Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([NH:5][C:6]([C:8]1([CH2:22][CH2:23][CH2:24][CH2:25][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: CCCCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-butylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([CH:3]([OH:14])[C:4]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:6]([O:7][CH3:8])[CH:5]=1)[CH3:2].[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19]>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:12]=[CH:13][C:4]([CH:3]([O:14][CH2:19][C:18]#[CH:17])[CH2:1][CH3:2])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: CCC(O)c1ccc(OC)c(OC)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(CC)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 20.8 g of α-ethylveratryl alcohol in 15 ml of dimethylformamide is added dropwise with stirring to a suspension of 12.5 g of sodium hydride in 75 ml of dimethylformamide. The mixture is stirred for 0.5 hour at room temperature (about 22°C.), and 11.8 g of propargyl bromide are then added dropwise, the temperature not being allowed to exceed 30°C. After stirring for 3 hours at room temperature, the mixture is cooled in a ice-bath to 5°C., decomposed with ice-cold water at a temperature of approximately 15°C. and extracted three times with 150 ml of diethyl ether. The extract is washed neutral with water, dried over sodium sulphate, filtered and the filtrate evaporated to dryness under reduced pressure. The oily residue is chromatographed on silica gel using benzene/ether (9:1 parts by volume) as the elution agent. There is obtained 1,2-dimethoxy-4-[1-(2-propynyloxy)propyl]-benzene; nD24 = 1.5248.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCOCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with morpholine to give (2S)-1-(tert-butoxycarbonyl)-2-morpholinocarbonylpyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7–2.0 (m, 4H), 2.1–2.2 (m, 1H), 2.4–2.5 (m, 1H), 2.6–2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.4 (m, 2H), 3.4–3.8 (m, 10H); Mass Spectrum: M+H+ 229.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Cl:8][C:9]1[CH:14]=[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: Clc1cc(N2CCOCC2)ccn1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
To a solution of triethylamine (1.0 equiv.) and 2,4-dichloropyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then stirred at RT for 45 hr. LCMS analysis indicated the formation of the desired product (M+H=199, Rt=0.29 min, major) and the undesired isomer (M+H=199, Rt=0.33 min, minor). The reaction mixture was concentrated in vacuo and purified via ISCO to yield 4-(2-chloropyridin-4-yl)morpholine as a light brown solid (28%). LCMS (m/z) (M+H)=299.0, Rt=0.29 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.18-3.37 (m, 4H) 3.72-3.91 (m, 4H) 6.51-6.61 (m, 1H) 6.61-6.69 (m, 1H) 8.05 (d, J=6.26 Hz, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:68])[N:7]([C@H:34]1[CH2:38][CH2:37][N:36]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:35]1=[O:67])[CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:69]([C:71]1[CH:78]=[CH:77][C:74]([CH2:75]O)=[CH:73][C:72]=1[F:79])#[N:70].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:68])[N:7]([C@H:34]1[CH2:38][CH2:37][N:36]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:35]1=[O:67])[CH2:8][CH2:9][C:10]1[N:11]([CH2:75][C:74]2[CH:77]=[CH:78][C:71]([C:69]#[N:70])=[C:72]([F:79])[CH:73]=2)[CH:12]=[N:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxo-pyrrolidin-3-yl}-{2-[1-(triphenylmethyl)-1H-imidazol-4-yl]ethyl}carbamic acid tert-butyl ester, as described above in Step G, (720 mg, 0.785 mmol) and 4-cyano-3-fluorobenzyl alcohol, as described above in Step H, (142 mg, 0.940 mmol) in dry CH2Cl2 (7 mL) were added N,N-diisopropylethylamine (0.342 mL, 1.96 mmol), followed by trifluoromethanesulfonic anhydride (0.158 mL, 0.940 mmol), dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and was stirred for 18 hours, then concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and the resulting solution was stirred at ambient temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned between saturated aqueous NaHCO3 (5 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with EtOAc—1% MeOH—0.1% NH4OH to yield the desired product as a pale foam.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].Cl.[NH2:31][CH2:32][CH2:33][N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36].C[O-].[Na+]>CCO>[CH3:38][S:35]([N:34]([CH3:39])[CH2:33][CH2:32][NH:31][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4])(=[O:37])=[O:36]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN(CCN)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 34.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (49 mg, 0.26 mmol), and NaOMe (14 mg, 0.26 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the residue was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 11.4 mg of the title compound as a light yellow solid. MS: (+) m/z 507.36 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[OH-].[Na+].Cl>CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH3:16])=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2])(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(C(=O)C(C)C)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C(C)C)cc1C(=O)O
Yield: 100.5 %

