Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:19][O-:20].[Na+]>S1(CCCC1)(=O)=O.O>[CH3:19][O:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccc2ccnc(Nc3nc(C)cs3)c2n1
Temperature: 100 °C
Yield: 78.9 %

Procedure:
To a solution of (2-chloro-[1,7]naphthyridin-8-yl)-(4-methyl-thiazol-2-yl)-amine (0.055 g, 0.20 mmol) in 1.5 ml sulfolane was added g sodium methylate (0.55, 1.0 mmol). The reaction mixture was heated for 10 min at 100° C. under microwave irradiation. The reaction mixture was diluted with water and extracted with three portions of methyl-tert.-butyl ether. The combined organic layers were washed with two portions of water, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (0.043 g, 79%) as an off-white solid, MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1COCC1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: CN(C)CCN
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Reaction time: 18 h
Yield: 15.8 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (500 mg, 1.79 mmol) and 2-dimethylaminoethylamine (316 mg, 3.58 mmol) in THF (35 ml) was stirred in an ice bath for 1 hour then at 20-25° for 18 hours. After removing THF under reduced pressure, the residue was partitioned between saturated Na2CO3 solution and EtOAc. The organic extract was washed (saturated NaCl solution), dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography over silica gel (elution with 5% MeOH-95% CHCl3) gave an oil which when triturated with EtOAc afforded 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoic acid (90 mg, 16%), m.p. 193° decomposed with effervescence.
Reaction SMILES: C[C:2]([OH:5])([CH3:4])[CH3:3].C(#N)C.[CH3:9][O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=C(C=C)[CH:23]=3)[CH:18]=[N:17]2)=[CH:13][CH:12]=1.CCCCCC.CC[O:37]CC>O>[CH3:9][O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:3]([C@H:2]([OH:5])[CH2:4][OH:37])[CH:23]=3)[CH:18]=[N:17]2)=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc2cnn(Cc3ccc(OC)cc3)c2c1
Solvent: CC#N
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(Cn2ncc3ccc([C@H](O)CO)cc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
A mixture of tBuOH (10 mL), H2O (10 mL), ACN (1.8 mL) and ADmix-α (1.28 g) was stirred for 5 min at room temperature and then cooled to 0° C. at which time 1-(4-methoxybenzyl)-6-vinyl-1H-indazole (320 mg, 1.21 mmol) was added. The reaction was stirred for 18 h and allowed to warm to room temperature. The reaction was then diluted with H2O (25 mL) and extracted 3× with CH2Cl2. The organic layer was separated, washed with brine, dried over MgSO4 and the solvent removed to give a white solid which was sonicated with hexane/Et2O (1:1) and then filtered to give the title compound (270 mg, 75% after drying); 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.58 (s, 1H), 7.19-7.13 (m, 3H), 6.82 (d, J=8.4 Hz, 2H), 5.56 (s, 2H), 4.82-4.79 (m, 1H), 3.73 (s, 3H), 3.69-3.59 (m, 2H); MS ESI 298.9 [M+H]+, calcd for [C17H18N2O3+H]+ 299.14.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[CH2:13]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:28])[CH:25](O)[OH:26])[CH2:20][CH2:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>O>[F:1][C:2]([F:11])([F:12])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[O:26][CH2:25][CH:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)[CH2:28][O:10]2)[CH2:7][CH2:8]1
Reactant: CCCCC[C@H]1CC[C@H](C(C)C(O)O)CC1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](C2COC([C@H]3CC[C@H](C(F)(F)F)CC3)OC2)CC1

Procedure:
A mixture of 0.02 mol of tras-4-trifluoromethyl-1-formylcyclohexane (prepared as in Example 3), 0.02 mol of 2-(trans-4-pentylcyclohexyl)propanediol (prepared as in DE 3,227,916), 30 ml of toluene and 0.5 g of pTSOH is heated for 6 hours on a water separator. The product is obtained after customary work-up and crystallization.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
