Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CCN([CH:18]([CH3:20])[CH3:19])C(C)C.C[CH2:22][O:23][C:24](C)=[O:25]>CCCCO.CCCCCC.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>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:24]([O:23][CH2:22][CH2:20][CH2:18][CH3:19])=[O:25])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CCOC(C)=O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCO
Solvent: CCCCCC
Product: CCCCOC(=O)c1ccc2c(c1)CCC2=O
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-1-indanone (5.0 g, 23.7 mmol), DIEA (14.4 mL, 82.9 mmol) and PdCl2(PPh3)2 in n-BuOH (50 mL) was purged with carbon monoxide for 5 min and then stirred under a CO balloon at 115° C. for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through Celite. Solvent evaporation in vacuo followed by filtration on a short column of silica gel and eluted with CH2Cl2 gave the crude product. Chromatography (10% EtOAc in Hexane) afforded butyl 1-oxoindane-5-carboxylate. HPLC/MS: m/z=233.1 (M+1), Rt=3.55 min. 1H NMR (CDCl3): δ 8.18 (1H, s), 8.06 (1H, d, J=8.0 Hz), 7.82 (1H, d, J=8.0 Hz), 4.39 (2H, t, J=6.5 Hz), 3.23 (2H, t, J=6.0 Hz), 2.78 (2H, t, J=6.0 Hz), 1.81 (1H, m), 1.52 (2H, m), 1.02 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([O:13]CC)=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)O)cc(C)c1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.0 g, 4.54 mmol) in MeOH (30 mL) and THF (10 mL) was added 6N NaOH (2 mL, 12.00 mmol). The suspension was heated to 60° C. and stirred for 2 hr. (The reaction cleared up right away.) LCMS indicated that the reaction was complete. The reaction was cooled to RT and concentrated to near dryness. The slurry was neutralized with 6N HCl (2 mL) diluted with water, filtered, washed with water and dried under vacuum to give the product 5-cyano-6-methoxy-4-methylpicolinic acid (0.76 g, 3.95 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.65 (br. s., 1H), 7.73 (s, 1H), 4.03 (s, 3H), 2.54 (s, 3H). MS(ES)+ m/e 192.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10][C@@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:9])=[O:5])[CH3:2].[Br:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>CCOC(C)=O.C(#N)C>[Br-:25].[CH2:1]([O:3][C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10][C@@H:11]1[CH:16]2[CH2:15][CH2:14][N+:13]([CH2:26][C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([CH2:18][CH2:17]2)[CH2:12]1)=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(ethoxycarbonylamino)-2-phenylacetate (C34) (60.0 mg, 0.18 mmol) in EtOAc (2 ml) and acetonitrile (0.5 ml), was added 2-bromo-1-phenylethanone (39.5 mg, 0.20 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The resulting solid was triturated in i-Pr2O/EtOAc (1/1) to obtain (3R)-3-(2-(ethoxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (76 mg; 80% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CCCCCC.[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:29][C:27]1([C:58]1[CH:63]=[C:62]([CH:64]=[O:65])[C:61]([CH3:66])=[CH:60][C:59]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[S:29][C@:27]1([C:58]1[CH:63]=[C:62]([CH:64]([OH:65])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=2)[C:61]([CH3:66])=[CH:60][C:59]=1[O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C(O)c2cc([C@]3(O)S[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 1-bromo-4-(methoxymethoxy)benzene (1.55 g, 7.13 mmol) in tetrahydrofuran (7.5 mL), 2.67 M n-butyllithium in hexane (2.58 mL, 6.9 mmol) was added dropwise at −60° C. under a nitrogen atmosphere. Then, a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-5-thio-D-glucopyranose (1.80 g, 2.30 mmol) in tetrahydrofuran (10 mL) was added dropwise and stirred at −78° C. for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give the titled compound (1.2 g, 57%) as a yellow amorphous substance.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10][C:11]([OH:13])=[O:12])[CH:8]=[CH:9][C:2]1=2.[CH3:14]O>Cl>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH2:5][CH2:4][C:3]=2[CH:6]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCS2
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc2c(c1)CCS2
Temperature: 65 °C
Yield: 94 %

