Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Pd+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Pd].[C:11]1([CH3:32])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[P:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].Br[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1.[C:42](#[N:45])[CH:43]=[CH2:44].C([O-])(=O)C.[Na+]>CN(C)C=O.O>[C:1]([O-:4])(=[O:3])[CH3:2].[Pd+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[C:11]1([CH3:32])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[P:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].[CH:38]([C:37]1[CH:40]=[CH:41][C:34]([CH:44]=[CH:43][C:42]#[N:45])=[CH:35][CH:36]=1)=[O:39]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A stock solution of 0.0561 g (2.5×10-4 mol) of palladium acetate and 0.304 g (10-3 mol) of tri-o-tolylphosphine in 100 ml of N,N-dimethylformamide (DMF) is prepared under argon. 1 ml of stock solution [containing 0.000561 g (2.5×10-6 mol) of palladium acetate, Pd content=0.01 mol %, and 0.00304 g (10-5 mol) of tri-o-tolylphosphine], 4.63 g (25 mmols) of 4-bromobenzaldehyde, 2.08 ml (31.25 mmols) of acrylonitrile and 2.56 g (31.25 mmols) of anhydrous sodium acetate are then added, under argon, to 9 ml of DMF, and the mixture is stirred at 120° C. for 6 hours. The mixture is then poured into 100 ml of water, which is extracted with twice 25 ml of methylene dichloride, and the extract is dried for 15 minutes with 5 g of magnesium sulfate. After the methylene dichloride and a little DMF have been removed on a rotary evaporator, the crude product is distilled in vacuo. 3.2 g (20 mmols) of 4-formylcinnamonitrile are obtained in the form of a nearly white solid; yield 81% of theory (conversion figure 8100); melting point 92°-98° C.; boiling point 157°-163° C./133 Pa. Analysis for C10H7NO (molecular weight 157.17): calculated C 76.42: H 4.49; N 8.91, found C 76.35; H 4.60; N 9.01. The product is a mixture of isomers consisting of approx. 77% of trans-isomer and 23% of cis-isomer.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCCCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv) and piperidine (0.70 mL, 6.7 mmol, 12 equiv) in methylpyrrolidone (6.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (10.0 mL) and the resultant solids were filtered. The solids were purified by column chromatography on silica gel (15% EtOAc in hexanes as elunant) to provide N-(4-mesitylthiazol-2-yl)-2-(piperidin-1-yl)isonicotinamide (87.2 mg, 0.20 mmol) as yellow solids in 38% yield: 1H NMR (CDCl3, 500 MHz) δ 8.29 (d, J=5.1 Hz, 1H), 7.15 (s, 1H), 6.83-6.90 (m, 3H), 6.79 (s, 1H), 3.61-3.63 (m, 4H), 2.31 (s, 3H), 2.08 (s, 6H), 1.57-1.67 (m, 6H); ESI-MS: m/z 407.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]3[CH2:12][CH2:13][NH:14][CH2:15][CH:6]3[C:5]=2[CH:4]=1)[CH3:2].[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([CH2:23][CH2:24][CH2:25]Cl)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]3[CH2:12][CH2:13][N:14]([CH2:25][CH2:24][CH2:23][C:21](=[O:22])[C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:28][CH:27]=4)[CH2:15][CH:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CCc1ccc2c(c1)C1CNCCC1N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1ccc2c(c1)C1CN(CCCC(=O)c3ccc(F)cc3)CCC1N2
Reaction time: 9 h

Procedure:
