Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:12])(=[O:11])[CH2:7][C:8]([OH:10])=[O:9].C(OC(=O)C)(=O)C.[CH3:20][C:21]([CH3:23])=O>>[C:6]1(=[O:12])[O:11][C:21]([CH3:23])([CH3:20])[O:10][C:8](=[O:9])[CH2:7]1
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
The diisopropylidene methylene dimalonate used in this Example was prepared by adding 1.5 ml concentrated sulfuric acid over a 20 minute period to a stirred slurry of 52 grams malonic acid (0.5 mol) and 60 ml acetic anhydride (0.6 mol) in an erlenmeyer flask reactor. After the reactants were stirred for 3 hours at room temperature, 40 ml acetone (0.55 mols) were added with cooling and the reactants were maintained at 5° C for 16 hours. The crystalline product was filtered, washed with ice water and dried yielding 32 grams isopropylidene malonate having a melting point of 97°-98° C. A solution of 14.4 grams of isopropylidene malonate (0.1 mol), 4.0 grams of 37% aqueous formaldehyde (0.05 mol) and 40 ml dimethyl formamide was maintained at room temperature for 3 hours in an erlenmeyer flask. After the addition of 25 ml water, white crystals precipitated from the dimethyl formamide. The crystals were washed with water and dried yielding 10 grams of diisopropylidene methylene dimalonate which melted at from 152°-153° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>C(O)CCC>[BrH:1].[NH2:20][C:18]1[S:19][CH2:2][C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)=[N:16][N:17]=1
Reactant: NNC(N)=S
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCCCO
Product: Br
Product: NC1=NN=C(c2cc(O)c(O)c([N+](=O)[O-])c2)CS1
Temperature: 25 °C

Procedure:
A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 461 mg of thiosemicarbazide in 20 ml of n-butanol is heated to boiling under reflux for 60 minutes. After cooling to room temperature the crystals are filtered under suction and recrystallized from n-butanol. There is obtained 5-(2-amino-6H-1,3,4-thiadiazin-5-yl)-3-nitropyrocatechol hydrobromide of m.p. 265°-267°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]Br.C([O-])(=[O:14])C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][OH:14]
Reactant: Clc1cc(Cl)c(CBr)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1c(Cl)cc(Cl)cc1Br
Yield: 56.6 %

Procedure:
Heat a mixture of 22 g of 2-bromo-4,6-dichlorobenzyl bromide, 30 g anhydrous sodium acetate and 80 mL of glacial acetic acid for 18 hr at 100° C. Evaporate the mixture to a dry residue. Treat the residue with 200 mL of ethanol and 200 mL of 2N NaOH. Stir the mixture at reflux for 3 hr. Cool the mixture and concentrate the cooled mixture to 50 mL. Extract the cooled concentrate with Et2O. Dry the extract over anhydrous K2CO3 and evaporate it to a dry residue. Recrystallize the residue from toluene-hexane to give 10 g of 2-bromo-4,6-dichlorobenzyl alcohol, mp 111°-112° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[Cl:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:15][C@H:3]1[C@@H:2]([NH:1][C:24]([C:19]2[NH:20][C:21]([CH2:22][CH3:23])=[C:17]([Cl:16])[N:18]=2)=[O:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](Cl)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2Cl)nc1Cl
Yield: 73.4 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl cis(±)-4-amino-3-chloropiperidine-1-carboxylate obtained in Example (198a) (134 mg, 0.571 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (99.7 mg, 0.571 mmol), 1-hydroxybenzotriazole hydrate (116 mg, 0.856 mmol), WSC hydrochloride (164 mg, 0.856 mmol) and triethylamine (119 μL, 0.856 mmol), to obtain 164 mg of the title compound (73%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].O1CCOCC1.CC(C)([O-])C.[K+].Cl[C:23]1[N:24]=[N+:25]([O-:30])[C:26]([Cl:29])=[CH:27][CH:28]=1>CS(C)=O>[Cl:29][C:26]1[N+:25]([O-:30])=[N:24][C:23]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:28][CH:27]=1
Reactant: Cc1cccc(C)c1O
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(C)c1Oc1ccc(Cl)[n+]([O-])n1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
268 mg (2.20 mmol) of 2,6-dimethylphenol, 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) were mixed, 270 mg (2.41 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 370 mg (2.24 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 10 hours and allowed to stand for 2 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, gradient) to obtain 350 mg (1.39 mmol, Yield: 63.1%) of 6-chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[N+:6]([C:9]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][CH:13]=1)([O-:8])=[O:7]>C(Cl)Cl>[NH4+:6].[N+:6]([C:9]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[S:1]([O-:3])(=[O:5])=[O:2])([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)[O-]
Product: [NH4+]
Reaction time: 0.25 h

