Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](O)([O-])=O.[OH:5][C@H:6]1[C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[C:20](OC)[C:8]=2[N:7]1[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24].[CH2:31]([O:34]C(N1C[C@H](O)C[C@H]1CO[Si](C(C)(C)C)(C)C)=O)C=C.[CH2:52]([O:59]C(N1C[C@H](O)C[C@H]1C(O)=O)=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:31][O:34][C:19]1[C:18]([O:59][CH3:52])=[CH:17][C:9]([C:10]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:6][OH:5])=[O:16])=[C:8]([NH:7][C:23]([O:25][CH2:26][C:27]([Cl:28])([Cl:30])[Cl:29])=[O:24])[CH:20]=1
Reactant: COc1cccc2c1N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: COc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(C(=O)N2CCCC2CO)cc1OC

Procedure:
Oxalyl chloride (0.38 mL, 4.33 mmol) was added to the crude Troc-protected anthranilic acid, prepared in the previous reaction, together with 2 drops of dry DMF in dry dichloromethane (30 mL). After initial strong effervescence, the mixture was allowed to stir at room temperature overnight. The resulting acid chloride was added dropwise, over 30 minutes, to a solution of 2S-(+)-pyrrolidinemethanol (0.44 g, 4.33 mmol) and TEA (1.37 ml, 9.85 mmol) of dry dichloromethane (15 mL) at −16° C. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with dilute HCl (1N, 2×30 mL), satd. aqueous NaHCO3 (2×30 mL), water (30 mL) and brine (30 mL). The organic layer was then dried over MgSO4 and evaporated to give a yellow oil. The crude product was purified by flash chromatography (petroleum ether/ethyl acetate=50/50) to yield the product (1.2 g, 70%) as a pale yellow oil: 1H NMR (270 MHz, CDCl3) δ1.75 (m, 2H); 1.92 (m, 1H); 2.17 (m, 1H); 3.53 (m, 2H); 3.72 (m, 1H); 3.86 (s, 3H); 3.93 (s, 3H); 4.19 (m, 1H); 4.43 (m, 1H); 4.77 (d, J=12 Hz, 1H); 4.85 (d, J=12 Hz, 1H); 6.85 (s, 1H); 7.69 (s, 1H); 9.08 (bs, 1H). 13C NMR (67.8 MHz, CDCl3) δ25.1; 28.2; 51.4; 56.0; 56.4; 60.8; 65.9; 74.4; 95.3; 104.7; 110.7; 116.3; 130.8; 144.4; 151.0; 152.1; 170.4. MS: m/e (relative intensity) 454 (M−1, 5), 356 (3), 306 (10), 275 (5), 206 (100), 179 (15), 150 (10), 136 (3), 70 (45). HRMS Calculated for C17H21C13N2O6: 454.0465. Found: 454.0464. [α]25D=−72.2° (c=0.18, CHCl3).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]3[CH3:37])[CH:10]=2)[O:5][C:4]([CH3:39])([CH3:38])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:54]([CH:61]([CH3:63])[CH3:62])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:39][C:4]1([CH3:38])[CH2:3][CH:2]([O:1][Si:54]([CH:61]([CH3:63])[CH3:62])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]3[CH3:37])[CH:10]=2)[O:5]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4′-{[1-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (3.1 g) and 2,6-lutidine (2.1 mL) in dichloromethane (30 mL) was added triisopropylsilyl trifluoromethanesulfonate (3.2 mL), and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (4.1 g, 100%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:33]([C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]=1[O:46][CH3:47])[C:40](O)=[O:41])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:8][N:7]1[C:40](=[O:41])[C:39]1[CH:43]=[C:44]([C:48]([CH3:49])([CH3:50])[CH3:51])[C:45]([O:46][CH3:47])=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:38]=1)=[O:5])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1C(=O)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To the solution of (2S,4S)-4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-pyrrolidine-2-carboxylic acid ethyl ester (32) (0.39 g, 0.88 mmol) in dry CH2Cl2 (20 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.23 g, 0.88 mmol). To the reaction was added EDC (0.34 g, 1.76 mmol) and DMAP (cat), and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 0.46 g of desired product.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13].B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[C:1]1([CH2:7][CH:8]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: SCCCS
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(CC2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 33.9 g (280 mmol) of phenylacetaldehyde and 35.6 g (330 mmol) of 1,3-propanedithiol in 300 mL of methylene chloride at 0° C., was added, dropwise over a period of 30 minutes, 10 mL of boron trifluoride etherate. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h at ambient temperature. The reaction mixture was made basic by the addition of 180 mL of 5% aqueous potassium hydroxide solution and the resultant mixture was stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic extract was washed with 1N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled to afford 53.62 g (91% yield) of the title compound, b.p. 150° C. (2 mm Hg); 1H NMR (CDCl3) δ1.75-1.95 (1H, m), 2.05-2.17 (1H, m), 2.75-2.91 (4H, m), 3.03 (2H, d, J=9 Hz), 4.25 (1H, t, J=9 Hz), 7.17-7.38 (5H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[N+:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:19])=[O:18].C(OC(=O)C)(=O)C>>[CH3:24][O:23][C:21](=[O:22])[C:20]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[CH:3][N:2]([CH3:16])[CH3:1]
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 80.4 %

