Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(C=O)cc21
Temperature: 97.5 °C
Reaction time: 24 h
Yield: 105.3 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (51 mg, 0.12 mmol), cyclopropylboronic acid (21 mg, 0.24 mmol), powdered K3PO4 (103 mg, 0.48 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in PhMe (2 mL) and H2O (0.1 mL) was heated with stirring in a sealed tube under Ar at 95-100° C. for 1 d. The crude mixture was concentrated and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound as a clear oil (40 mg, quant): 1H NMR (400 MHz, CDCl3) δ ppm 10.13 (s, 1H), 8.02 (s, 1H), 7.87 (d, J=8.28 Hz, 1H), 7.70 (d, J=8.28 Hz, 1H), 5.71 (s, 2H), 3.54 (d, J=8.53 Hz, 2H), 2.19-2.28 (m, 1H), 1.06-1.12 (m, 4H), 0.89 (d, J=8.28 Hz, 2H), −0.07 (s, 9H); MS ESI 317.1 [M+H]+, calcd for [C17H24N2O2Si+H]+ 317.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[CH:9]1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=1
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2Cl)n(C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
7-(2-Chlorophenyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (138 mg) and N-chlorosuccinimide (78 mg) were suspended in N,N-dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 151 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[CH:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1cc(C(F)(F)F)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (70 mg), [4-(trifluoromethyl)thiophen-2-yl]methanol (50 mg) and triphenylphosphine (144 mg) in tetrahydrofuran (3 ml) was added bis(2-methoxyethyl)azodicarboxylate (129 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (15 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.OCC1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1.N1CCCC1>ClCCl>[N:3]1([CH2:6][C:7]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:2][CH2:1]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(CO)cc2)C1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(CN3CCCC3)cc2)C1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 56.3 %

Procedure:
Triethylamine (0.47 g, 3.4 mmol) and methanesulfonyl chloride (0.12 ml, 1.6 mmol) were added to an ice-cooled solution of 3-(4-hydroxymethylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.39 g, 1.34 mmol) in dichloromethane and stirred for 7.5 hr. Pyrrolidine (1.0 ml, 12 mmol) was added to the solution and stirred overnight. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure and the residue was purified by silica gel chromatography (eluent; ethyl acetate to ethyl acetate/methanol=1/1, then methanol only) to give 3-(4-(1-pyrrolidinyl)methylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.26 g, 56%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CN(C)C=O.S(Cl)(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C1(C)C=CC=CC=1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was dissolved/suspended in toluene (1200 mL), dimethylformamide (0.15 mL) was added and the suspension was stirred during the dropwise addition of thionyl chloride (53.5 mL, 87.2 g, 0.73 mol). The reaction mixture was heated to reflux under nitrogen and stirred for 2 h, during which time much, but not all of the aldehydo-acid passed into solution. A further quantity of thionyl chloride (20 mL, 32.6 g, 0.27 mol) was added and reflux continued overnight. The clear reaction mixture was evaporated, and the residue dissolved in anhydrous tetrahydrofuran (1500 mL). The solution was cooled in an ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol (2.5 equivalents)) was added dropwise to the stirred solution. The ice-bath was removed and stirring continued for 2.5 h. The reaction mixture was filtered to remove the white crystalline diethylamine hydrochloride by-product. The crystals were washed with ethyl acetate (2×600 mL), and the washings set aside. The tetrahydrofuran filtrate was evaporated, and the residue dissolved in the ethyl acetate washings. The solution was washed sequentially with 1 M-hydrochloric acid (2×600 mL), water (2×300 mL), dilute sodium carbonate solution (saturated Na2CO3:H2O, 1:1, 2×600 mL), water (2×300 mL) and saturated sodium chloride solution (300 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated to yield 4-formyl-N,N-diethylbenzamide as a pale brown oil (115.7 g, 84%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:6]#[N:7].N(CCO)(CCO)CCO.C[Si]([N:45]=[N+:46]=[N-:47])(C)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6]1[NH:47][N:46]=[N:45][N:7]=1
Reactant: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCN(CCO)CCO
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2Cl)c2nnn[nH]2)cc(C(F)(F)F)c1
Yield: 85 %