Procedure:
5-Isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol) was dissolved in methanol (5 mL). 2N Aqueous sodium hydroxide (1 ml) was added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (134 mg, yield: quantitative) as a white crystal.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([CH3:12])[N:11]=2)[C:7]=1[Cl:8].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C)C=O.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.[Cu]I>[Cl:8][C:7]1[N:6]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=[N:3][C:2]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cn2c(Cl)c(Br)ncc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cn2c(Cl)c(C#C[Si](C)(C)C)ncc2n1
Temperature: 45 °C
Reaction time: 14 h
Yield: 51.3 %

Procedure:
A mixture of 6-bromo-5-chloro-2-methylimidazo[1,2-a]pyrazine (0.710 g, 2.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.1 g, 0.1 mmol), (trimethylsilyl)acetylene (0.90 mL, 6.3 mmol), copper(I) iodide (0.04 g, 0.2 mmol), and triethylamine (0.803 mL, 5.76 mmol) in N,N-dimethylformamide (8.5 mL) was heated in an oil bath at 45° C. and stirring for 14 h. The reaction was quenched with water (20 ml) and was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (10 ml), saturated NaCl (10 ml), dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 10-20% EtOAc in hexanes to give the desired product (0.39 g, 76%). LCMS calculated for C12H15ClN3Si (M+H)+: m/z=264.1. Found: 264.0.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:58])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])[N:24]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>[Pd].CO>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:58])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)c1c[nH]c(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)n1)C(=O)OC
Yield: 47.7 %

Procedure:
A mixture of dimethyl N-{2-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethynyl]-1-triphenylmethylimidazol-4-ylcarbonyl}-L-glutamate (390 mg, 0.5 mmol) and 10% palladium-on-carbon catalyst (390 mg) in methanol (15 mL) was stirred under 50 psi of hydrogen for 7 days at room temperature. The workup was performed as described in Example 2 to yield 130 mg (48%) of dimethyl N-{2-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]imidazol-4-ylcarbonyl}-L-glutamate as a pale yellow solid, mp 129-131° C.: 1H NMR (CDCl3) δ 11.35 (br s, 1H), 8.95 (br s, 1H), 7.54 (d, 1H, J=8.4 Hz), 7.49 (s, 1H), 4.75 (m, 1H), 3.69 (s, 3H), 3.60 (s, 3H), 3.30 (M, 1H), 2.87 (m, 1H), 2.80-2.60 (m, 3H), 2.43 (m, 2H), 2.27 (m, 1H), 2.15-1.92 (m, 2H), 1.80-1.60 (m, 3H), 1.26 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([O:16]C)[CH:11]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=1
Reactant: COc1ccc(-c2ccnc(OC)c2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2cc[nH]c(=O)c2)c(F)c1
Yield: 86.9 %

Procedure:
4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine (1.34 g, 5.72 mmol) was stirred in concentrated hydrochloric acid (25.5 mL) at reflux for 18 h. The reaction was cooled to 0° C. and neutralized with solid NaOH. The resulting solids were collected by filtration and dried under vacuum to yield the title compound (1.09 g, 87%) as a light brown solid: 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.38 (m, 2H), 6.97-6.85 (m, 2H), 6.42-6.33 (m, 2H), 3.80 (s, 3H); ESI MS m/z 220 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:27][CH:26]=1)=[O:33]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CC(C)(C)C(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1-(4-Hydroxyphenyl)-2,2-dimethyl-propan-1-one from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C24H30O6 [M+NH4]+: 437 [M+H]+: 415.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH2:13])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH:13][C:35]([CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[O:36])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.22 g (0.85 mmol) 4-(benzyloxy)-2-methyl-6-nitroaniline were placed in 5 mL DCM. 0.17 mL (1.00 mmol) DIPEA and 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cn2ccccc2n1
Yield: 8.4 %