Procedure:
Fuming sulfuric acid (8 mililiter (hereinafter mL) was cooled to -20° C. and 2-(2-nitro-4-trifluoromethyl-phenoxy)-4,5-dichlorobenzene (8 g, 22.8 mmol) in methylene chloride (8 mL) was added to the solution. The mixture was stirred for 15 min and then quenched in ice. Extraction with ethyl acetate followed by flash chromatography (silica gel, methylene chloride/isopropanol/ammonium hydroxide) gave the title compound. 1H NMR (400 MHz, CD3OD) δ8.31 (d, 1H), 8.11 (s, 1H), 7.87 (dd, 1H), 7.4 (s, 1H), 7.16 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]=[C:7]=[O:8])[CH3:2].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])[CH3:2]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCOCCN=C=O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 2-ethoxyethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with saturated sodium chloride aqueous solution (each 30 ml., 2 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-ethoxyethyl)carbamoyl]-5-fluorouracil (1.82 g.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.C1C(=O)N([Br:24])C(=O)C1>C1COCC1.CN1C(=O)CCC1>[Br:24][C:14]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:16][CH:15]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=3
Reactant: Cc1cc2nc(Cl)c3nccn3c2cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)c3ncc(Br)n3c2cc1C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred suspension of 4-chloro-7,8-dimethyl-imidazo[1,2-a]quinoxaline (32.2 g, 0.148 mot) in THF/NMP 2:1 (312 mL) was added NBS (26.3 g, 0.148 mot) in one portion at room temperature. After stirred for 18 h, additional NBS (13.1 g, 0.074 mot) was added and the mixture was stirred for additional 2 h at room temperature. After removal of the THF portion of the organic phase by vacuum evaporation, water was added (520 mL). The precipitate was filtered and the residue was washed with water, diethyl ether and dried to give 35 g of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ=8.54 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 2.20 (6H, s) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][O:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20].[CH2:23]1COC[CH2:24]1>C(Cl)(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH2:15][O:16][CH3:17])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:19][CH3:20])([CH2:15][O:16][CH3:17])[CH2:23][CH3:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClC(Cl)Cl
Product: CCC(CC)(COC)N1CCN(Cc2ccccc2)CC1
Product: COCC1(N2CCN(Cc3ccccc3)CC2)CC1

Procedure:
To a solution of 1-(4-benzyl-piperazin-1-yl)-2-methoxy-ethanone (2.60 g) in dry THF (30 mL) at −10° C. was added titanium isopropoxide (3.22 mL), followed by ethyl magnesium bromide (1.0M solution in THF, 22.05 mL). The reaction mixture was heated to reflux for 2 days. After cooling the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 1-benzyl-4-(1-methoxymethyl-cyclopropyl)-piperazine (452 mg) and 1-benzyl-4-(1-ethyl-1-methoxymethyl-propyl)-piperazine (248 mg). Transfer hydrogenation conditions using ammonium formate and 10% Pd/C in MeOH afforded the desired compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([F:8])[O:7][C:4]1(F)F.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[CH3:4][O:7][C:3]([C:11]([O:15][CH3:14])=[O:12])([C:2]([F:10])([F:9])[F:1])[F:8]
Reactant: CO
Reactant: C[O-]
Reactant: FC(F)(F)C1(F)OC1(F)F
Agent: [Na+]
Product: COC(=O)C(F)(OC)C(F)(F)F