(2.15 ml, 16.8 mmol) Dibenzylamine was dissolved in acetonitrile (30 ml). Potassium carbonate (2.3 g, 16.8 mmol, 1.5 equiv.) and 1-bromo-3,3-dimethylbutan-2-one (1.5 ml, 11.2 mmol, 1.0 equiv.) were added and the mixture was stirred for 16 hours at 90° C. The reaction mixture was extracted with sat. NaHCO3-solution and two times EtOAc. The organic layers were extracted with water, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (70 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(dibenzylamino)-3,3-dimethylbutan-2-one (1.6 g, 48.5% yield) was obtained as a yellow oil, MS: m/e=296.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19]O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:33][C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([CH2:19][S:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:12][CH2:13][CH2:14][O:15]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCC1(CCOc2ccnc(CO)c2C)OCCO1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCCO1
Reaction time: 0.83 h
Yield: 79.8 %

Procedure:
The (3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl)methanol (450 mg, 1.6 mmol) obtained in the step (3e) was mixed with tetrahydrofuran (10 ml). The mixture was cooled on ice in a nitrogen atmosphere. To this, triethylamine (0.446 ml, 3.2 mmol), and methanesulfonyl chloride (0.186 ml, 2.4 mmol) were added and stirred for 50 minutes under ice-cooling. To the reaction mixture, 2-mercaptobenzimidazole (240 mg, 1.6 mmol) was added and stirred at room temperature overnight. To the reaction mixture, an aqueous solution of sodium hydrogen carbonate was added and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. After silica gel was added to the solution, the solution was concentrated. The dried residue was subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (528 mg, 79.8%) as a colorless viscous oil.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH2:52]>CN(C=O)C.C(OCC)(=O)C>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]=[CH2:44])[CH2:18][CH2:19]3)[N:13]([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C=CCCCCCCCI
Reactant: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCCCCN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(cyclohexylamino)-1-(4-iodophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one dihydrochloride (400 mg, 0.76 mmol, intermediate II.1.c.1) in DMF (6 mL) was added diisopropylethylamine (0.333 mL, 1.9 mmol) and the reaction mixture was stirred at rt for 10 min. Potassium carbonate (210 mg, 1.52 mmol) and 9-iodononene (230 mg, 0.91 mmol, prepared from 9-hydroxynonene, iodine, triphenylphosphine and imidazole) were added. The reaction mixture was stirred at 100° C., sealed, for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water. The organic layer was concentrated in vacuo and the residue was purified by reverse phase preparative HPLC (5- 95% MeCN/H2O containing 0.1% TFA, C18). The desired fractions were basified with aqueous NaHCO3, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated in vacuo to provide the desired compound as a light brown solid. LRMS (M+1)=577.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18](CCO)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C.[C:33](O)(=[O:35])[CH3:34]>O>[CH2:9]([N:5]1[C:4](=[O:13])[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][CH2:34][CH2:33][OH:35])=[CH:20][CH:19]=2)[NH:7][C:6]1=[O:8])[CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)O
Reactant: Nc1ccc(CCO)cc1
Reactant: CCCCn1c(=O)cc(Cl)[nH]c1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(=O)cc(-c2ccc(NCCO)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 6-chloro-3-n-butyluracil (10.4 g, 51.3 mmol), 2-(4-aminophenyl)ethanol (10.0 g, 72.9 mmol) and ethyldiisopropylamine (18 ml, 0.1 mol) was heated with stirring under argon on a 150° oil bath for 1 hr 20 min. The mixture was cooled to room temperature, diluted with 50 ml of water, treated with 10 ml of acetic acid and stirred for crystallization overnight. A precipitated solid was filtered, washed with 2% acetic acid, dried on filter and dissolved in 100 ml of hot 96% ethanol. To the solution 100 ml of hot water was added followed by 1.0 g of charcoal. The mixture was filtered hot and crystallized on ice. Yellow solid was collected by filtration and dried in vacuum to yield 10.7 g of 40, mp 207-208° C. 1H NMR (DMSO-d5) δ0.88 (t, 3H, J=7.3 Hz, CH3), 1.25 (m, 2H, CH2), 1.46 (m, 2H, CH2), 2.70 (t, 2H, J=6.8 Hz, CH2), 3.60 (dd, 2H, J=11.8, 6.8 Hz, CH2), 3.68 (t, 2H, J=7.3 Hz, CH2), 4.62 (t, 1H, J=5.3 Hz, OH), 4.73 (d, 1H, J=1.8 Hz, 5-H), 7.10 (d, 2H, J=8.4 Hz, ArH), 7.23 (d, 2H, J=8.4 Hz, ArH), 7.10 (s, 1H, NH), 10.37 (s, 1H, NH).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH-].[Na+].[CH3:10][O:11][CH:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13]>N>[CH3:10][O:11][CH:12]([N:14]([CH3:5])[C:15](=[O:17])[CH3:16])[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: COC(C)NC(C)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: COC(C)N(C)C(C)=O