Procedure:
A solution of 14.6 g of 2-aminopyridine and 25.5 g of ethyl 4-chloroacetoacetate in 200 ml of acetonitrile was heated under reflux for 14.5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue thus obtained was mixed with an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 2.65 g of the title compound having Rf=0.33 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4n3)c2cc1OC
Temperature: 115 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (147 mg, 0.67 mmol) in toluene (3 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by 2-(chloromethyl)quinoline hydrochloride (158 mg, 0.74 mmol) and the mixture was stirred at 115° C. for 25 min under microwave irradiation. Another portion of a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) was then added at RT followed by 2-(chloromethyl)quinoline hydrochloride (70 mg, 0.33 mmol) and the mixture was stirred at 115° C. for 10 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) and neutralised with a 10% aqueous citric acid solution before extraction with CH2Cl2 (50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 100:7) gave 49 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol as a yellow solid. The free base (45 mg) was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (5.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol hydrochloride 23 as a yellow solid (54 mg, 19% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH2:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14])=[CH:6][CH:7]=1
Reactant: COCC(C)N
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC(C)NCc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.17 mmole) in 11 mL of dry acetonitrile is added 1.30 mL (12.3 mmol) of 2-amino-1-methoxypropane followed by 850 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 5 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 640 mg (48% yield) of (6-Chloro-pyridin-3-ylmethyl)-(2-methoxy-1-methyl-ethyl)-amine. Diagnostic C13 NMR (100 MHz, CDCl3) 17.2, 48.0, 52.3, 59.1, 77.2, 124.1, 135.3, 138.9, 149.5, 150.1 MS (217.2 (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][C:16]([NH2:18])=[O:17])=[C:9]2[S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=1)(=[O:21])=[O:20])(=[O:5])[CH3:4].O>O1CCCC1>[OH:5][CH:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][C:16]([NH2:18])=[O:17])=[C:9]2[S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=1)(=[O:21])=[O:20])[CH3:4]
Reactant: CC(=O)c1ccc2[nH]c(CC(N)=O)c(S(=O)(=O)c3cc(C)cc(C)c3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc(C(C)O)cc23)c1
Yield: 80.9 %

Procedure:
Sodium borohydride (0.03 g, 0.0008 mol) was added to a mixture of 5-acetyl-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (0.30 g, 0.0008 mol) in tetrahydrofuran (8.5 mL) containing 0.1 mL of water, then reaction was refluxed for 1 hour. After cooling, water was added while stirring for a few minutes, then the mixture was extracted with ethyl acetate, washed with brine and dried. Removal of the solvent furnished 0.25 g (83%) of satisfactory pure title compound, mp 260-260° C. (ethanol).
Reaction SMILES: [OH-].[NH4+:2].CO[C:5](=[O:29])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][C:13]=2[CH3:28])[CH2:8]1>CO>[F:27][C:23]1[CH:22]=[C:21]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]3[CH2:10][CH2:11][N:7]([CH2:6][C:5]([NH2:2])=[O:29])[CH2:8]3)=[C:13]([CH3:28])[CH:14]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: [NH4+]
Reactant: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Agent: [OH-]
Solvent: CO
Product: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A concentrated solution of ammonium hydroxide (2 mL) was added to a solution of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester (130 mg, 0.3321 mmol) in methanol (2 mL) and the resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure and the crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.102 g of 2-{3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetamide of a white foam: MS (M+H)=377.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[NH2:14][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:16]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:12][C:10]1[S:11][C:6]2[CH:5]=[C:4]([C:1]([NH:14][C@H:15]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@@H:16]3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:3])[NH:8][C:7]=2[C:9]=1[Cl:13]
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CS(=O)(=O)N[C@H]1c2ccccc2C[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4, 236 mg, 1.0 mmol), N-[(1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl]methanesulfonamide (226 mg, 1.0 mmol), DIPEA (174 μL, 1.0 mmol) and HOBT (135 mg, 1.0 mmol) were dissolved in DCM (10 mL) and stirred for approximately 5 mins. EDCI (240 mg, 1.25 mmol) was added and the reaction stirred for 20 hours. The volatiles were removed by evaporation, EtOAc (25 mL) added, the mixture washed with water (2×10 mL) and brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (430 mg, 97%) as a foam.