Procedure:
Hexafluoropropylene oxide (HFPO, 300 g) was added to 50 g of 25% sodium methoxide in methanol plus 450 g methanol at room temperature in a modification of the procedure of (J. Org. Chem. 31, 2312 (1960) to give CH3OCF(CF3)COOMe bp 110-118° C. This was direct fluorinated according to U.S. Pat. No. 5,488,142 and the product was methanolysed to give the same ester as in Example 11. One could then convert this to the perfluorovinyl ether as described above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:17]=[C:16]([NH:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[NH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)Cl.O=S(Cl)[Cl:34].[C:36]1([NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42]>C1COCC1>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:43][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][NH:18][C:16]2[NH:15][N:14]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[C:17]=2[Cl:34])=[CH:21][CH:22]=1
Reactant: COc1cc(-c2cc(NCc3ccc(C(=O)O)cc3)[nH]n2)cc(OC)c1OC
Reactant: Nc1ccccc1N
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(-c2n[nH]c(NCc3ccc(C(=O)Nc4ccccc4N)cc3)c2Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 389 (30 mg, 0.08 mmol) in a 1:1 mixture of DCM and SOCl2 (2 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated and treated with a solution of 1,2-phenylene diamine (18 mg, 0.16 mmol) in THF (2 mL) and stirred at room temperature for 15 min, concentrated under reduced pressure to produce a solid which was purified by preparative HPLC (column AQUASIL C-18; 5 μM; 230×21.2 mm; eluent 30-95% MeOH in water) to afford the title compound (8 mg, 20% yield). 1H NMR (MeOH-d4) 7.92 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H), 7.06 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.75 (t, J=7.2 Hz, 1H), 4.55 (s, 2H), 3.89 (s, 6H), 3.80 (s, 3H). LRMS: (calc) 507.2; (found) 508.3 (M+H1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([O:12]COC)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]1[CH:21]=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[CH:25]=[C:24]([CH2:36][OH:37])[C:23]=2[CH2:38][OH:39])[CH:19]=[CH:18][N:17]=1.Cl>O1CCOCC1.CO>[O:1]=[C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]1[CH:21]=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[CH:25]=[C:24]([CH2:36][OH:37])[C:23]=2[CH2:38][OH:39])[CH:19]=[CH:18][N:17]=1
Reactant: COCOc1cc(=O)n(-c2cc(-c3c(CO)c(CO)cc4cc(OC)c(OC)cc34)ccn2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(O)c5ccccc54)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
1-[2-(2-Oxo-4-methoxymethoxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.39 g) is dissolved in a mixture of dioxane (10 ml) and methanol (5 ml), and thereto is added 2M hydrochloric acid (2 ml). The mixture is warmed to 50° C., and stirred for 7 hours, and then concentrated under reduced pressure to remove the solvent. To the residue are added chloroform and water, and the chloroform layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give 1-[2-(2-oxo-4-hydroxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-naphthalene (0.79 g) which is listed in Table 7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=CC=2)=[CH:4][CH:3]=1.[Mg].[Cl-].[Cl-].C(C1C=C(C(C)(C)C)C=CC=1OP(O)O)(C)(C)C>O1CCCC1.O1CCCC1.CCCCCCC>[Br:14][C:11]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:8]=[CH:13][CH:12]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: CC(C)(C)c1ccc(OP(O)O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Brc1cccc2ccccc12
Yield: 200 %

Procedure:
4,4'-Biphenylene-bis- (1-naphthyl-phosphinous acid 2,4-di-tert-butylphenyl ester): in deviation from the general instructions, 200 mmol (=62.4 g) of 4,4'-dibromobiphenyl were subjected to a Grignard reaction with 600 mmol (=14.6 g) of magnesium filings in 600 ml of tetrahydrofuran under the action of ultrasound (40 kHz), and the product was then reacted with 400 mmol (=122.9 g) of phosphorous acid 2,4-di-tert-butylphenyl ester-dichloride in 700 ml of tetrahydrofuran/heptane=1/6. The Grignard reagent obtained from 82.8 g (400 mmol) of 1-bromonaphthalene was added dropwise to the resulting suspension. The mixture was filtered and the filtrate was concentrated in vacuo to give 175 g of yellow resin having a content of 76% of the above compound 31P-NMR: δ(CDCl103.7 ppm]. Pale yellow crystals of melting point 255° C. crystallized from acetone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[C@@H:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=C=N[C@H]1CCc2ccccc21
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 208.1 mg (1.2 mmol) of (S)-1-isocyanatoindane in THF/DMF at RT. Yield: 153 mg (41%), M+H+: 343.32.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[S:28][N:27]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:30]=4)[CH2:32][CH2:33]3)=[O:19])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc2ccc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)cc2o1