To methyl ethyl ketone (120 ml) are added 8-ethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (9 g), γ-(p-fluorobenzoyl)propyl chloride (12 g), potassium carbonate (12 g) and potassium iodide (11 g), and the mixture is refluxed with stirring for 9 hours. After cooling, the insoluble materials are filtered off and the filtrate is concentrated. The resulting residue is dissolved in a dilute hydrochloric acid and the solution is washed with benzene. The dilute hydrochloric acid layer is made alkaline with aqueous ammonia and extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and concentrated. The resulting residue is treated with ethanolic hydrochloric acid in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (12 g), m.p. 192° - 195°C (recrystallized from aqueous ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[NH:52][C:53](=[O:61])[C:54]2[CH2:60][O:59][CH2:58][CH2:57][C:55]=2[N:56]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([NH:49][CH2:50][C:51]3[NH:52][C:53](=[O:61])[C:54]4[CH2:60][O:59][CH2:58][CH2:57][C:55]=4[N:56]=3)=[O:17])[CH2:12][CH2:13]2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(C(=O)c2ccc(Cl)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.3 %

Procedure:
A solution of [4-(4-chloro-benzoyl)-piperidin-1-yl]-acetic acid (0.1 g, 0.36 mmol), EDCl (0.08 g, 0.43 mmol), HOBT (0.06 g, 0.43 mmol) and triethylamine (0.14 g, 1.4 mmol) in 20 mL of DMF, was stirred at ambient temperature for 20 min. then added 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.08 g, 0.43 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide crude product. Purification by flash chromatography gave the title compound (37.2 mg, 0.084 mmol, 24% yield) as a white solid. MS (ESI) m/z 445.2 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.12 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.83 (m, 6H), 2.21-2.30 (m, 1H), 2.50 (br. s., 2H), 2.94 (br. s., 1H), 2.99 (s, 2H), 3.32 (s, 2H), 3.35-3.46, (m, 1H), 3.83 (t, J=5.31 Hz, 1H), 4.19 (d, J=6.06 Hz, 1H), 4.34 (s, 2H), 7.60 (d, J=8.59 Hz, 2H), 8.00 (d, J=8.59 Hz, 2H), 8.20 (s, 1H) 12.40 (s, 1H). HRMS calculated for C22H26ClN4O4: 445.1643 (M+H). found (ESI, [M+H]+): 445.1658.
Reaction SMILES: [C:1]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([CH:9]([CH2:13][CH3:14])[C:10]([O:12][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C(=O)O)C(=O)c1ccccc1
Reactant: BrCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCC(C(=O)OCCCCCCCCBr)C(=O)c1ccccc1
Temperature: 50 °C

Procedure:
A mixture of benzoylbutyric acid (9.0 g, 46.8 mmol), 1,8-dibromooctane (31.5 g, 117.0 mmol), potassium carbonate (16.4 g, 117.0 mmol), dry DMF (70 mL), and a catalytic amount of tetra-n-butylammonium iodide (1.0 mol %) was stirred and heated at 50° C. overnight. The solvent was evaporated. The residue was washed with dilute HCl and then extracted into ether, washed with brine, and dried with MgSO4. The solvent and excess 1,8-dibromooctane were removed under reduced pressure. The crude product was chromatographed on silica using 0-20% ethyl acetate in hexane. Isolated yield=13.5 g (75%) as a colorless liquid. 1H NMR (CDCl3, 200 MHz): δ ppm 7.95 (dd, J=8.24, 1.49 Hz, 2H), 7.47 (m, 3H), 4.05 (t, J=6.64 Hz, 2H), 3.37 (t, J=6.81, 2H), 3.04 (t, J=7.13 Hz, 2H), 2.42 (t, J=7.20 Hz, 2H), 2.01 (m, 2H), 1.82-1.73 (m, 2H), 1.69-1.51 (m, 2H), 1.47-1.21 (m, 8H). 13C NMR (CDCl3, 50.28 MHz): δ 199.29, 173.25, 136.75, 133.00, 128.52, 127.94, 64.41, 37.40, 33.90, 33.34, 32.67, 28.96, 28.50, 27.97, 25.76, 19.34. HRMS (EI) m/z: 405 ((M+Na)+•). Elemental analysis: Calculated for C19H27BrO3: C, 59.53; H, 7.10; Br, 20.85; O, 12.52. Found: C, 59.77; H, 7.52.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[C:7]([N:9]=[C:10]=[S:11])[CH:6]=[CH:5][C:4]=1[N:12]1[C:16]([CH3:17])=[N:15][CH:14]=[N:13]1>>[F:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([NH2:1])=[S:11])[CH:6]=[CH:5][C:4]=1[N:12]1[C:16]([CH3:17])=[N:15][CH:14]=[N:13]1
