Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH:9]([C:38]([O:40][CH3:41])=[O:39])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([C:38]([O:40][CH3:41])=[O:39])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[O:37]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(N)C(=O)OC)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 1-{2-[bis(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate in DCM (0.05 M) a large excess (>100 eq) of TFA was added and the solution stirred at RT for 20 min. Volatiles were removed in vacuo and the residue partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound (quant). MS (ES+) m/z 463 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([NH:19]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>CO>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:9]([OH:30])=[O:8]
Reactant: O=C(C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CO
Product: N[C@H](CC(=O)O)Cc1ccccc1
Yield: 92.9 %

Procedure:
The 3(S)-{{(benzyloxy)carbonyl}amino}-4-phenylbutyric acid benzyl ester (from step A) (10.97 g, 27.2 mmol) in MeOH (1 L) was stirred at room temperature for 7 h under an hydrogen atmosphere (1 atmosphere) in the presence of 20% Pd (OH)2/C (50 mg). The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to yield 4.53 g (93% yield) of 3(S)-amino-4-phenylbutyric acid as a white solid. A suspension of NaHCO3 (12.74 g, 152 mmol) in MeCN (1.55 L) was stirred and heated to gentle reflux. Mesyl chloride (2.15 mL, 27.8 mmol) was added, followed by the portionwise addition of the preceding acid (4.53 g, 25.3 mmol) over 5 h. After 16 h under reflux, the solid was removed by filtration at 60° and the filtrate was concentrated under reduced pressure. The residual solid was triturated with EtOAc and filtered. The filtrate was concentrated and the residue purified by flash chromatography (SiO2, 40% EtOAc in hexane) to give 4(S)-benzylazetidin-2-one (2.20 g, 54% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.35-7.17 (m, 5H), 5.83 (brs, 1H), 3.88-3.82 (m, 1H), 3.08 (ddd, J=14.8, 5.0, 2.2 Hz, 1H), 2.98 (dd, J=13.7, 5.7 Hz, 1H), 2.84 (dd, J=13.7, 7.9 Hz, 1H), 2.70 (ddd, J=14.9, 2.0, 1.3 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O:20][CH2:19][C:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: OCc1scc2c1-c1ccccc1Oc1ccccc1-2
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOCc1scc2c1-c1ccccc1Oc1ccccc1-2

Procedure:
Starting from the alcohol 12 (0.25 mmole) and 2-dimethylaminoethylchloride-hydrochloride (2.5 mmoles), an oily product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=3)=[CH:19][C:18]1=2
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(S(N)(=O)=O)c3)cc21

Procedure:
Prepared according to procedure B from 3-bromobenzenesulfonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 242-244° C. (dec) 1H-NMR (DMSO-d6) δ 10.28 (s, broad 1H), 8.07(s, 1H), 7.9(d, 1H, J=7.80 Hz), 7.78 (d, 1H, J=7.86 Hz), 7.64 (t, 1H, J=7.79 Hz), 7,59 (m, 2H), 7.42(s, broad 2H), 7.02(d, 1H, J=8.86 Hz), 1.68 (s, 6H); MS m/z 331 (M+H). Anal. Calc. for C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43. Found: C, 57.49; H, 5.08; N, 8.05.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].O1CC[CH2:20][CH2:19]1>[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3]([O:5][CH2:19][CH3:20])=[O:4])=[CH:10][CH:11]=1
Reactant: CCCC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: C1CCOC1
Agent: [Pd]
Product: CCCC(C)(C(=O)OCC)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
2.6 g of 2-methyl-2-(4-nitrophenyl)pentanoic acid are dissolved in 30 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 2.2 g (95%) of ethyl 2-(4-aminophenyl)-2-methylpropanoate; LC-MS retention time: 1.99 min.
Reaction SMILES: [ClH:1].Cl.CO[CH:5]1[N:10]([CH2:11][CH2:12][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH:8](C2C(OC(F)(F)F)=C(C3C=CC=CC=3)C=CC=2)[N:7]([CH3:37])[CH2:6]1.Cl.Cl.[CH3:40][O:41][C:42]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]([F:58])([F:57])[F:56])[CH:49]=2)=[CH:46][C:45](C(C2(O)CCCCC2)CN2CCNCC2)=[CH:44][CH:43]=1>>[ClH:1].[ClH:1].[CH3:40][O:41][C:42]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]([F:56])([F:57])[F:58])[CH:49]=2)=[CH:46][C:45]([CH:12]([C:13]2([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:11][N:10]2[CH2:9][CH2:8][N:7]([CH3:37])[CH2:6][CH2:5]2)=[CH:44][CH:43]=1
Reactant: COC1CN(C)C(c2cccc(-c3ccccc3)c2OC(F)(F)F)CN1CCC1(O)CCCCC1
Reactant: COc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1-c1cccc(OC(F)(F)F)c1
Agent: Cl
Product: COc1ccc(C(CN2CCN(C)CC2)C2(O)CCCCC2)cc1-c1cccc(OC(F)(F)F)c1

