Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c(=O)n1C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(Cl)cc(C(=O)NCC2CCNCC2)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of tert-butyl 4-({[(5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate as prepared in 6(1) (4.77 g, 11.2 mmol) in 10% hydrochloric acid methanol solution (30 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo. The residue was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL). To the resulting solution was added potassium carbonate (3.0 g, 21.7 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was filtered through a pad of Celite, washed with methanol/tetrahydrofuran (v/v=1/1, 200 mL). The filtrate was concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (v/v/v=10/1/0.2) to give 3.43 g (94%) of the title compound as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: O=C(C1CCCc2c1c1ccccc1n2CCOCc1ccccc1)N1CCCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(C1CCCc2c1c1ccccc1n2CCO)N1CCCCC1
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a solution of [9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (22) (600 mg, 1.4 mmol) in methanol (15 mL) was added a slurry of Pd/C (200 mg) in methanol (10 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo. The crude material was triturated to afford 332 mg (71%) of [9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (23) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 21.2, 21.9, 24.7, 27.4, 36.4, 43.4, 45.0, 47.0, 60.9, 107.8, 109.0, 117.7, 119.0, 120.7, 126.6, 136.2, 137.2, 173.5
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][C:10]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O)C.C([BH3-])#N.[Na+]>C1COCC1.O>[C:1]1([CH2:7][NH:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CCC2(C1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CC2(CCC1NCc1ccccc1)OCCO2
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Ethyl 8-[(phenylmethyl)amino]-1,4-dioxaspiro-[4.5]-dec-7-ene-7-carboxylate (395.4 g, 1.3 mole) and acetic acid (75.0 ml, 1.3 mole) were added to ethanol (4 l). Sodium cyanoborohydride (82.0 g, 1.3 mole) was added in portions over 3 hours. The mixture was stirred overnight, then poured into water. The pH was adjusted to 10, and the product was extracted with methylene chloride, which was then dried with sodium sulfate and evaporated to give a yellow oil having small clear lumps in it. This was dissolved in THF and poured through 3 inches of basic alumina, which was then rinsed well with THF. The filtrate was evaporated to give 397.2 g (99.9%) of the title product as a yellow-green oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[CH3:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1>>[CH3:22][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3][C:2]([N:33]4[C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=[C:32]4[CH3:31])=[N:7][C:6]=3[C:8]=2[CH3:24])[CH2:13][CH2:14]1)([CH3:23])[C:19]([NH2:21])=[O:20]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cc1c(CN2CCN(C(C)(C)C(N)=O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(C)(C)C(N)=O)CC2)sc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc12

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide and 2-methyl-1H-benzo[d]imidazole were reacted to give 230. LCMS: M+H+=549.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]([CH3:11])[C:9]#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH:6]=1
Reactant: CC(Cl)C#N
Reactant: Fc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C#N)n1cc(F)cn1
Temperature: 100 °C
Yield: 82 %

Procedure:
4-Fluoro-1H-pyrazole (300 mg, 3.49 mmol), 2-chloropropanenitrile (374 mg, 4.18 mmol), cesium carbonate (1.84 g, 5.23 mmol) and anhydrous acetonitrile (5.0 mL) were added into a round bottom flask. The reaction mixture was heated to 100° C. for 2 h. Water was added and the mixture was extracted with ether (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford 2-(4-Fluoro-1H-pyrazol-1-yl)propanenitrile (398 mg, 82%). MS (EI+) (M+) 139, GCMS retention time: 0.78 min (Method O).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:21])[O:6][C:7]2[C:14]([O:15][CH2:16][CH3:17])=[C:13]([O:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:19]([O:18][C:13]1[CH:12]=[CH:11][C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:5](=[O:21])[O:6][C:7]=2[C:14]=1[O:15][CH2:16][CH3:17])[CH3:20]
Reactant: CCOc1ccc2c(C)c(CCCl)c(=O)oc2c1OCC
Reactant: COc1ccccc1N1CCNCC1
Product: CCOc1ccc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1OCC
Yield: 13 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-7,8-diethoxy-4-methyl-2H-1-benzopyran-2-one (Example 33) and 1-(2-methoxyphenyl)piperazine; yield 13% of crude product.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>C(C1CCNCC1)C1C=CC=CC=1.C(O)C>[CH2:6]([CH:9]1[CH2:14][CH2:26][N:23]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:22][CH2:10]1)[C:5]1[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: c1ccc(CC2CCNCC2)cc1
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-benzylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=461.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C[N:9](C)[CH2:10][CH2:11][NH2:12].CN1CCOCC1>ClCCl>[CH:3]([CH2:2][C:1]([NH:9][CH2:10][CH2:11][NH2:12])=[O:6])([CH3:5])[CH3:4]
Reactant: CN(C)CCN
Reactant: CC(C)CC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC(=O)NCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Isovaleroyl chloride (5 g, 38 mmole) in dichloromethane was added dropwise to a stirred solution of N,N-dimethylethylene diamine (3,38 g, 38 mmole) and NMM (7.75 g, 76.7 mmoles) in CH2Cl2 at 0° C. The reaction mixture was stirred at room temperature for four hours when the solvent was evaporated. The residue was taken up in 5 M NaOH (50 ml) and extracted with ethyl acetate (2×100 ml). The ethyl acetate was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4) and evaporated. The residue was dissolved in diethyl ether and 5 M HCl in ethyl acetate (10 ml) added. The resulting solid was filtered, washed with diethyl ether (5+10 ml) and dried under high vacuum.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:13]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:20]=1)[CH3:12]
Reactant: CCOc1ccc(N)cc1
Reactant: Oc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCOc1ccc(Nc2cccc3ccccc23)cc1
Temperature: 220 °C
Yield: 97 %

