Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([N:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1([CH3:20])[CH3:19])=[O:12])=[O:8])=[O:4].[CH:21](=O)[CH:22]([CH3:24])[CH3:23]>CO>[CH3:19][C:14]1([CH3:20])[NH:15][C:16](=[O:18])[CH2:17][N:13]1[C:11](=[O:12])[CH2:10][NH:9][C:7](=[O:8])[CH2:6][N:5]1[C:3](=[O:4])[CH2:2][NH:1][CH:21]1[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C=O
Reactant: CC1(C)NC(=O)CN1C(=O)CNC(=O)CNC(=O)CN
Solvent: CO
Product: CC(C)C1NCC(=O)N1CC(=O)NCC(=O)N1CC(=O)NC1(C)C

Procedure:
A solution of 1-[2-[2-(2-aminoacetamido)acetamido]acetyl]-2,2-dimethyl-4-imidazolidinone (0.5 g) and isobutyraldehyde (0.18 ml) in methanol (5 ml) was refluxed for 0.5 hours.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[O:8])=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCC1CC1)c1ccc(Cl)s1
Temperature: 70 °C

Procedure:
To a solution of 5-chlorothiophene-2-carboxylic acid (5.00 g) in DMF (50 mL) were added potassium carbonate (6.38 g) and (bromomethyl)cyclopropane (4.47 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.54 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:2]1.B.[O:20]1CCCC1>>[N:13]1([CH2:12][CH2:11][CH2:10][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][CH:2]2[OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1=C(CCCN2CCCCC2)c2ccccc2C1
Reactant: C1CCOC1
Agent: B
Product: OC1Cc2ccccc2C1CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[3-(3-Indenyl)propyl]piperidine (48.2 g, 0.2 M) is dissolved in 400 ml tetrahydrofuran and stirred in a nitrogen atmosphere while 400 ml 1M borane in tetrahydrofuran is added dropwise over a period of 1 hour. The mixture is left stirring overnight at room temperature. Most of the solvent is then removed in vacuo. The viscous residue is dissolved in 500 ml 95% ethanol, treated with 20 g NaOH and then 65 ml of 30% H2O2 is added dropwise over a period of 30 minutes. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 21/2 hours. The mixture is then taken to near dryness in vacuo. The residue is then extracted three times with benzene. The benzene extracts are dried, filtered and the solvent is removed in vacuo leaving 57 g of oil. The VPC of this material indicates ~ 97% purity.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[N:18]1[NH:19][N:20]=[N:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCOCCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:21]1[NH:20][N:19]=[N:18][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=3)[N:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(-c2nn[nH]n2)cc1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOCCO
Solvent: O
Product: COc1ccc2nc(-c3ccc(-c4nn[nH]n4)cc3)c(C(F)(F)F)nc2c1
Temperature: 120 °C

Procedure:
2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11, 321 mg) was treated with (4-(2H-tetrazol-5-yl)phenyl)boronic acid (256 mg), K2CO3 (338 mg) and PdCl2(dppf) (27 mg) in diethylene glycol methyl ether (3 mL) and water (0.8 mL) in a sealed microwave tube and heated at 120° C. with microwave for 1.5 h. The resultant mixture was diluted with water (20 mL) and acidifed to pH 4 to precipatate the desired product. The solids were collected by filtration, dried under vacuum and trituated with DCM to give 360 mg of gray solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@H]4NS(C)(=O)=O)n3)cc2CC1
Temperature: 120 °C
Yield: 75.4 %

Procedure:
N-[trans-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentyl]-methanesulfonamide (60 mg, 0.185 mmol), 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (40 mg, 0.185 mmol) and camphorsulfonic acid (64 mg, 0.278 mmol) were combined in 2 mL isopropanol and heated at 120° C. in microwave for a total of 90 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column using a gradient of 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 71 mg (76%) of a pale yellow solid. Compound 1: mp 74° C.; MS (ES+ calculated—508; found—509 M+H). 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.06 (d, J=9 Hz, 1H), 6.96 (s, 1H), 6.38 (br s, 1H), 5.39 (d, J=6 Hz, 1H), 5.32 (s, 1H), 4.16 (m, 1H), 3.55 (t, J=6 Hz, 2H), 3.38 (s, 3H), 2.93 (m, 4H), 2.85 (s, 3H), 2.76 (m, 4H), 2.30 (m, 2H), 1.86 (m, 2H), 1.23 (t, 2H) ppm.
Reaction SMILES: N12CCCN=C1CCC[CH2:3][CH2:2]2.C(I)C.[C:15]([NH:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22])(=[O:17])[CH3:16].C(NC(NC(OCC1C=CC=CC=1)=O)(C)C(OCC)=O)(=O)C>C(#N)C>[C:15]([NH:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:21]([O:23][CH2:2][CH3:3])=[O:22])(=[O:17])[CH3:16]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)NC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C)(NC(C)=O)NC(=O)OCc1ccccc1
Solvent: CCI
Solvent: CC#N
Product: CCOC(=O)[C@@H](CNC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.45 ml., 3.0 mmole) and ethyl iodide (0.3 ml., 3.75 mmole) are added to a solution of (R)-3-(acetylamino)-2-[[(benzyloxy)carbonyl]amino]propanoic acid (0.7 g., 2.5 mmole) in acetonitrile (15 ml.). The reaction is allowed to stir overnight then concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2N hydrochloric acid (2×50 ml.), sodium bicarbonate (2×50 ml.), and brine, and then dried over sodium sulfate. The solvent is removed in vacuo and the resulting oil is chromatographed on silica gel eluting with ethyl acetate to yield 0.6 g. of (R)-3-(acetylamino-2-[[(benzyloxy)carbonyl]amino]propanoic acid, ethyl ester as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17](O)[CH:16]=[C:15](O)[C:3]=1[C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.Cl.C[OH:23]>>[O:1]1[C:2]2[C:3](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:14])[C:5]([OH:23])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(C=Cc1ccc(O)cc1)c1c(O)cc(O)cc1O
Reactant: CO
Agent: Cl
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12

