Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:32])[CH2:12][O:11][S:10](=[O:14])(=[O:13])[N:9]1[CH:15](C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1(C)COS(=O)N1C)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1([CH3:32])[CH2:12][O:11][S:10](=[O:13])(=[O:14])[N:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2C(C)(C(=O)OC(C)(C)C)COS2(=O)=O)cc1
Agent: CN1S(=O)OCC1(C)C(=O)OC(C)(C)C
Product: CN1C(C)(C(=O)OC(C)(C)C)COS1(=O)=O
Yield: 94 %

Procedure:
The same reaction conditions used to obtain 14a were applied to 42 mg of 13b (0.18 mmol), providing 14b (42 mg, 94%) as a white solid: mp 54-55° C. (EtOAc/hexane); 1H NMR (CDCl3) δ1.50 (9H, s), 1.52 (3H, s), 2.93 (3H, s), 4.22 (1H, d, J=8.8), 4.88 (1H, d, J=8.8). Anal. (C9H17NO5S) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:5]([CH3:8])([CH3:6])[CH3:4])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Reaction time: 12 h
Yield: 116.9 %

Procedure:
2-(4-hydroxyphenyl)acetic acid (1.0 g, 6.57 mmol) was diluted with THF (4 mL) followed by the addition of Reactant 2 (2.63 g, 13.1 mmol). The reaction was stirred for hours 12 hours. The reaction was filtered and loaded directly onto a biotage 40M cartridge eluting with hexanes:ethyl acetate (3:1) to yield tert-butyl 2-(4-hydroxyphenyl)acetate (800 mg, 58.4% yield) as a clear oil that later solidified to a white solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:26][C:27]([C:29]1[NH:30]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)[CH:33]=1)=O.N[C@H](CO)C>>[OH:26][CH2:27][C@@H:29]([NH:30][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:33]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)nn1C
Agent: C[C@H](N)CO
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)N[C@@H](C)CO)n(C)n1
Yield: 89 %

Procedure:
As described for example 6, 2-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (90 mg, 0.27 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using L-alaninol instead of ethanolamine, to the title compound (91 mg, 89%) which was obtained as a colorless oil. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCc4cc(OC)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylate (118 mg, 0.28 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (55.6 mg, 1.39 mmol, 5.00 equiv) in water (2 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with of H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 75% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 57 mg (40%) of 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylic acid as a orange solid.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:13]2[C@H:8]([C:9]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Sn](Cl)(Cl)(Cl)Cl>CO>[CH2:1]([N:4]1[C@@H:13]2[C@H:8]([C:9]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC[C@H]2c3ccc([N+](=O)[O-])cc3CC[C@@H]21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: C=CCN1CCC[C@H]2c3ccc(N)cc3CC[C@@H]21
Yield: 46.3 %

Procedure:
(4aS,10bS)-4-Allyl-8-nitro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (0.85 g, 3.12 mmol) was dissolved in MeOH (50 mL) and tin chloride (3.50 g, 15.5 mmol) added. The solution was heated to reflux for 3 h and then evaporated. The residue was partitioned between ethyl acetate and NaOH (2M), and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by preparative HPLC (20-90% MeOH) to give the 3 amino isomers. The product was obtained as a yellow oil (0.35 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH3:35][NH:36][CH3:37]>>[CH3:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5]([N:36]([CH3:37])[CH3:35])=[N:6][CH:7]=1
Reactant: CNC
Reactant: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(S(C)(=O)=O)ncc2C)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(N(C)C)ncc2C)c1