Procedure:
A solution of 5 gm of the compound from Step C, 50 mL of 2-methyl THF 5 mL, triethanolamine and 2.5 mL of trimethyl silyl azide was heated at 50° C. until reaction completion. When the reaction was judged complete, the reaction mixture was cooled and 50 mL of 1 N sodium hydroxide added, The layers were separated and the organic layer washed with 50 mL of 10% citric acid. The organic layer was concentrated and triturated with hexane to yield 4.6 of the desired compound. 85% yield. 1H NMR (400 MHz, CDCl3) 7.84 (s, 2H), 7.74 (m, 3H), 4.90 (s, 4H)C, H, N, Calculated, (found) 42.92 (42.98), 2.20 (1.97), 13.90 (13.54)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Cl)(Cl)Cl.[CH3:18][S:19][C:20]#N.[OH2:22]>C1(C)C=CC=CC=1>[CH3:18][S:19][C:20]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O
Reactant: CSC#N
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: CSC(=O)c1cccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 1.67 g of carbazole in 10 ml of toluene was added 5.4 ml of a solution of 2.04M boron trichloride--toluene under ice-cooling, and the mixture was refluxed with heating on an oil bath for 1 hr. After ice-cooling, the mixture was mixed with 1 ml of methyl thiocyanate, stirred at room temperature for 3 hr., mixed with 30 ml of water and refluxed with heating on an oil bath for 1 hr. The product was extracted with toluene, dried over anhydrous magnesium sulfate, chromatographed on a column of 10 g of silica gel and eluted with toluene. The eluate was concentrated to give 2.16 g of the crude crystals. Recrystallization from methylene chloride--ether gave 2.08 g of carbazol-1-thiocarboxylic acid S-methyl ester melting at 122°-123° C. as crystals.
Reaction SMILES: Cl.[S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])(=[O:4])=[O:3].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[S:2]([N:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)([CH3:5])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 120 °C
Yield: 69.1 %

Procedure:
1-Mesylpiperazine hydrochloride (4.24 g) was added to a solution of methyl 6-chloronicotinate (1.7 g) and N,N-diisopropylethylamine (6.3 ml) in dimethylacetamide (20 ml) and the mixture was heated at 120° C. for 2 hours. The mixture was allowed to cool to ambient temperature and poured onto crushed ice/water (50 ml) to precipitate a tan solid. The solid was collected by filtration and dried at 80° C. for 18 hours in a vacuum oven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05 g),
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34].[CH3:35][N:36]1CCNC[CH2:37]1.ON1C2C=CC=CC=2N=N1.Cl.[CH2:53]([N:55]=[C:56]=N)[CH3:54].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28]([N:55]5[CH2:53][CH2:54][N:36]([CH3:37])[CH2:35][CH2:56]5)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34]
Reactant: CCN=C=N
Reactant: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)O)n4Cc4ccccc43)cc2C)CCC[C@H]1O
Reactant: CN1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)N5CCN(C)CC5)n4Cc4ccccc43)cc2C)CCC[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
10-[4-((3R)-3-Hydroxy-2-methyl-cyclohex-1-enyl)-3-methyl-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step B (0.200 g, 0.438 mmol), N-methyl piperazine (0.058 mL, 0.526 mmol), 1-hydroxy benzotriazole (0.065 g, 0.482 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.482 mmol) were combined in amine-free N,N-dimethylformamide (1.8 mL), followed by addition of N,N-diisopropylethyl amine (0.114 mL, 0.657 mmol). The reaction was stirred at room temperature for 18 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 8% of methanol in chloroform followed by precipitation from diethyl ether with petroleum ether, to provide 0.200 g of the title compound as a white solid, m.p.102-153° C., [β]589=+18.89 (c=1, chloroform).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#C.[CH2:25](N(CC)CC)[CH3:26].Cl>O1CCCC1>[C:25]([C:19]1([NH:18][S:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)#[CH:26]
Reactant: C#CNC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
4-Methanesulfonyl-phenylmethanesulfonyl chloride (10.7 g, 40 mmol) in 100 ml dry tetrahydrofuran was added to a solution of ethynylcyclohexylamine (4.93 g, 40 mmol) and triethylamine (6.13 ml, 44 mmol) in dry tetrahydrofuran (100 ml) at 0-5° C. Then the mixture was stirred for 1 hour at room temperature, poured into 0.05 N hydrochloric acid and stirred again. The precipitate was filtered off, washed with water and dried to yield N-(1-ethynylcyclohexyl)-4-methanesulfonyl-phenylmethane sulfonamide (11.7 g, 82%) as a solid. 1H-NMR (CDCl3) δ 7.93 (d, 2 H), 7.65 (d, 2 H), 4.61 (s, 2 H), 4.32 (s, 1 H), 2.75 (s, 1 H), 3.05 (s, 3 H), 2.15 (m, 2 H), 1.63 (m, 7 H), 1.27 (m, 1 H); MS (IS): 354.1 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)C1CCCCC1)OCC
Agent: Cl
Product: NCC(CP(O)O)C1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.4 g of ethyl 3-amino-2-cyclohexylpropyl(diethoxymethyl)phosphinate in 30 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 hour. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 10 ml of water under reduced pressure. The crude product is then dissolved in 20 ml of water washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml of dry ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-cyclohexylpropylphosphonous acid m.p. 235°-240° C., 31P=28.2 pm (D2O).
Reaction SMILES: [F:1][C:2]([F:13])([CH:10]([F:12])[F:11])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O>[F:1][C:2]([F:13])([CH:10]([F:11])[F:12])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C/C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl (E)-4,4,5,5-tetrafluoropent-2-enoate (15.9 g, 0.08 mol) was dissolved in ethanol (30 ml), 4M NaOH was added (15 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with water, washed with ethylacetate, acidified with 1M HCl and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, the solvent was removed under reduced pressure. 12.8 g of a colourless oil were obtained (0.074 mmol, 93%). MS (ESI) m/z=170.9 [M−1]−.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])C.C(O)CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[O:3]1[CH2:1][CH2:13][CH2:12][O:11][CH:4]1[C:5](=[O:10])[CH:6]=[C:7]([CH3:8])[CH3:9]
Reactant: CCOC(OCC)C(=O)C=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: OCCCO
Product: CC(C)=CC(=O)C1OCCCO1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 64.2 %