Procedure:
In an analogous manner to Example 24, 1-[1-[6-methoxy-3′-(trifluoromethoxy-1,1′-biphenyl-3-yl]-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(3′-trifluoromethoxy-6-methoxy-1,1′-biphenyl-3-yl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 251). MS m/z 493; HRMS: calcd for C27H35F3N2O3+H, 493.26780; found (ESI, [M+H]+), 493.2692.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH:7](Br)[C:6]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4].[C:15](#[N:17])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH:7]([C:15]#[N:17])[C:6]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: COC(=O)C1=C(C(=O)OC)C(Br)CC1
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: COC(=O)C1=C(C(=O)OC)C(C#N)CC1
Yield: 25 %

Procedure:
3-Bromo-cyclopent-1-ene-1,2-dicarboxylic acid dimethyl ester was dissolved in acetonitril under inert conditions. Tetraethylammoniumcyanide (1.1 eq) was added in one portion. The mixture was stirred under inert gas until the reaction was finished (2 h monitored by TLC). The solvent was removed in vacuum and the residue was purified by flash chromatographie using a hexane/ethylacetat gradient to give 3-Cyano-cyclopent-1-ene-1,2-dicarboxylic acid dimethyl ester in 25% yield.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:14])[C:12]=1[CH3:13]>CN(C)C=O>[F:14][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:12]=1[CH3:13])[C:4]#[N:5]
Reactant: Cc1c(F)cncc1Br
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1c(F)cncc1C#N
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
Copper cyanide (1.87 g, 0.021 mol) was added at room temperature to a sealed tube containing a solution of 3-bromo-5-fluoro-4-methylpyridine (E; 2.0 g, 0.0105 mol) in dimethylformamide (20 mL). The reaction mixture was heated to 150° C. for 16 h. It was then cooled to RT, quenched with 20% aqueous ammonia (30 mL) solution and stirred for 5 min. The reaction mixture was extracted with diethyl ether (2×100 mL). The organic layers were washed with water (2×50 mL), dried over anhydrous sodium sulphate and concentrated to afford 5-fluoro-4-methylnicotinonitrile. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.56 (s, 1H), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:22]#[N:23])[CH:3]=1.Cl.[NH2:25][OH:26]>CO>[NH2:23][C:22](=[N:25][OH:26])[C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:12][CH2:13]2)[CH:5]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=NO)cc(Cl)n2)CC1