Reaction time: 3 h
Yield: 457.4 %

Procedure:
25 g (0.2 mole) of dimethyl sulfate are added to 500 ml of 50% strength sodium hydroxide solution at 5°-10° C., and 158 g (1.25 moles) of dimethyl sulfate and 117 g (1.0 mole) of N-α-methoxyethyl-acetamide are simultaneously added dropwise in the course of 3 hours, while stirring. After a further 3 hours, 50 ml of concentrated ammonia are added, and after 30 minutes, the phases are separated in a separating funnel and the aqueous layer is extracted with diethyl ether. After stripping off the solvent, distillation of the residue in vacuo gives 120 g (92% of theory) of N-α-methoxyethyl-N-methyl-acetamide of boiling point18 76°-81° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13].C(N(CC)CC)C.[P:24]([O-:29])([O:27][CH3:28])[O:25][CH3:26]>C(#N)C>[OH:13][CH:12]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])/[CH:11]=[C:10](\[CH3:14])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:15])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1]
Reactant: COP([O-])OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COP(=O)(OC)C(O)/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of farnesal (245 mg, 1.11 mmol) in acetonitrile (1.1 ml) under argon at room temperature (r.t), was added triethylamine (0.31 ml, 2.22 mmol) and dimethyl phosphite (0.153 ml, 1.67 mmol) and the resulting mixture stirred at r.t. for 24 hr. The reaction mixture was concentrated in vacuo, the resulting residue was chromatographed over silica gel eluted with ethyl acetate to afford the title compound as a colorless oil: NMR (CDCl3) δ 1.60 (6H, s), 1.68 (3H, s), 1.71 (3H, d, J=3.1 Hz), 1.80-2.30 (9H, m), 3.80 (6H, m), 4.69 (1H, dt, J=9 and 5.4 Hz), 5.00-5.20 (2H, m), 5.34 (1H, m).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[C:30]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCCc2ccccc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 3-Phenyl-propylamine. MS (ESI): 447.4 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:22]=1
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 3-bromomethyl-benzoic acid methyl ester (1.2 g, 5.16 mmol) and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester 1.03 g (65%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].C(O)(=O)C.[Br:25]Br>C(Cl)(Cl)Cl>[Br:25][C:6]1[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[O:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (4.5 g) in 200 ml chloroform with 3 ml acetic acid, was added dropwise 1.5 ml bromine at 0° C. The solution was then allowed to warm to room temperature and was stirred for another 4 hours. The reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of bromine disappeared. The reaction mixture was then extracted with dichloromethane (100 ml×2) and the organic layer was dried over anhydrous magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by recrystallization from hexane and ethylacetate to afford 4.5 g of 4-bromo-2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. mp: 130-131° C. NMR: δ0.88 (t, J=7.5 Hz, 6H), 1.95 (q, J=7.5 Hz, 4H), 3.11 (s, 3H), 8.12 (d, J=8.7 Hz, 2H), 8.42 (d, J=8.7 Hz, 2H). IR (cm−1): 2973, 1705, 1583, 1558, 1315, 1160, 1084.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH-:11].[Na+]>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(COCc2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Sordaricin benzyl ester (161.2 mg) was dissolved in 6 mL of N,N-dimethylformamide and p-methoxybenzyl chloride (1 mL) was added followed by excess sodium hydroxide (50 mg of a 60% dispersion in mineral oil). The mixture was stirred overnight. The mixture was diluted with ether and carefully washed with water. The ether layer was dried over anhydrous sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel chromatography to give 192.5 mg (93%) of the p-methoxybenzyl ether.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:23]([C:21]1[CH:20]=[CH:19][C:3]([NH:4][C:5]2[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:22]=1)#[CH:24]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 68 %