Procedure:
A solution of 1b (1.02 g, 5.49 mmol) and 1,3-propanediol (0.600 mL, 8.23 mmol) in benzene (10.8 mL) was treated with p-toluenesulfonic acid (522 mg, 2.75 mmol). The reaction mixture was stirred at 80° C. for 4.5 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with Et2O. The organic extract was washed (water), dried (Na2SO4), concentrated to a brown liquid, and chromatographed [silica, hexanes/EtOAc (5:1)] to afford a yellow liquid (600 mg, 64%): 1H NMR δ 1.40-1.45 (m, 1H), 1.96 (s, 3H), 2.20 (s, 3H), 2.12-2.25 (m, 1H), 3.83-3.92 (m, 2H), 4.20-4.26 (m, 2H), 4.79 (s, 1H), 6.42 (s, 1H); 13C NMR δ 21.7, 25.9, 28.5, 67.3, 101.4, 119.0, 161.2, 192.1; ESI-MS obsd 193.0833, calcd 193.0835 [(M+Na)+, M=C9H14O3].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25][C:26](=[O:28])[CH3:27])=[CH:18][C:17]=2[O:29]C(=O)C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25][C:26](=[O:28])[CH3:27])=[CH:18][C:17]=2[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
A mixture of N-(1-benzylpiperid-4-yl)-2-acetoxy-4-acetamido-5-nitrobenzamide (1.4 g; 0.0031 moles) [prepared by the procedure described in Example 1], sodium hydroxide (0.3 g; 0.0062 moles), water (25 ml) and ethanol (12.5 ml) was boiled under reflux for 3 hours. Then the mixture was diluted with water, neutralized with diluted hydrochloric acid and the solid filtered off, washed with water and diethyl ether to give 1.1 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-acetamido-5-nitrobenzamide, m.p. 220°-222° C.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.[CH3:19][OH:20]>C(O)(C)(C)C.O>[C:4]([O:1][C:19]([N:14]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15]1)=[O:20])([CH3:9])([CH3:5])[CH3:3]
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN[C@@H](Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.87 %

Procedure:
6.67 ml (16.68 mmol, 1.00 eq.) of a 2.5 N aq. NaOH-solution were added to a solution of 2.94 g (16.68 mmol) 2-(S)-Benzyl-piperazine in 80 ml tert-Butanol and 80 ml H2O. After cooling to 0° C. 3.64 g (16.68 mmol, 1.00 eq.) Boc-anhydride was added and the mixture was stirred at 0° C. for 2 h. Then the solution was warmed to r.t. and stirred overnight. After evaporating the tert-Butanol the mixture was extracted with CH2Cl2. The comb. org. fractions were dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2/MeOH (10+1)) yielded 3.82 g (13.82 mmol, 82.87%) 3-(S)-Benzyl-piperazine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: C[N:2]([CH:21]1[CH:28]2[CH2:29][C:24]3([C:31](O)=[O:32])[CH2:25][CH:26]([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[OH-]>C(Cl)Cl.O>[CH3:35][NH:36][C:31]([C:24]12[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:30][CH:22]([CH:21]3[NH:2][C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])(=[O:9])=[O:10])([CH3:6])[CH3:5])[CH2:23]1)[CH2:25]2)=[O:32]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)O)(C3)C2)S(=O)(=O)c1ccccc1C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(C(C)(C)C(=O)NC1C2CC3CC1CC(C(=O)NC)(C3)C2)S(=O)(=O)c1ccccc1C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylic acid (380 mg, 0.82 mmol) was dissolved in CH2Cl2 (10 ml), and added with EDCI (314 mg, 1.64 mmol) and HOBT (222 mg, 1.64 mmol), followed by stirring for 30 minutes. 30% NH4OH aqueous solution (5 ml) was added thereto, followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×3), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxamide (296 mg, 0.64 mmol, 78%).
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:19][C:18]3[C:13](=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([O:20][CH3:21])[CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1.IC.[CH:27]1C=CC=CC=1>O.CN(C)C=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:27])[CH2:19][C:18]3[C:13](=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([O:20][CH3:21])[CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(Br)cc1)C2
Reactant: c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(Br)cc1)C2
Reaction time: 2 h

Procedure:
Sodium methoxide (28.4 g., 0.522 mole) is added to a stirred mixture of 2-(4-bromophenyl)-5-methoxy-6,7-dichloro-1-indanone (134.6 g., 0.348 mole), iodomethane (217 ml., 3.48 mole), dry benzene (1700 ml.) and dry dimethylformamide (1700 ml.) under nitrogen in an ice-water bath. The reaction mixture is left to come to ambient temperature over 2 hours, then poured into water (8 l.) to precipitate 92.2 g. of 2-(4-bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 200°-203° C., which is not soluble in the benzene present.