Procedure:
TEA (0.24 ml, 1.78 mmol) was added to a solution of tert-butyl 1-(6-chloro-4-cyanopyridin-2-yl)piperidin-4-ylcarbamate (Intermediate 53, 0.4 g, 1.19 mmol) in MeOH (2 ml), followed by the addition of hydroxylamine hydrochloride (0.82 g, 1.19 mmol). The mixture was refluxed for 4 h, then the solvent was removed in vacuo to give the desired product. (410 mg).
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:21]([O:28][CH3:29])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:17]([F:30])=[CH:16][C:15]=1[C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)[N:34]=[CH:33][C:32]=1[C:41]([OH:43])=O.N>CN(C=O)C>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:21]([O:28][CH3:29])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:17]([F:30])=[CH:16][C:15]=1[C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)[N:34]=[CH:33][C:32]=1[C:41]([NH2:3])=[O:43]
Reactant: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(=O)O)cnn2[C@H]2CCOC2)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(N)=O)cnn2[C@H]2CCOC2)cc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 43.6 %

Procedure:
A 5 N aqueous sodium hydroxide solution (0.8 mL) was added to a solution of ethyl 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (397 mg) in ethanol (5 mL), and the reaction mixture was stirred at 70° C. for 1 hour. After cooling the reaction mixture to room temperature, chloroform and brine were added, and the mixture was adjusted to pH 6 with 5 N hydrochloric acid and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrates was concentrated under reduced pressure to give 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid (457 mg) as a crude. CDI (211 mg) was added to a solution of the carboxylic acid (457 mg) in DMF (6 mL), and the reaction mixture was stirred at room temperature. After 75 minutes, a 28% aqueous ammonia solution (0.88 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the precipitated solid was removed by filtration and washed with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/n-heptane, 60% to 80% to 85%) to give title compound (199 mg). This title compound was used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:33])([F:34])[F:35])[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2ccccc2C(F)(F)F)n1
Yield: 45.5 %

Procedure:
A mixture of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (70 mg, 0.2 mmol), 2-hydroxybenzotrifluoride (34 mg, 0.21 mmol) and potassium carbonate (31 mg, 0.22 mmol) in 5 ml acetonitrile was refluxed overnight. Water was added to the mixture. The product was extracted with ethylacetate, concentrated and purified by trituration with diethyl ether to give the title compound as colorless solid (43 mg, 45%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:35])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH:22]1([CH2:21][N:17]2[C:18]3[C:13](=[C:12]([OH:35])[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[O:10])=[N:20][CH:19]=3)[CH:14]=[C:15]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:16]2=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
A mixture of 4-[(1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-butyric acid ethyl ester (39 mg, 0.079 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 464.41 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].BrC1C(O)=C([C:18]([O:21][CH3:22])=CC=1)C(O)=O>N1C2C(=CC=CC=2)C=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:18][O:21][CH3:22]
Reactant: COc1ccc(Br)c(O)c1C(=O)O
Reactant: COc1ccc(Br)c(O)c1
Solvent: c1ccc2ncccc2c1
Product: COCOc1cc(OC)ccc1Br