Procedure:
288 parts of α-naphthol, 411 parts of p-phenetidine and 10 parts of triphenyl phosphite are mixed and heated to 220° C. At this temperature, the elimination of water commences. In the course of 8 hours, the reaction temperature rises to 250° C, at which stage the reaction has ended. 36 parts of water are removed. After removing excess p-phenetidine, N-p-ethoxy-phenyl-α-naphthylamine distils at a boiling point of 233° - 235° C/5 mm Hg. 510 parts of end product of melting point 73° - 75° C are obtained. This corresponds to a yield of 97% of theory.
Reaction SMILES: O[CH2:2][C@H:3]([NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:14]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].C(NS([N+](CC)(CC)CC)(=O)=O)(OC)=O>C1COCC1.O>[CH3:18][C:16]1[N:15]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:14]=[C:13]([C:11]2[O:12][CH2:2][CH:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:17]=1
Reactant: Cc1ccc(Cn2nc(C(=O)N[C@@H](CO)c3ccccc3)cc2C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cn2nc(C3=NC(c4ccccc4)CO3)cc2C)cc1
Temperature: 70 °C
Yield: 69.4 %

Procedure:
A mixture of N-[(1R)-2-hydroxy-1-phenylethyl]-5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxamide (Step 1, 350 mg, 1.0 mmol) and carbomethoxysulfamoyltriethylammonium hydroxide inner salt (Burgess' reagent, 310 mg, 1.03 mmol) in THF (20 mL) was heated at 70° C. for 1 h. After being cooled to rt, the mixture was diluted with water (10 mL), and the organic phase was extracted with ethyl acetate (1×25 mL), washed with brine (1×25 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 20% EtOAc in hexanes to afford the title compound as a yellow oil (230 mg, 69%): 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.34 (m, 2H), 7.24-7.28 (m, 3H), 7.12 (d, 2H), 7.01 (d, 2H), 6.52 (s, 1H), 5.27-5.32 (m, 1H), 5.29 (s, 2H), 4.69-4.75 (m, 1H), 4.06-4.12 (m, 1H), 2.25 (s, 3H), 2.22 (s, 3H); ES-MS m/z 332.20, HPLC RT (Method B) 3.20 min.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.O.NN>C(O)C>[F:29][C:2]([F:1])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][NH2:16])[N:8]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 60.1 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-(2-phthalimidoethylthio)pyrimidine (0.6 g.) ethanol (20 ml.) and 99% hydrazine hydrate (0.5 ml.) was heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N hydrochloric acid and the mixture filtered. The filtrate was basified with 17 N NaOH and the mixture extracted three times with ether. The combined ether extracts were dried and then evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrimidine (0.25 g.) which was used without further purification.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].Cl.CN(C)CCCN=C=NCC.[C:20](O)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a stirring solution of 1.71 g (14.75 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 2.22 ML (17.2 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-dimethylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4.96 g (17.7 mmol) of linoleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is recrystallized from pentane at -78° C. to give a solid which melts upon warming to room temperature giving 1.67 g (30%) of 4-hydroxy-3-[(Z,Z)-1-oxo-9,12-octadecadienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:40]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCO2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=489.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][S:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19](O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.[C:29]([O:33][CH3:34])(=[O:32])[CH2:30][SH:31]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:13][S:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])=[CH:17][CH:16]=1
Reactant: CSc1ccc(C(O)c2ccccc2)cc1