Procedure:
In a round bottom flask was placed (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid (525 mg, 2.70 mmol), methanol (15 mL) and hydrochloric acid (2 drops). The reaction mixture was heated to 65° C. for 16 h. It was then concentrated in vacuo to remove the methanol, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl ester (528 mg, 94%) as a yellow oil: ES-HRMS m/e calcd for C11H12O2S (M+H)+ 209.0631, observed 209.0631.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.S(Cl)([Cl:13])=O>ClC(Cl)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([Cl:13])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)ccn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-pyridine-2-carboxylic acid (2.0 g, 12.8 mmol) in dichloroethane (43 mL) was added thionyl chloride (2.8 mL, 38.5 mmol) and DMF (2-3 drops). The suspension was warmed to 85° C. After 1 h, the resulting clear, yellow solution was cooled to rt and concentrated. The residue was dissolved in DCE and concentrated. This process was repeated two additional times to give a yellow liquid which crystallized upon standing to give a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:30]([Si:33](Cl)([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:33]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine (656, 0.877 g, 2.42 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (60% dispersion in mineral oil, 140 mg, 3.6 mmol) was added at room temperature. After 20 minutes, triisopropylsilyl chloride (513 μL, 2.42 mmol) was added dropwise. The reaction was stirred for four hours. The reaction was poured into water and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate and brine. The organic portion was dried over anhydrous sodium sulfate and filtered. The filtrate was adsorbed onto silica gel and purified by silica gel chromatography using 20-80% ethyl acetate/hexane. The resulting material was purified a second time with 5-30% gradient ethyl acetate/hexane to provide the desired compound (657, 831 mg, 66%). MS (ESI) [M+H+]+=519.4.
Reaction SMILES: [NH2:1][CH:2]([CH:21]([CH3:23])[CH3:22])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4].[Cl:24][C:25](=[CH2:28])[CH2:26]Br.[Cl:29][C:30]([CH3:34])=[CH:31][CH2:32]Cl>>[Cl:24][C:25](=[CH2:26])[CH2:28][NH:1][CH:2]([CH:21]([CH3:23])[CH3:22])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4].[Cl:29][C:30]([CH3:34])=[CH:31][CH2:32][NH:1][CH:2]([CH:21]([CH3:23])[CH3:22])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4]
Reactant: C=C(Cl)CBr
Reactant: CC(C)C(N)C(=O)OCc1cccc(C(=O)c2ccccc2)n1
Reactant: CC(Cl)=CCCl
Product: C=C(Cl)CNC(C(=O)OCc1cccc(C(=O)c2ccccc2)n1)C(C)C
Product: CC(Cl)=CCNC(C(=O)OCc1cccc(C(=O)c2ccccc2)n1)C(C)C