Procedure:
1-Bromo-2-hydroxy-4-methoxybenzene. 3-Bromo-2-hydroxy-6-methoxybenzoic acid [T. de Paulis et. al. J. Med. Chem., (1985), 28, 1263-1269] (5 g, 0.02 mol) was heated in quinoline (200 mL) at 160° C. for 1 h. On cooling, the product was partitioned between Et2O and 3 M HCl. The organic extract was washed with water and brine then dried (MgSO4), filtered and evaporated to give the title compound which was recrystallized from 5% ethyl acetate/hexane (4 g, 97%); m.p. 40-42° C. Anal, Calc. for C7H7BrO2 : C, 41.41; H, 3,48. Found C, 41.39; H, 3.37.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:13]=[C:14]1[O:18][C:16](=[O:17])[CH2:15]1>Cl>[C:16]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:17])[CH2:15][C:14]([CH3:13])=[O:18]
Reactant: OCC1CC1
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To 13.2 g (179 millimole) of cyclopropyl-carbinol dissolved in 18.1 g (179 millimole) of triethylamine was slowly added 14 ml (179 millimole) of diketene at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 30 minutes, diluted with 3% aqueous HCl solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under the reduced pressure to obtain 24 g of cyclopropylmethyl acetoacetate as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH:23]=O)[CH:16]=[CH:15]1>O1CCCC1.C(OCC)(=O)C>[C:3](/[CH:5]=[CH:23]/[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[NH:14][CH:15]=[CH:16]2)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#C/C=C/c1cccc2cc[nH]c12
Reaction time: 0.25 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.10 g, 2.5 mmol) was added in portions over 10 minutes to a stirred solution of diethyl cyanomethylphosphonate (0.44 g, 2.5 mmol) in tetrahydrofuran (10 ml) cooled in ice. The mixture was stirred for 15 minutes then a solution of 7-indole carboxaldehyde (0.30 g, 2.1 mmol) in tetrahydrofuran (2 ml) was added dropwise. The mixture was stirred for 30 minutes, diluted with ethyl acetate, washed with water, dried and evaporated. The residue was chromatographed on silica in ethyl acetate-hexane (1:3) to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1>CN(C=O)C>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=1)[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (61 mg, 0.235 mmol), was dissolved in DMF (1.0 mL) and cesium carbonate (77 mg, 0.235 mmol) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (72 mg, 0.235 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then filtered through a pad of Celite®. The filtrate was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (28.6 mg). LCMS m/z=486.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH2:17])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH:17][C:31](=[O:33])[CH3:32])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)c(Cl)c1
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
To a solution of Example 37A (358 mg, 1.02 mmol) and triethylamine (426 μL, 3.06 mmol) in dichloromethane (5 mL) was added acetic anhydride (116 μl, 1.22 mmol) at ambient temperature. The reaction was stirred for 10 minutes and was then concentrated on a rotary evaporator. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 30% to 80% ethyl acetate in hexanes to give 338 mg (94%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (d, J=7.35 Hz, 3H) 1.87 (s, 3H) 3.82 (s, 3H) 4.98-5.18 (m, 1H) 6.89 (s, 1H) 7.05 (dd, J=9.19, 2.94 Hz, 1H) 7.27 (d, J=2.94 Hz, 1H) 7.56 (d, J=9.19 Hz, 1H) 7.94 (s, 1H) 8.51 (d, J=7.72 Hz, 1H); MS (ESI) m/z 394.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
A mixture of 197b (500 mg, 1.8 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (530 mg, 2.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.5 mL, 0.90 mmol), and propan-2-ol (20 mL) was stirred at 100° C. for 15 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197c as a brown solid (375 mg, 45%). MS-ESI: [M+H]+ 465.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][C@H:21]([O:23][C:24]4[CH:29]=[N:28][C:27]([C:30]([CH3:32])=[CH2:31])=[CH:26][N:25]=4)[CH2:22][C@H:16]3[CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][C@H:21]([O:23][C:24]4[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N:25]=4)[CH2:22][C@H:16]3[CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(C)(C)C)c4)CCN3C2)cn1
Agent: [Ni]
Solvent: CCO
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(C)(C)C)c4)CCN3C2)cn1
Yield: 56 %

Procedure:
(7R,8aS)-2-[(3-tert-Butylphenyl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine (164.3 mg, 0.360 mmol, Example 113) in ethanol (5 mL) was added to Raney® nickel 2800 water slurry (202.9 mg, 1.556 mmol) in a 20 mL pressure bottle. The mixture was stirred under 30 psi of hydrogen at ambient temperature for 15 hours. The mixture was filtered through a polypropylene membrane, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluted with ethyl acetate/hexane (3:7) to give the title compound (56% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (m, 6H), 1.33 (s, 9H), 1.62 (m, 1H), 1.94 (m, 2H), 2.26 (m, 4H), 2.99 (m, 2H), 3.54 (m, 1H), 3.62 (m, 1H), 3.79 (m, 1H), 5.20 (m, 1H), 7.59 (m, 2H), 7.67 (m, 1H), 7.78 (s, 1H), 8.06 (m, 1H), 8.20 (m, 1H); MS (ESI) m/z 459 (M+H)+.