Procedure:
4-{2-Fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with K2CO3 in MeOH/THF as for example 12, step B. The resulting crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-(4-ethynyl-2-fluoroanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (68%), m.p. (EtOAc/MeOH) 249-252° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.42 (br s, 1H), 10.44 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.45 (dd, J=11.4, 1.9 Hz, 1H), 7.33 (dd, J=8.3, 1.3 Hz, 1H), 5.63 (s, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.23 (s, 1H), 3.46 (q, J=5.9 Hz, 2H), 3.31-3.22 (m, 2H), 1.66 (pentet, J=6.7 Hz, 2H). Anal. Calcd for C17H16FN3O3: C, 62.0; H, 4.9; N, 12.8. Found: C, 62.0; H, 5.2; N, 12.8.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Nc1cccc(F)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 83 %

Procedure:
Starting from 2-amino-6-fluorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (190 mg; 83% yield).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([CH2:7][C:8](O)=[O:9])#[N:6].C(N=C=NC(C)C)(C)C.O>O1CCCC1.CC#N>[CH:1]1([NH:4][C:8](=[O:9])[CH2:7][C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: N#CCC(=O)O
Reactant: NC1CC1
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCC(=O)NC1CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
Cyclopropylamine (5.0 grams, 88 mmole) was combined with 7.5 grams (g) (88 mmol) of cyanoacetic acid in 50 milliliters (ml) tetrahydrofuran (THF) and 50 ml CH3CN. Diisopropylcarbodiimide (20 g, 97 mmol) dissolved in 10 ml THF was added dropwise. The reaction mixture exothermed and a white precipitate formed. The mixture was stirred at 20° C. for 20 hours, 5 ml water was added and the reaction mixture was stirred another 5 minutes. The precipitate was filtered off and the filtrate evaporated giving a white solid which was then recrystallized to yield 9.2 g (74 mmol) of N-(cyclopropyl)-2-cyanoacetamide, a white solid (m.p. 104°-106° C.) (84% yield).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].CC(N(C)C)=O.[C:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:3][N:2]([CH3:1])/[CH:4]=[C:20](/[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)\[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CN(C)C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccncc1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
Pyridinium p-toluene sulfonate (7.8 mg; 0.031 mmol) and DMF.DMA (5.35 mL; 40.3 mmol) were added to a solution of ethyl isonicotinoylacetate (6.0 g; 31.0 mmol) in anhydrous toluene (40 mL) and the mixture was heated to 90° C. for 3 hours. The mixture was cooled, water (50 mL) was added and the product was extracted with DCM (3×50 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a purple oil (7.68 g; 99.8%). The compound was used directly without any further purification.
Reaction SMILES: [CH3:1][NH2:2].Cl.[OH-].[K+].[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH:19]=O)[CH:9]=1>CO>[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19][NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: COc1cc(C(CC=O)c2ccccc2)c2cc[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To a mixture of MeNH2·HCl (0.60 g, 9 mmol) and KOH (0.1 g, 1.8 mmol) in MeOH (5 ml) was added a solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionaldehyde CXVIII (0.25 g, 0.89 mmol) in MeOH (6 ml) at RT. The resulting mixture was stirred at room temperature for 5 minutes and NaCNBH4 (21 mg, 0.33 mmol) was added. The reaction mixture was stirred for 45 minutes at room temperature and then quenched with HCl (1M, 50 ml). The resulting mixture was extracted with Et2O (25 ml), and the aqueous layer was basified until pH>12 by addition of a saturated solution of NaOH (50 ml). The aqueous layer was extracted with Et2O (35 ml). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) to afford [3-(6-Methoxy-1H-indol-4-yl)-3-phenyl-propyl]-methyl-amine compound CXIX (33 mg, 13% yield). MS (M+H)=295.