Procedure:
Using the method of Example 2, (6-benzoyl-2-pyridyl)methyl 2-amino-3-methylbutanoate is reacted with each of 2-chloro-2-propen-1-yl bromide and 3-chloro-2-buten-1-yl chloride to yield (6-benzoyl-2-pyridyl)methyl 2-[N-(2-chloro-2-propenyl)amino]-3-methylbutanoate and (6-benzoyl-2-pyridyl)methyl 2-[N-(3-chloro-2-butenyl)amino]-3-methylbutanoate.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([O:21][CH3:22])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:22][O:21][CH:4]([O:3][CH3:2])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][N:18]([CH:25]2[CH2:26][O:23][CH2:24]2)[CH2:19][CH2:20]1
Reactant: O=C1COC1
Reactant: COC(OC)c1nc2c(cc1C1CCNCC1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1C1CCN(C3COC3)CC1)CCCN2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-(dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (Intermediate 342, 0.94 g, 2.294 mmol), 3-oxetanone (0.777 g, 10.78 mmol) and Et3N (0.96 ml, 6.88 mmol) in 1,2-dichloroethane (50 ml) was cooled to 0° C., treated with sodium triacetoxyborohydride (1.54 g, 6.88 mmol) and then slowly warmed to room temperature. After 1.5 h, the reaction mixture was poured into H2O and evaporated to dryness. The crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 0.1% TFA in H2O/acetonitrile 70:30 to 5:95). The product-containing fractions were treated with NaHCO3 and then concentrated to dryness. The residue was suspended in MeOH, stirred for 1 h and filtered, washing with additional MeOH. The filtrate was evaporated to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.34 min; ESI-MS 348.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[O:20][CH3:21])[CH:6]=[C:7]([Br:10])[C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)c(F)c(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
3,5-dibromo-4-fluoroaniline (1.6 g, 4.16 mmol) was dissolved in DCM (41.6 ml). Pyridine (0.90 ml, 11.13 mmol) was added and the reaction mixture cooled to 0-5° C. Methyl chloroformate (0.66 ml, 8.52 mmol) was added dropwise via syringe. The reaction mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was diluted with additional 50 ml dichloromethane and washed with 0.5 M citric acid twice, NaHCO3 solution once and brine once, then dried over MgSO4, filtered and evaporated to dryness. Chromatography on silica (gradient from 100% hexanes to 100% DCM) gave methyl (3,5-dibromo-4-fluorophenyl)carbamate (1.22 g) as a colorless fluffy solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:13]CS([O-])(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[N:23]([CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:19][CH:20]([CH3:22])[CH3:21])=[N+:24]=[N-:25]
Reactant: CC(C)CC(CCS(=O)(=O)[O-])NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(CN=[N+]=[N-])NC(=O)OCc1ccccc1

Procedure:
To the crude [2-(benzyloxycarbonylamino)-4-methyl-pentyl]methanesulfonate from the above reaction in DMF (50 mL), was added sodium azide 2.43 g. The reaction mixture was then heated to 85 degrees for 3 hrs. After cooling, ethyl acetate (300 mL) and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to afford the crude benzyl N-[1-(azidomethyl)-3-methyl-butyl]carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine 7.21 g and stirred under nitrogen for 16 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0-10%) to afford benzyl N-[1-(aminomethyl)-3-methyl-butyl]carbamate (4.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[N:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1.CC(O)=O.O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Cn1nc(-c2ccccc2)nc1N
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)nn2C)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 19.1 %

Procedure:
To a solution of 1-methyl-3-phenyl-1,2,4-triazol-5-amine (320 mg, 2 mmol) in 10 mL dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The salt was partitioned between EtOAc and water. The EtOAc phase was extracted alternately with 1M NaOH and H2O. The basic phase was made acid (pH˜3) with 1M HCl and extracted with EtOAc. The organic phase was evaporated in vacuo, toluene was added and was again evaporated in vacuo to give a white solid. The product was taken up in hot HOAc (16 mL), diluted with H2O (10 mL) and seeded to give 143 mg of white needles with mp 279-280° C. after drying in vacuo.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC#N>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:23]
Reactant: CCOC(=O)CCCCBr
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCCCN1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
Sodium carbonate (2.12 g) was added to the solution of homopiperazine (10.0 g; 5 eq.) and ethyl 5-bromovalerate (4.18 g; 1 eq.) in CH3CN (120 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was filtered thru a celite pad. The filtrate was concentrated. The remaining residual was dissolved in CHCl3 (120 mL), washed by H2O (50 mL×3) and brine (50 mL×1), dried by Na2SO4 and concentrated to give 5-[1,4]diazepan-1-yl-pentanoic acid ethyl ester (4.0 g), which was carried on for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.09 (q, 2H, J=7.0 Hz), 2.90 (m, 4H), 2.63 (m, 4H), 2.47 (t, 2H, J=7.0 Hz), 2.29 (t, 2H, J=7.0 Hz), 2.07 (bs, 1H), 1.73 (m, 2H), 1.60 (m, 2H), 1.48 (m, 2H), 1.22 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[C:29]([F:32])[C:28]([OH:33])=[CH:27][CH:26]=2>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O.O>[F:32][C:29]1[C:28]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:27][CH:26]=[C:25]2[C:30]=1[CH:31]=[C:23]([CH3:22])[NH:24]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCc1ccccc1