Procedure:
This was prepared in the same manner as the product of example 244, using the sulfone from example 253 and dimethylamine as the amine, to give the title compound as a foam, 0.14 g, (74%).
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])=[CH:6][CH:7]=2)=[O:32])=[CH:29][CH:28]=1)=[O:26]
Reactant: Nc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)Nc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
Commercially available 4-formylbenzoic acid (5.0 g, 33.3 mmol) was dissolved in a mixture of anhydrous tetrahydrofuran (100 ml) and anhydrous N,N-dimethylformamide (1 ml) and the mixture was cooled with stirring to 0° C. To the resulting mixture was added dropwise oxalyl chloride (3.8 ml, 43.3 mmol). The mixture was stirred at room temperature for 30 minutes and then at 40° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure and then in vacuo to afford 4-formylbenzoyl chloride. 4-(2,2,3,3-Tetrafluoropropoxy)aniline (646 mg, 2.9 mmol), described in Chem. Pharm. Bull., 44 (2), 314 (1996), and N,N-diisopropylethylamine (1.21 ml, 7.0 mmol) were dissolved in anhydrous tetrahydrofuran (8 ml) and the mixture was cooled to 0° C. with stirring. To the resulting mixture was added dropwise a solution of 4-formylbenzoyl chloride (561 mg, 3.33 mmol) obtained above in anhydrous tetrahydrofuran (2 ml). This mixture was stirred at room temperature for 17 hours and then at 40° C. for 20 minutes. At the end of this time, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture in an ice bath and the mixture was partitioned between ethyl acetate and water. The organic layer was washed sequentially with 0.5N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-formyl-4′-(2,2,3,3-tetrafluoropropoxy)benzanilide (634 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].C1CCN2C(=NCCC2)CC1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][C:37](=O)[O:38]CC)=[N:28]1>CS(C)=O>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][C:37]([N:7]2[CH2:6][CH2:5][C:4]([C:2]#[N:3])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)=[O:38])=[N:28]1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC1(c2ccccc2)CCN(C(=O)Nc2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
4-Cyano-4-phenylpiperidine hydrochloride (Aldrich Co., 217 mg) was dissolved in dimethyl sulfoxide (3 ml) and DBU (0.16 ml) was added thereto. The mixture was stirred at room temperature for 30 min, and ethyl 1H-indazol-3-ylcarbamate (200 mg) and potassium fluoride-alumina (40 wt %, 200 mg) were added to the mixture. By the following operation as in Example 1, 4-cyano-4-phenyl-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide (253 mg, yield 75%) was obtained.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([N:21]([CH3:34])[C:22]3[N:27]=[C:26]([S:28][C:29]#[N:30])[C:25]([N+:31]([O-])=O)=[CH:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].CN1CCCC1=O.Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:29]1[S:28][C:26]2[N:27]=[C:22]([N:21]([CH3:34])[C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:20]=[CH:19][CH:18]=3)[N:23]=[CH:24][C:25]=2[N:31]=1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the above-mentioned crude product of 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl](methyl)amino}-5-nitropyrimidin-4-yl thiocyanate and reduced iron (368 mg, 6.59 mmol) in ethanol (8 mL)/1-methylpyrrolidin-2-one (2 mL) was added 1N hydrochloric acid (2 mL), and the mixture was stirred at 100° C. for 30 min. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution (1.5 mL), the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 2×20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (211 mg, 36%) as pale-purple crystals.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:33][CH3:34])=[C:29](O)[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[C:19]([F:37])[CH:18]=1>N1C=CC=CC=1>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:33][CH3:34])=[C:29]([O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[C:19]([F:37])[CH:18]=1
Reactant: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Triflic anhydride (620 mg, 2.2 mmol) was added to 4-(4-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinoline (637 mg, 2 mmol) in pyridine (6 ml) at 0° C. over 5 minutes. The mixture was stirred 1 hour and left to warm up to ambient temperature. The volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and water containing 1M hydrochloric acid. The organic layer was dried (MgSO4), insoluble materials were removed by filtration and the volatiles were removed by evaporation. The resulting crude oil was purified by flash chromatography eluting with ethyl acetate/isohexanes (1/9 increasing to 9/1). The volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-trifluoromethylsulphonyloxyquinoline (560 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1>CC(C)=O>[C:3]([O:2][CH2:1][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1)(=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(CO)ccc1O
Reactant: CCCCCCCCCC(=O)OC
Solvent: CC(C)=O
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
This compound was synthesized by the method described in Kobata et al. (Biosci. Biotechnol. Biochem., 66(2), 319-327, 2002). Decanoic acid methyl ester (2.13 mL, 10.5 mmol), vanillyl alcohol (1.62 g, 10.5 mmol), molecular sheaves 4 Å (10 g), and Novozyme 435 (2.5 g) were added to acetone (50 mL) and stirred for 2 hours at room temperature. The reaction solution was filtered through cellite and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography, yielding 2.25 g (7.30 mmol, 73.0 percent) of vanillyl decanoate in the form of a colorless oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH:32]1([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[CH:32]1([CH2:36][O:37][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:35][CH2:34][CH2:33]1
Reactant: OCC1CCC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOCC4CCC4)CC3)c[nH]c12
Yield: 12.6 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), cyclobutylmethanol (86 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (5.6 mg, 12.6%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CCl)cn1
Yield: 125.6 %