Procedure:
A solution of 2,2,2-trichloroethyl (2-methyl-1,3-benzoxazol-6-yl)carbamate (200 mg, 0.618 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (152 mg, 0.618 mmol), diisopropylethylamine (0.215 ml, 1.24 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 75.6 mg (29.1%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([NH:31][CH3:30])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: COc1cc(C(=O)O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(OC)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.6 %

Procedure:
A mixture of (1R,10R,11S,16S)-3-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (80) (0.26 g, 0.61 mmol), HATU, (0.36 g, 0.93 mmol), NMM (0.20 mL, 1.9 mmol) and methylamine (2 M in THF, 1.5 mL, 3.0 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h in a sealed tube. The reaction mixture was concentrated under reduced pressure and the residue was quenched with water. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-3-methoxy-N,1,11,15,15-pentamethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxamide (81) (0.11 g, 41%) as a white solid. 1H NMR (CDCl3): δ 7.67 (d, 1H), 7.61 (d, 1H), 6.27 (s, 1H), 3.91 (s, 3H), 3.40-3.17 (m, 3H), 3.01 (d, 3H), 2.30 (d, 1H), 1.78-1.28 (m, 10H), 1.23-1.00 (m, 3H), 0.97 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H). MS m/z 434 (C24H35NO4S+H+).
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[IH:19].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[I:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:18]
Reactant: I
Reactant: O=C1CCCCCCCCCCCCCCCO1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCI
Temperature: 100 °C

Procedure:
16-Hexadecanolide (5.0 g, 0.02 mol) was added to a mixture of HI (30 g) and acetic acid (20 g). The mixture was heated to 100° C. overnight. After cooling it was poured into a cold sodium thiosulphate solution (150 mL, 10%) and extracted using CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated to give a white solid. The crude product was recrystallised from diethyl ether. Yield: 4.8 g (64%)
Reaction SMILES: N(C(C)=O)[C@H:2]([C:7]([NH:9][C@H](C(O)=O)CC(C)C)=[O:8])[CH2:3][CH:4]([CH3:6])C.[NH2:21][C@H:22](C(O)=O)CCCNC(=N)N.C[N-]OC.[CH3:37][CH2:38]N(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]1([C:7]2[O:8][CH:22]=[N:21][N:9]=2)[CH:3]=[CH:4][CH:6]=[CH:38][CH:37]=1
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[N-]OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: c1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetyl-Leu-Leu-OH (133 mg) and arginine (Mtr) -N-methyl-N-methoxy amide (200 mg) were dissolved in 10 mL of DMF and were treated with 243 uL of DIEA and 212 mg of HBTU. The reaction stirred at room temperature for 15 hours and was worked up according to method A. Drying over Na2SO4, rotary evaporation of the solvent and flash chromatography on silica gel (50% acetone in hexane) provided 270 mg of the title compound as a foam.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.P(Br)(Br)[Br:13]>C(OCC)C>[CH2:1]([Br:13])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2c(c1)OCO2
Solvent: CCOCC
Product: BrCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 182 %

Procedure:
To a solution of piperonyl alcohol (5.0 g, 32.86 mmol) in anhydrous diethyl ether (80 mL) was added PBr3 (1.56 mL, 16.43 mmol) in one portion, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (100 mL) and washed with H2O (2×50 mL), saturated NaHCO3 (2×50 mL), and brine (2×50 mL). The ether layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford piperonyl bromide (6.43 g, 91%) as a yellow-grey solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]([S:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]([OH:20])[C:17]([CH3:22])([CH3:21])[C:16]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:7].C(N(CC)CC)C>CCOCC>[CH3:7][N:6]([S:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]([O:20][C:1]([CH3:2])=[O:3])[C:17]([CH3:21])([CH3:22])[C:16]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:5]
Reactant: CC(=O)Cl
Reactant: CN(C)S(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(O)O2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1Oc2ccc(OS(=O)(=O)N(C)C)cc2C1(C)C

Procedure:
At -8°C to -12°C and while stirring, 10.3 parts by weight of acetyl chloride was added to a solution of 28.7 parts by weight of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl dimethylaminosulfonate and 14.1 parts by weight of triethylamine in 110 parts by weight of ether. The mixture was worked up as in Example 1, the compound 2,3-dihydro-3,3-dimethyl-2-methylcarbonyloxybenzofuran-5-yl dimethylaminosulfonate being obtained in the form of crystals; melting point: 67° to 68°C.