Procedure:
A mixture of 63.0 g (0.29 mol) of the compound of Example 14 and 35.7 g (0.30 mol) of methyl nitroacetate in 600 ml. of acetic anhydride was heated at 85° for 2 hours. The resulting product was worked up and recrystallized from benzene-DMF (2:1) affording 74.9 g (81%) of product as red orange crystals, m.p. 211°-214°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:36]=[CH:37][CH:38]=2)[CH2:33]1>CN(C)C=O>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:34]=2[CH2:33][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:41][CH2:40]3)[CH2:43][CH2:44]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 4-morpholinobenzoic acid (0.89 g, 4.3 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) in anhydrous N,N-dimethylformamide (30 mL) was added 1,1'-carbonyldiimidazole (0.73 g, 4.3 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (1.0 g, 4.1 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/ concentrated ammonium hydroxide (95:5:0.5) as the eluent gave 1.5 g (85% yield) of the title compound as white crystals: mp 230-231° C.; [α]21D -49° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (10, M+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of N-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (96 mg, 0.22 mmol, Example 71) in CH2Cl2 (3 mL) was added TFA (3 mL). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated and dried in vacuo to yield N-[4-(2-aminoethyl)phenyl]{2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+): 348 (M+H); (ES−): 346 (M−H). Calc'd. for C20H21N5O−347.17.
Reaction SMILES: CS(O[C:6]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[CH3:17][C:15]1[CH:14]=[CH:13][C:7]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:16]=1
Reactant: Cc1ccc(C(C)C(=O)O)c(OS(C)(=O)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(C(C)C(=O)O)cc1

Procedure:
To a solution of 77.5 g. of 2-methane-sulphonyloxy-4-methyl-hydratropic acid in 600 ml. of methanol 84 ml. of triethyl amine and 6 g. of a 5% palladium on charcoal catalyst are obtained, and the mixture is hydrogenated at 25° C. until a calculated amount of hydrogen is used up. Catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the solution is acidified with a 20% aqueous hydrochloric acid solution. The separated 4-methyl-hydratropic acid is extracted with chloroform and the chloroform extract is dried over sodium sulphate. Evaporation of the solution affords 4-methylhydratropic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:29])([CH3:28])[CH2:19][C:20]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:21][OH:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:29])([CH3:28])[CH2:19][C:20]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH:21]=[O:22])=[CH:16][CH:17]=1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
0.674 ml of oxalyl chloride in 16.8 ml of dichloromethane is mixed at −78° C. with 1.15 ml of DMSO in 3.4 ml of dichloromethane. After 5 minutes, 2 g of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol in 6.8 ml of dichloromethane is added in drops at −78° C. After 15 minutes, it is mixed with 4.7 ml of triethylamine and slowly heated to room temperature. It is washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 98:2), 1.07 g of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is obtained as a colorless oil. 300 mg thereof was heated with 194 mg of 5-amino-2-methylquinoline in 9 ml of glacial acetic acid for 4.5 hours to 130° C. After toluene is added, it is concentrated by evaporation in a vacuum. The residue is taken up in methanol and mixed at 0° C. with 153 mg of sodium borohydride. It is allowed to stir for 5 hours at room temperature, and water is added. The batch is concentrated by evaporation in a vacuum, extracted with ethyl acetate, washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 100:0->85:15), 163 mg of the title compound is obtained as a yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:12]([CH3:31])=[N:13][C:14]2[C:19]([N:20]=1)=[C:18]([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)[CH:17]=[CH:16][CH:15]=2.[NH2:32][CH:33]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34]1>CS(C)=O>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][CH:33]([NH:32][C:11]2[C:12]([CH3:31])=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]([C:21]2[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=2)[CH:17]=[CH:16][CH:15]=3)[CH2:34]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CCS(=O)(=O)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCS(=O)(=O)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), (±) 3-amino-tetrahydrothiophene 1,1-dioxide (54.7 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(((±)-1,1-dioxidotetrahydro-3-thiophenyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 11.52-11.67 (m, 1H), 7.80-7.88 (m, 1H), 7.59-7.69 (m, 1H), 7.34-7.41 (m, 1H), 7.25-7.33 (m, 1H), 6.98-7.07 (m, 1H), 6.85-6.98 (m, 1H), 4.91-5.02 (m, 1H), 3.61-3.72 (m, 2H), 3.39-3.49 (m, 3H), 3.21-3.28 (m, 1H), 2.87-2.97 (m, 2H), 2.65-2.74 (m, 1H), 2.55-2.60 (m, 3H), 2.25-2.40 (m, 1H). m/z (ESI, +ve) 412.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O>[CH3:20][CH:19]([O:18][C:17]1[C:8]([O:7][CH2:24][CH:23]=[CH2:22])=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:21]
Reactant: COC(=O)c1cccc(OC(C)C)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(OC(C)C)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Cesium carbonate (2.05 g, 6.2 mmol) was added to a solution of methyl 2-hydroxy-3-(propan-2-yloxy)benzoate (123c, 539 mg, 2.40 mmol) in N,N-dimethylformamide (9.6 mL), causing a thick paste to form. Allyl bromide (0.25 mL, 3.0 mmol) was added and the mixture stirred at room temperature for 1.5 hours. Deionized water (15 mL) was added, and the solution extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (ethyl acetate/heptane) to give methyl 3-(propan-2-yloxy)-2-(prop-2-en-1-yloxy)benzoate (123d, 474.5 mg, 79% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[CH2:13][C@H:12]1[C:26](O)=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>N1C=CC=CC=1>[CH3:40][C:37]([O:36][C:34]([C:33]1[CH:41]=[CH:42][C:30]([NH:29][C:26]([C@@H:12]2[CH2:13][C@H:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)[CH2:15][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:27])=[CH:31][CH:32]=1)=[O:35])([CH3:38])[CH3:39]
Reactant: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
To a solution of the compound prepared in Example 4 (0.20 g, 0.40 mmol) and 2-methyl-2-propanyl 4-aminobenzoate (0.154 g, 0.80 mmol) in pyridine (50 mL) was added 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.630 mg 3.2 mmol) at 0° C. The reaction was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the resulting residue diluted with dichloromethane (20 mL). This solution was washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 40 g, 20-80% ethyl acetate/hexanes) gave the title compound (0.185 g, 65%) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:12][S:13]([C:16]1[CH:21]=[C:20]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-c2cccc(S(C)(=O)=O)c2)n1
Yield: 47.7 %