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with DMAP (1.5 eq), 2-methyl-4-fluoro-5-hydroxyindole (WO0047212) (1 eq) in dioxane (20 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg).
Reaction SMILES: [Cl:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28]4=[C:29]([CH2:31][CH2:32][N:27]4[C:26](=[O:33])[CH2:25][CH2:24]3)[CH:30]=2)=[O:20])[CH2:13][CH2:12]1.[K].[I-].[K+]>C(#N)C>[ClH:1].[CH:2]1([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28]5=[C:29]([CH2:31][CH2:32][N:27]5[C:26](=[O:33])[CH2:25][CH2:24]4)[CH:30]=3)=[O:20])[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: ClC1CCc2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CC#N
Product: Cl
Product: O=C(CCC1CCN(C2CCc3ccccc32)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reaction time: 12 h
Yield: 27.4 %

Procedure:
1-Chloroindane (360 mg) was added to a suspension of 8-[3-(4-piperidinyl)propanoyl]1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (700 mg), potassium carboante (700 mg) and potassium iodide (catalytic amount) in acetonitrile (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (15 ml) and ethyl acetate (20 ml) were added to the residue, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as colorless crystals (285 mg) having a melting point of 111 to 113° C. The free base compound (270 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (270 mg) as pale yellow amorphous powders.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2c3ccccc3-c3noc4c3C2CCC4)cc1
Temperature: 90 °C

Procedure:
In 50 ml dry DMF were combined 2.10 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 2.0 g milled anhydrous K2CO3 and 1.3 ml benzylbromide. The mechanically stirred mixture was heated under nitrogen at 90° C. for 18 hours. During the first 4 hours, 1 ml benzyl bromide was added every hour as TLC analysis indicated it was being consumed. For the work-up, the mixture was poured into excess water and extracted with DCM. The DCM layer was concentrated to an oil and the oil was purified on a silica column (flash chromatography) using DCM as an eluent. The product-containing fractions were combined and concentrated to a solid. The solid was recrystallized from EtOAc/hexanes and dried in a vacuum desiccator to yield 2.10 g of product, m.p. 162°-163.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:16]([O:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[N+:13]([O-:15])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(c(Cl)c1O)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(c(Cl)c1OCc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
5-Chloro-6-hydroxy-7-nitrotetralin (2.28 g, 10.0 mmol) was dissolved in dry DMF (40 mL) and flushed with argon. Benzyl chloride (11.5 mL, 100.0 mmol) n-Bu4NI (95 mg, 0.25 mmol) and K2CO3 (41.5 g, 30.0 mmol) were added. The reaction mixture was stirred for 24 h at room temperature, protected from light. The salts were filtered off and the solvent and excess of BnCl were co-evaporated with xylene (3×200 mL) and CH2Cl2 (200 mL), followed by vacuum-drying. The crude product (5.8 g) was purified by flash column chromatography (SiO2, CHCl3 -Hexane 1:1) and afforded the title compound (2.20 g). Mp 80°-82° C.; 1H NMR (DMSO-d6): δ 7.73 (s, 1 H), 7.48-7.37 (m, 5 H), 5.06 (s,2 H), 2.79-2.75 (m, 4 H), 1.79-1.69 (dm, 4 H); 13C NMR (DMSO-d6): δ 144.81, 142.14, 135.79, 135.56, 129.55, 128.42, 123.40, 106.20, 105.51, 75.80, 28.63, 27.65, 21.55, 21.36; MS (TSP): m/z (rel.int.) 337/335 (M+NH4, 30/100).