyridin-3-yl)-1-(2,3,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.73 (s, 1H), 8.47 (d, 1H), 7.2 (d, 1H), 7.11 (s, 1H), 7.04 (d, 2H), 6.90 (d, 1H), 4.15 (dd, 2H), 3.78 (dd, 1H), 3.6 (dd, 1H), 2.9 (m, 2H), 2.7 (dd, 1H), 2.43 (s, 3H), 2.4 (s, 3H), 1.6 (s, 3H), 1.14 (d, 3H). Separation by chiral HPLC provided diastereomers II-146a-d.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[S:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>CC(C)=O>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:13][C:1](=[O:3])[CH3:2])=[S:12])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1ccc(C(=S)NC(C)=O)cc1
Yield: 72.2 %

Procedure:
A solution of acetyl chloride (4.69 g, 59.8 mmol) in acetone (20 mL) was added dropwise to a solution of 4-methoxythiobenzamide (5.00 g, 29.9 mmol) and pyridine (4.76 g, 60.1 mmol) in acetone (30 mL). The reaction mixture was heated to reflux for 30 min then poured onto ice water. The resulting precipitate was isolated via filtration and dried under vacuum overnight to provide a light yellow/orange solid (4.52 g, 72%). 1H NMR (400 MHz, CDCl3) δ 2.56 (s, 3H), 3.87 (s, 3H), 6.89 (dd, J=6.9, 2.0 Hz, 2H), 7.77 (dd, J=6.9, 2.0 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2([CH3:14])[CH2:13][CH2:12]2)=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[CH:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:29])=[CH:23][CH:24]=2)[CH:8]=[CH:7][C:6]=1[CH2:9][O:10][C:11]1([CH3:14])[CH2:12][CH2:13]1)([CH3:17])[CH3:16]
Reactant: C#Cc1ccc(COC2(C)CC2)c(C(C)C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.2 %

Procedure:
Using General Procedure F; 4-ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene (Intermediate 166, 78.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 94.0 mg, 0.34 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. Column chromatography (2-5% EtOAc-hexanes) afforded 77.0 mg (60%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]3[C:14]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH:18][C:5]3=[CH:4][C:3]1=2.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40].Cl>C(Cl)Cl>[C:39]([N:18]1[C:5]2[C:6](=[CH:7][C:8]3[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:32])([CH3:1])[C:3]=3[CH:4]=2)[C:14]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)=[N:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2)(=[O:41])[CH3:40]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Nc1ccccc1N=C3c1ccc(C(=O)O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2N=C(c2ccc(C(=O)O)cc2)c2cc3c(cc21)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution 4-(7,7,10,10-tetramethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]-cyclohepta[1,2-b]naphthalen-12-yl)benzoic acid (27) (0.47 mmol) and pyridine (1.2 mmol) in CH2Cl2 (4 mL) is treated with acetyl chloride (1.0 mmol) and stirred at room temperature for 6 h. The mixture is poured into 1 N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solid is purified by reversed-phase HPLC (0.1% TFA, 30-100% gradient CH3CN) to give the acid (29).