Procedure:
To a stirred solution of (6-methyl-3-pyridinyl)methanol (166 mg, 1.35 mmol) in dichloromethane (10 ml) was added thionyl chloride (108 μl, 1.48 mmol) giving a colourless solution. After 30 minutes the mixture was concentrated giving a brown solid (240 mg, quant. yield) that was used directly in the next step without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[CH:26](N(C)C)[N:27]([CH3:29])[CH3:28])(C)(C)C>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[O:14])/[C:12](=[CH:26]\[N:27]([CH3:29])[CH3:28])/[CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(c2ccccc2)C1
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC(c2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 185.9 %

Procedure:
A mixture of 1-boc-3-phenyl-piperidin-4-one (100 mg, 0.35 mmol) and tert.-butoxy-bis(dimethylamino)methane (94 mg, 0.48 mmol) was stirred at 110° C. for 2 hours. The reaction was evaporated to dryness, treated twice with toluene and evaporated under reduced pressure to dryness to yield the title compound (215 mg, 188%) as a brown oil which was used directly in the next step without further purification. MS ISP (m/e): 331.4 (79) [(M+H)+], 275.1 (100) [(M-isubutene +H)+].
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[C:7]1[C:23](=[O:25])[CH3:24])([O:3][CH2:4][CH3:5])=[O:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH:7]1[C:23](=[O:25])[CH3:24])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)n1c(C(C)=O)c(CCNC(C)=O)c2cc(OC)ccc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)cc2C(CCNC(C)=O)C1C(C)=O

Procedure:
The product N-[2-(1-carbethoxy-2-acetyl-5-methoxyindol-3-yl)ethyl]acetamide (100 mg) is dissolved in ethanol (10 ml) in a round-bottomed flask (25 ml), 100 mg of Pd(OH)2 are added and the mixture is stirred for 12 h at a normal pressure of hydrogen. After filtration, N-[2-(1-carbethoxy-2-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([CH3:13])[CH:15]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CNCCC#Cc1ccccn1
Product: Cc1cccc(C(=O)N(C)CCC#Cc2ccccn2)c1
Yield: 29 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3-methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 25 mg of N,3-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a yellow pale oil (Yield: 29%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15](O)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[BH4-].[Na+].Cl>C1COCC1.C(OC(Cl)=O)C.O>[CH2:1]([N:8]1[CH:9]([CH2:15][OH:16])[CH2:10][O:11][CH2:12][C:13]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1COCC(=O)N1Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C1COCC(CO)N1Cc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a stirred solution of 4-benzyl-5-oxomorpholine-3-carboxylic acid (450 mg, 1.91 mmole) and triethylamine (0.28 mL, 2.5 mmole) in THF, ethylchloroformate (0.2 mL) was added dropwise for 20 min at −10° C. The reaction mixture was stirred for additional 30 min and filtered. The filtrate was added for 30 min to a solution of NaBH4 (200 mg, 5.28 mmole) in water (15 mL) at 0° C. The reaction mixture was stirred for 4 h at 10° C. and acidified with 2M HCl. THF was evaporated under reduced pressure and the aqueous residue extracted into DCM, washed with saturated NaHCO3 (20 mL), dried over Na2SO4, concentrated and purified by flash chromatography using eluent 5% MeOH in DCM to get the title compound (170 mg) as oily mass, m/z 222.
Reaction SMILES: [F:1]/[C:2](/[S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])=[CH:3]\[CH2:4][OH:5].N1C=CC=CC=1.[CH:20](OC(=O)C)=[O:21]>O>[CH:20]([O:5][CH2:4]/[CH:3]=[C:2](\[F:1])/[S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])=[O:21]
Reactant: CC(=O)OC=O
Reactant: CCCCCCS(=O)/C(F)=C/CO
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCS(=O)/C(F)=C/COC=O