Reactant: Cc1ncnn1-c1ccc(N=C=S)cc1F
Reactant: N
Product: Cc1ncnn1-c1ccc(NC(N)=S)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
Step C (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 1-(2-fluoro-4-isothiocyanatophenyl)-5-methyl-1H-1,2,4-triazole (3.18 g, 13.6 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated in vacuo. The resulting solid was dried under high vacuum to afford 1-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (3.21 g, 94% yield) as an off-white solid. LC-MS (M+H)+ 252.1. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.06 (s, 1 H), 7.93 (dd, J=12.8, 2.1 Hz, 1 H), 7.54 (t, J=8.7 Hz, 1 H), 7.37 (dd, J=8.5, 1.8 Hz, 1 H), 2.32 (s, 3 H)
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]=1[F:18])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:27][CH:26]=[CH2:25])[CH2:16][CH2:17]2)[C:7]=1[F:18])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 2-fluoro-3-piperidin-4-ylphenyl methanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 313 (M+, 28), 312 (25), 286 (42), 234 (bp), 207 (19).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.COC1N=C([Sn](CCCC)(CCCC)CCCC)C([N+]([O-])=O)=CC=1.FC(F)(F)S(O[C:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH3:54])[CH:49]=2)[CH:44]=1)(=O)=O>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([C:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH3:54])[CH:49]=3)[CH:44]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1nc(OC)ccc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1nc(OC)ccc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 2-chloro-6-methoxy-3-nitropyridine according to an analogous synthetic method to Preparation Example 76, 6-methoxy-3-nitro-2-tributylstannylpyridine (5.5 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (1.5 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 6-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)-3-nitropyridine (933 mg). This compound (930 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (340 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[C:2]2[C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[CH:15][N:14](S(C3C=CC=CC=3)(=O)=O)[C:11]2=[N:12][CH:13]=1>CCO.[OH-].[Na+]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[C:2]2[C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(C4=CC5CCC4C5)cc23)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2c[nH]c3ncc(C4=CC5CCC4C5)cc23)cn1
Reaction time: 0.33 h

Procedure:
5-(bicyclo[2.2.1]hept-2-en-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 2 (63 mg, 0.146 mmol) in EtOH (1.50 mL) and 10% aqueous NaOH (0.75 mL), was deprotected as described in the general procedure A for the deprotection of 7-azaindoles by refluxing for 20 min. The reaction was quenched by addition of a saturated solution of NaHCO3 (15 mL) and the mixture was stirred for 20 minutes. It was extracted with EtOAc (3×15 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product purified by PTLC using EtOAc as the eluent to give (I-136) (24.8 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 1.16-1.25 (m, 2H), 1.32 (d, J=8.2 Hz, 1H), 1.59-1.63 (m, 1H), 1.80-1.89 (m, 2H), 3.04-3.08 (m, 1H), 3.42-3.45 (br s, 1H), 4.01 (s, 3H), 6.35 (d, J=3.1 Hz, 1H), 7.39 (d, J=2.3 Hz, 1H), 7.64 (s, 1H), 7.78 (d, J=0.5 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 10.09 (br s, NH, 1H).