Procedure:
Ethyl 2-bromothiazole-4-carboxylate (1 g), 3-(methylsulphonyl)phenyl-boronic acid (1.02 g, 1.2 equivalents) and potassium carbonate (1.76 g) are introduced in dioxane (12.5 ml). (1,3-Diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride (288 mg) is added, and the mixture is stirred under reflux under protective gas for 18 h. Dioxane is then removed in a rotary evaporator, and the residue is taken up in ethyl acetate and water. The organic phase is separated off and the aqueous phase is back-extracted twice with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate and concentrated. Purification by column chromatography on silica gel (ethyl acetate/hexane) results in a white solid (629 mg).
Reaction SMILES: I[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][CH:37]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)nc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.050 g; 0.106 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.044 g; 0.317 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g; 0.010 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.046 g; 0.211 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (10-80%) in heptane furnished 0.025 g (54%) of the title compound as a light yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH2:7][C:8]1[CH:9]=[NH+:10][CH:11]=[CH:12][CH:13]=1>>[ClH:3].[Cl:5][CH2:7][C:8]1[CH:9]=[NH+:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc[nH+]c1
Agent: Cl
Product: ClCc1ccc[nH+]c1

Procedure:
reacting thionyl chloride with 3-hydroxymethyl pyridinium hydrochloride to form 3-chloromethyl pyridinium hydrochloride, at least a portion of which forms as a solid in the reaction mixture.
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15](NC)[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH2:25])=O.[CH:26](OCCCC)=O>>[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:26][NH:25][CH3:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CNC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CCCCOC=O
Agent: Cl
Product: CNCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 1.5 h
Yield: 60 %

Procedure:
114 mg (0.376 mmol) of -(7-Benzenesulfonyl-chroman-4-yl)-methylamine HCl salt was dissolved in excess butyl formate and heated to reflux for 15 minutes. The resulting formamide was cooled to room temperature, concentrated, the residue dissloved in 3 mL THF and then reduced by adding 5 μL (1.5 eq., 0.563 mmol) of 10M BH3.DMS complex. The mixture was stirred for 1.5 h and quenched with methanol, partitioned between ethyl acetate and water, dried, concentrated and treated with 2 N HCl/EtOH and ether to provide 80 mg (60%) of (7-benzenesulfonyl-chroman-4-ylmethyl)-methyl-amine as the HCl salt, MS: 318 (M+H).