Procedure:
To a mixture of (E)-3-fluoro-3-hexylsulfinyl-2-propenol (0.21 g, 1.0 mmol) and 2 ml of pyridine cooled to -30° is added through syringe acetic-formic anhydride (0.4 ml). The mixture is allowed to warm to 10° over a period of 1 hour. It is then diluted with water, extracted with hexane, washed with aqueous 2N H2S04, then water, then aqueous NaHCO3, finally brine and is dried. The product is purified by prep. TLC to give (E)-3-fluoro-3-hexylsulfinyl-2-propenyl formate (cpd. 3, Table A).
Reaction SMILES: [C:1]1(=[O:11])[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:10]=[C:2]12.Br[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1>>[N+:19]([C:16]1[N:17]=[CH:18][C:13]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]3[C:1]2=[O:11])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=C1NCCN2CCCC=C12
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: O=C1C2CCCCN2CCN1c1ccc([N+](=O)[O-])nc1
Yield: 80.6 %

Procedure:
Following general N—C coupling procedure 1, hexahydro-pyrido[1,2-a]pyrazin-1-one (0.300 g, 1.945 mmol), was combined with 5-bromo-2-nitropyridine (0.395 g, 1.945 mmol, 1.0 eq), and gave 2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.481 g, 1.567 mmol) in 81% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.27-1.53 (m, 2H) 1.54-1.61 (m, 4H) 1.66-1.81 (m, 1H) 1.94 (d, J=12.55 Hz, 1H) 2.22 (td, J=11.80, 3.01 Hz, 1H) 2.39 (d, J=12.55 Hz, 1H) 2.68-2.83 (m, 2H) 2.96-3.12 (m, 2H) 3.49 (d, J=3.51 Hz, 1H) 3.56 (dd, J=10.79, 2.26 Hz, 1H) 4.16 (td, J=11.29, 4.52 Hz, 1H) 8.13 (dd, J=8.53, 2.51 Hz, 1H) 8.29 (d, J=8.53 Hz, 1H) 8.68 (d, J=2.51 Hz, 1H); MS m/z 277.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:9]=1[S:19](=[O:22])(=[O:21])[NH2:20])=O.[OH-].[Na+].Cl>>[CH3:18][S:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:5]([CH2:4][C:3]([OH:2])=[O:23])=[N:20][S:19](=[O:22])(=[O:21])[C:9]=2[CH:10]=1)(=[O:17])=[O:16]
Reactant: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 100 °C
Reaction time: 21 h
Yield: 92.6 %

Procedure:
N-(4-Methanesulfonylamino-2-sulfamoylphenyl)-malonamic acid methyl ester (prepared as described in Example 1i, 21.75 g, 59.53 mmol) was dissolved in an aqueous solution of sodium hydroxide (7.14 g, 178.5 mmol; dissolved in 180 mL water) at 25° C. The reaction mixture was heated to 100° C. for 1 h, then was gradually cooled over 30 min to 0° C. 12.0 M Aqueous hydrochloric acid solution (20 mL, 240 mmol) was added dropwise over 10 min via addition funnel resulting in the formation of a tan precipitate. The mixture was allowed to warm to 25° C. and was stirred at that temperature for 21 h. The precipitate was collected by filtration, washed with water (150 mL), and was dried in a vacuum oven at 45° C. for 22 h to afford (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (18.36 g, 55.1 mmol, 93%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.03 (3H, s), 3.56 (2H, s), 7.32-7.34 (1H, m), 7.51-7.54 (2H, m), 10.09 (1H, s), 12.26 (1H, s), 13.01 (1H, bs). LC-MS (ESI) calcd for C10H11N3O6S2 333.01, found 334.1 [M+H+].