Reaction SMILES: Cl.[CH:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:16][NH:15][CH2:14][CH2:13][C:5]=13.[BH4-].[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:6]3[C:7]=2[C:3]=1[C@H:4]1[CH2:16][NH:15][CH2:14][CH2:13][C@H:5]13
Reactant: c1cc2c3c(c1)c1c(n3CC2)CCNC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4,5,7,8,9,10-Hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole from Example 1 (0.50 g, 2.14 mmol) was stirred under N2 in TFA (15.5 mL) at 0° C. for 10 minutes. NaBH4 (0.44 g, 6.4 mmol) was added slowly keeping the temperature below 2° C. The reaction was allowed to warm to room temperature and stirred overnight. Ice chips were then added and the reaction basified to pH 12 with 50% aqueous NaOH. The aqueous layer was then extracted with CHCl3 (3×20 mL). The combined extracts were washed with brine, H2O and dried (Na2SO4) and evaporated affording the title compound (0.42 g, 100%). 1H NMR (CDCl3, 300 MHz) δ6.94 (d, 1H, J=7.7 Hz), 6.88 (d, 1H, J=6.9 Hz), 6.63 (t, 7.3, 1H, J=7.3 Hz), 3.64 (dt, 1H, J=8.0, 1.5 Hz), 3.29-3.5 (m, 2H), 3.05-3.29 (m, 3H), 3.03 (dd, 1H, J=11.7, 3.6 Hz), 2.72-3.02 (m, 2H), 1.66-1.90 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1O)=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1CCc2ccccc2C1O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccccc2CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
A mixture of 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-naphthol (2.45 g, 11.1 mmol), triethylamine (2.70 g, 26.7 mmol) and tetrahydrofuran (50 ml) was cooled to 0° C., followed by adding dropwise thereto methanesulfonyl chloride (1.53 g, 13.3 mmol). The reaction mixture was stirred at 0-5° C. for 1.5 hours and then at room temperature for 7 hours, and allowed to stand overnight at room temperature. The reaction mixture was poured into a cold aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:99) to obtain 2.12 g of ethyl 3,4-dihydronaphthalene-2-carboxylate.
Reaction SMILES: [CH2:1]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([C:13]1[S:14][C:15]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-dodecylthiophene (5.18 g, 20.5 mmol) in dry THF (90 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 12.3 mL, 30.8 mmol) was then added slowly. This mixture was stirred at −78° C. for additiona 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 31 mL, 31.0 mmol) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and the reaction mixture was diluted with hexane (200 mL), washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (8.35 g, 98.0%), which was directly used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:6]=2[C:7]=1[CH3:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:2]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:6]=2[C:7]=1[CH3:8])=[O:1]
Reactant: Cc1c(CO)oc2cccc(O)c12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1c(C=O)oc2cccc(O)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound of step A (356 mg) in methylene chloride (50 ml) is added pyridinium chlorochromate (648 mg). Stir the reaction mixture at room temperature for 1.5 hours and then filter through a bed of Florisil. Evaporate the filtrate and purify the residue by chromatography over 30 g of silica gel, using methylene chloride-ethyl acetate as eluent to obtain the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
A solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (212 mg) in acetic anhydride (10 mL) was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 and washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The oily residue was crystallized from AcOEt to give the title compound (130 mg) as white crystals.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([CH3:22])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=CN(C)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.15 g 0.6 mmol) in DMF (2 mL) was added sodium hydride (60%, 28 mg, 0.7 mmol) at 0° C. and a solution of MeI (38 μL, 0.7 mmol). The mixture was stirred for 30 min at 0° C. Water was added to the reaction mixture, which was then extracted by DCM. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (5:95) and then further purified by preparative HPLC to afford the title compound (86 mg); 1H-NMR (CDCl3): δ 10.50 (1H, s), 8.26 (1H, m), 7.77 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.05 (2H, m), 5.35 (1H, s), 4.28 (2H, q), 3.54 (2H, t), 3.26 (3H, s), 3.14 (2H, m), 1.36 (3H, t). MS (ES): 271 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O-:9])=[O:8])[C@@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C[C@@H]([NH3+])C1C=CC=CC=1.Cl.CCO>O>[OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[C@@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1
Agent: C[C@@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1

Procedure:
The salt from Step A was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of EtOAc. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid. [α]D (EtOH)=-19.9 (c=0.675).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][N:31]([C:15](=[O:16])[C@@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:30][CH2:29]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Product: CN(C)C1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1

Procedure:
The title compound was prepared according to EXAMPLE 35 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228) and dimethylpiperidin-4-yl amine (Preparation 90). Purification by preparative HPLC gave the title compound as a yellow crystalline solid. m/z (ES+)=472.34 [M+H]+; RT=2.64 min.