Reactant: COC(=O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CSC(c1ccccc1)c1ccc(SC)cc1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of ρ-toluenesulfonic acid monohydrate (50 mg, 0.3 mmol) in 10 mL of toluene, which contains 300-500 mg of activated 3 Å molecular sieves, is added 4-methylthiobenzhydrol (0.30 g, 1.3 mmol) and methyl thioglycolate (140 μL, 1.6 mmol), and the reaction is stirred for 2 hours. The reaction is diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water, followed by brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is chromatographed on silica gel eluting with ethyl acetate:toluene:hexane (2:18:80) to give 0.23 g (56%) of methyl [[(4-methylthiophenyl)phenylmethyl]thio]acetate as an oil.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH3:16])[C:6]=1[F:17].C(OCC)(=O)C.N>CN(C)C=O>[CH2:15]([O:14][C:7]1[C:6]([F:17])=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[C:2]#[N:3])[CH3:16]
Reactant: CCOc1ccc(Br)c(F)c1OCC
Reactant: N#C[Cu]
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C#N)c(F)c1OCC
Temperature: 155 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Copper(I)cyanide (6.8 g, 68.3 mmol) was added to a solution of 1-bromo-3,4-diethoxy-2-fluorobenzene (12.0 g, 45.6 mmol) in N,N-dimethylformamide (DMF) (60 mL) at room temperature, and this was then stirred at 155° C. for 3 hours. The reaction solution was cooled on ice. Following addition of ethyl acetate and 28% aqueous ammonia, the organic layer was separated and washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed after filtration, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 9.0 g of the subject compound (yield: 94.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([OH:31])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([N:40]2[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][CH2:39]2)=[O:31])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCN(S(C)(=O)=O)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid and 1-methanesulfonyl-piperazine hydrochloride. White solid. MS (m/z): 576.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 120 °C
Yield: 11.5 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added ethanesulfonyl chloride (19 μl, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (3 mg, 11%). 1H NMR (300 MHz, DMSO-d6): δ 0.98 (d, J=6.62 Hz, 6 H) 1.22 (t, J=7.35 Hz, 3 H) 1.58 (m, 2 H) 1.70 (m, 1 H) 3.20 (q, J=7.35 Hz, 2 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.65 (d, J=2.57 Hz, 1 H) 7.74 (d, J=9.19 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.35 (s, 1 H) 14.15 (s, 1 H). MS (ESI−) m/z 518 (M−H)−.
Reaction SMILES: [OH:1][C:2]1([CH2:19][OH:20])[C:6](=[O:7])[O:5][C@H:4]2[C:8]3[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]12[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=3[CH3:17].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:20][CH2:19][C:2]2([OH:1])[C:6](=[O:7])[O:5][C@H:4]3[C:8]4[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]23[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=4[CH3:17])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(CO)C3(O)CC[C@@]2(C)CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Reaction time: 72 h

Procedure:
Compound of example 2 (126.6 mg, 0.449 mmol) was dissolved in dichloromethane (5 mL). Tosyl chloride (427.9 mg, 2.24 mmole), pyridine (355.05 mg, 4.48 mmole) and DMAP (2 mg) were added to this solution and reaction mixture was stirred for 72 hours. Reaction mixture was extracted with dichloromethane (5 mL). Dichloromethane was removed and crude product was purified by column chromatography (silica gel, 5-10% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][OH:32])=[CH:24][N:23]=1.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][O:32][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][N:23]=1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCc1cnc(C)c(O)c1C=O

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoyl chloride (800 mg, 2.7 mmol) in methylene chloride (10 ml) was added slowly dropwise to a mixture of pyridoxal hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol) and 4-(N,N-dimethylamino)pyridine (few mg, catalytic amount) in methylene chloride (20 ml) at 0° C. under nitrogen. On completion, as indicated by tlc, the mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane), yielding 2-methyl-3-hydroxy-4-formyl-5-(z,z,z-octadeca-6,9,12-trienoyloxy)methyl pyridine as a colourless oil which subsequently solidified.