Procedure:
Determination of flavonoid glycosides and narichalcone (2′,4′,6′,4-tetrahydroxychalcone) in tomato fruit is carried out using a non-hydrolysing method as follows: 40 mg of freeze-dried tomato tissue is weighed and transferred to a 10 ml Pyrex glass tube. To each tube 4 ml of 75% aqueous methanol acidified with HCl to pH 2 is added. The tubes are closed with screw tops containing a Teflon inlay and incubated at room temperature (20-25° C.) for 1 hr with continuous mixing on a roller band.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:12]I.[H-].[Na+]>O1CCCC1>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CI
Reactant: OCCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a stirred solution of 3-(4-chlorophenyl)propanol (9.61 g, 54.17 mmol) and methyl iodide (7.0 ml, 112 mmol) in dry tetrahydrofuran (85 ml) under nitrogen was added 60% sodium hydride (2.83 g, 70.8 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was treated with ice/water (150 ml), extracted with methylene chloride (3×250 ml), and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. Chromatography of the residual yellow oil on silica gel eluting with hexane afforded the title compound as a yellow oil (8.69 g, 86% from 3-(4-chlorophenyl)propionic acid) which was characterized by NMR spectral analysis.
Reaction SMILES: [NH2:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:7](=[O:27])[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4].[C:40]([O:44][C:45]([NH:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:40]([O:44][C:45](=[O:46])[NH:47][C:48]([C:49](=[O:50])[NH:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:12](=[O:13])[NH:14][CH3:15])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:7](=[O:27])[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4])([CH3:53])[CH3:52])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (44 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (44 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford 45 mg (93% yield) of the desired product. MS (ESMS) m/z 716.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1.C(O)C.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][O:17][C:14](=[O:16])[CH3:15])=[N:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C)[n+]([O-])c1
Solvent: CCO
Product: COc1ccc(COC(C)=O)nc1
Temperature: 115 °C

Procedure:
5-Methoxy-2-methyl-pyridine 1-oxide (9.25 g, 66.5 mmol) was suspended in acetic anhydride (31 ml) under an argon atmosphere. The mixture was heated to ca.115° C. and this temperature was maintained for a further 5 h and the mixture turned black. Ethanol (2.5 ml) was added and the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with 10% K2CO3 and water. The aqueous phases were back extracted with ethyl acetate and the combined organic phases were dried (MgSO4) filtered and concentrate under reduced pressure. The crude oil was purified using Kugelrohr distillation (90-100° C./0.1 mbar) yielding a colorless oil: 10.7 g (80%); 1H NMR (CDCl3) δ 2.13 (s, 3H), 3.86 (s, 3H), 5.16 (s, 2H), 7.18-7.31 (m, 2H), 8.30 (d, 1H) MS: m/e=181.2 (M), 138.0 (M−COCH3)
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C=O.[C:17](O)(=O)[CH2:18][C:19]([OH:21])=[O:20].N1C=CC=CC=1>>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:17]=[CH:18][C:19]([OH:21])=[O:20]
Reactant: CC(C)CCCCCCCCCCCC=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: CC(C)CCCCCCCCCCCC=CC(=O)O
Reaction time: 3 h

Procedure:
13-methyl-tetradecanaldehyde (56.5 g, 0.25 mole), malonic acid (26.5 g, 0.51 mole), and pyridine (30.8 ml, 0.374 mole) were added to a flask and refluxed with heating for 3 hours. After cooling down 30% sulfuic acid was added and the reaction mixture was stirred for 3 hours under ice bath and then extracted by diethyl ether. Diethyl ether was removed by evaporation and product was subject to vacuum fractional distillation and 170–172° C./1.0 mmHg fraction was collected as 15-methyl-2-hexadecenoic acid (50.9 g, yield rate 76%).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [K].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([O:21][CH3:22])[C:16](=[O:20])[O:17]2)=[CH:12][C:11]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)C1C=CC=CC=1>O.[Pd]>[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([O:21][CH3:22])[C:16](=[O:20])[O:17]2)=[CH:12][C:11]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1
Reactant: COc1cc2cc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)cc2oc1=O
Agent: [Pd]
Agent: [K]
Solvent: O
Product: COc1cc2cc(N3CC(=O)NS3(=O)=O)c(O)cc2oc1=O
Reaction time: 18 h

Procedure:
To a solution of 5-(7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt in water (10 mL), is added 10% Pd/C (0.014 g). The suspension is stirred under an atmosphere of H2 for 18 h. The aqueous solution is filtered through Celite and the water is removed by lyophilization. The crude solid is purified by preparative HPLC to afford 5-(7-hydroxy-3-methoxy-2-oxo-2H-chromen-6-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a pale-yellow powder: 1H NMR (DMSO-d6) δ 7.66 (s, 1H), 7.27 (s, 1H), 6.77 (d, J=3.54 Hz, 1H), 4.03 (s, 2H), 3.77 (s, 3H); (M−H)−=325.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.CN(C=O)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:29][CH:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCC(O)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.7 ml; 5.05 mmol; 7 eq) and trans-4-aminocyclohexanol hydrochloride (547.1 mg; 3.61 mmol; 5 eq) are added successively. DMF (0.2 ml) is added to dissolve the amine and the reaction mixture is stirred overnight at room temperature. The reaction mixture is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (120 mg; 21%).
Reaction SMILES: C1(CCl)C=CC=C(CCl)C=1.C(O[CH:15]([O:22]C(=O)C)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=O)C.[C:26]([O-])(=[O:28])C.[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1.O.C(N(CC)CC)C>[C:16]1([CH2:15][OH:22])[CH:21]=[CH:20][CH:19]=[C:18]([CH2:26][OH:28])[CH:17]=1
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(OC(C)=O)c1ccccc1
Agent: ClCc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: OCc1cccc(CO)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
In a manner similar to that in Example 1, m-xylylene dichloride was converted into m-diacetoxymethylbenzene at 97° to 101° C. in 3 hours by use of a reactant mixture comprising 100 parts of m-xylylene dichloride (97.6% purity), 100 parts of anhydrous sodium acetate, 125 parts of monochlorobenzene, and 2 parts of triethylamine. To the reaction mixture was added 250 parts of warm water to dissolve the by-product sodium chloride. The mixture was left standing at 80° C. to allow it to settle in two layers. To the monochlorobenzene layer which had been freed from the catalyst amine by removing in the same manner as in Example 1, were added 46 parts of sodium hydroxide and 310 parts of water to allow the saponification to proceed at 94° C. for 2 hours. After saponification, the reaction mixture was neutralized with 3N hydrochloric acid and left standing at 82° C. to allow the mixture to settle in two layers. The aqueous layer containing m-xylylene glycol, was added at 80° C. 50 parts of monochlorobenzene to extract impurities. After separation, m-xylylene glycol was extracted from the purified aqueous layer with n-butyl acetate in the same way as in Example 1. The n-butyl acetate layers obtained by repeating batchwise extraction three times were combined, distilled to recover ethyl acetate, and dried in vacuo to obtain 76.0 parts of m-xylylene glycol (melting point, 53.5° - 55° C.) in a yield of 98.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CO.[C].[Rh].[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)c(F)c3)C2=N1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)c(F)c3)C2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
To a solution of 9-(2-fluorobiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in THF/methanol (30 mL/30 mL) was added 5% rhodium carbon (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 day. Platinum (IV) oxide (40 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 9 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, the obtained residue was purified by recrystallization (THF-ethyl acetate/diisopropyl ether) to give the title compound (121.2 mg).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[CH3:40][NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)Cl>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][N:41]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:40]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCC(O)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)CC(O)CO)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added 3-methylamino-1,2-propanediol hydrochloride (49 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 537 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:6])[C:3](O)=[O:4].C1N=C[N:19](C(N2C=NC=C2)=O)C=1.N>O1CCCC1>[CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:6])[C:3]([NH2:19])=[O:4]
Reactant: CC(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(Oc1cccc([N+](=O)[O-])c1)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
The mixture of 2-methyl-2-(3-nitrophenoxy)propanoic acid (1 g, 4.44 mmol) and CDI (1.080 g, 6.66 mmol) in Tetrahydrofuran (10 ml) was stirred at room temperature for 3 hr, ammonia (2.0 M in Methanol, 10 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under vacuum and the residue was treated with pentane to afford the title product (0.914 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH2:11]Br>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COC(=O)C(C)CCBr
Solvent: Cc1ccccc1
Product: COC(=O)C(C)CCN1CCCC1

Procedure:
Pyrrolidine (5.4 mL, 66 mmol) was dissolved in toluene (40 mL). 4-Bromo-2-methyl-butyric acid methyl ester (4.3 g, 22.0 mmol) was added and the reaction stirred at reflux for 2.5 hours. Removal of the solvent and of the excess amine at reduced pressure gave 2-methyl-4-(pyrrolidin-1-yl)-butyric acid methyl ester as a thick oil. The crude product was diluted with MeOH (3 mL) and 1.0M NaOH aq solution (22 mL) was added and the reaction stirred at reflux for 18 hours.