Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][CH:2]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CCCCC(N)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCCCC(NS(=O)(=O)c1ccc(C)cc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution (10 ml) of ethyl 6-amino-6-(2-naphthyl)hexanoate (1.0 g) and 4-methylbenzenesulfonyl chloride (0.73 g) in THF was added triethylamine (0.39 g) dropwise and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was dried and concentrated and the crude residue was recrystallized from ethyl acetate-hexane to provide the title compound (1.3 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].C(OCC)C>C(OCC)(=O)C>[ClH:35].[ClH:35].[CH:32]([N:29]1[CH2:28][CH2:27][CH:26]([O:25][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:24]3)[CH2:31][CH2:30]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (800 mg, 1.7 mmol) in ethyl acetate (25 ml) was treated with hydrogen chloride (5M in ethyl acetate, 12 ml) and the mixture stirred 72 h at room temperature. The resulting suspension was cooled to 0° C. (ice-bath), diethyl ether (2 ml) added and the mixture stirred 1 h. The precipitate was filtered and dried under vacuum to afford the title compound as an off-white solid. MS (m/z): 371.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10]>>[N:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CCCl
Reactant: c1cn[nH]c1
Product: O=C(O)CCn1cccn1

Procedure:
6.8 g of pyrazole were reacted with ethyl 3-chloropropionate as in Example 3 and processed further in a similar manner. 11.8 g ([lacuna] of theory) of 3-(N-pyrazolyl)propionic acid are obtained as a white powder of m.p. 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cc(F)cc2cn[nH]c12
Reactant: CC(C)CI
Product: COC(=O)c1cc(F)cc2cnn(CC(C)C)c12
Yield: 41 %

Procedure:
Compound 11 was prepared following general method 1, using 5-fluoro-1H-indazole-7-carboxylic acid methyl ester (see WO2011008572, incorporated by reference in its entirety) as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 41%.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([Cl:39])[CH:33]=2)=[CH:28][CH:27]=1)C1C=CC=CC=1>>[ClH:39].[OH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:33]=[C:34]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[N:35]=[C:36]([CH3:38])[N:37]=2)=[CH:30][CH:31]=1
Reactant: Cc1nc(Cl)cc(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: OCCCCN1CCC(c2ccccc2)CC1
Product: Cc1nc(OCCCCN2CCC(c3ccccc3)CC2)cc(-c2ccc(O)cc2)n1
Product: Cl

Procedure:
Using 4-(4-phenylpiperidino)-1-butanol and 6-(4-benzyloxyphenyl)-4-chloro-2-methylpyrimidine, the procedure of Reference Example 25, which appears hereinafter, was otherwise followed to provide the title compound. m.p. 182-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[OH:24])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: O=C(O)c1ccccc1O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccccc3O)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 2-hydroxybenzoic acid as brown solid (46%). MS 438 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([C:17](=[O:18])[C:16]([Cl:21])([Cl:20])[Cl:15])=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc2nccn12
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Yield: 74.2 %

Procedure:
To a solution of 25.22 g (0.133 mol) of 5-ethoxycarbonylimidazo[1,2-a]pyridine and 48.60 g (0.398 mol) of 4-dimethylaminopyridine was added dropwise 72.33 g (0.398 mol) of trichloroacetyl chloride. The mixture was heated for 63 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:1) to give 33.10 g of the desired compound (77.4%, yellow solid).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22](Cl)=[O:23])=[CH:17][CH:16]=1.C1C2C(=CC=CC=2)C=CC=1OCCOC1C=CC(C(=O)C(O)=O)=CC=1.Cl.[CH3:52][NH:53][OH:54]>ClCCl.N1C=CC=CC=1.O>[OH:54][N:53]([CH3:52])[C:22](=[O:23])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: CNO
Agent: Cl
Agent: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(O)C(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetyl chloride, derived from 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (0.312 g) in the previously described manner (Example 6), in dichloromethane was treated with a solution of N-methylhydroxylamine hydrochloride (0.094 g) in pyridine (1.5 mL). After the reaction solution was stirred at room temperature for 18 hours, it was concentated in vacuo and then diluted with water. The resulting fine yellow precipitate was filtered off, dried and crystallized from methanol-water to afford 0.129 g of N-hydroxy-N-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetamide, mp 161°-165° C.
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[Br:9][C:10]1[C:11]([OH:20])=[C:12]([C:16]([O:18][CH3:19])=[O:17])[S:13][C:14]=1[Br:15]>CN(C=O)C.C(OCC)C>[Br:9][C:10]1[C:11]([O:20][CH3:3])=[C:12]([C:16]([O:18][CH3:19])=[O:17])[S:13][C:14]=1[Br:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(Br)c(Br)c1O
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1sc(Br)c(Br)c1OC
Reaction time: 18 h
Yield: 80 %

Procedure:
9.97 ml of a solution of iodomethane and then 29.44 g of K2CO3 are added, dropwise, to a solution of 34.35 g of methyl 4,5-dibromo-3-hydroxythiophene-2-carboxylate in 150 ml of DMF and the mixture is left to stir for 18 hours at AT. After cooling, the reaction mixture is diluted in 100 ml of ethyl ether and filtered, and the filtrate is concentrated under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane/EtOAc mixture (85/15; v/v). 28.70 g of the expected compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:28]#[N:29])=[C:23](B(O)O)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=2)[CH:20]=1
Reactant: CCOC(=O)C(C(C)C)n1ccc(Br)cc1=O
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: CCOC(=O)C(C(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
240 mg (purity 92%, 0.73 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-methylbutanoate (racemate) and 172 mg (0.95 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/monodichloromethane adduct were reacted according to General Method 2A. Yield: 117 mg (purity 81%, 36% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=N1.CN1CCOCC1.N1CC=CC1>CN(C)C=O>[N:19]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[CH3:11])=[O:8])[CH2:20][CH:25]=[CH:24][CH2:23]1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C1=CCNC1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)N1CC=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
25.0 g (0.12 mol) of 4-bromo-2-methylbenzoic acid is dissolved in 250 mL of dimethylformamide and after the addition of 41.7 g (0.13 mol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 14.3 mL (0.13 mol) of N-methylmorpholine and 9.6 mL (0.12 mol) of 2,5-dihydropyrrole, the mixture is stirred for 16 hours at ambient temperature. Then it is poured onto ice water and extracted with ethyl acetate. The combined organic extracts are washed with sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated by evaporation. Yield: 31.6 g (97% of theory); Rf value: 0.45 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.CN.C1C=CC2N(O)N=[N:40][C:38]=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:40][CH3:38])=[O:30])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: COc1ncc(Br)c2c1c(-c1ccc(CC(=O)O)cc1)nn2-c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)cnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (4-(7-bromo-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetic acid (60 mg), methylamine hydrochloride (12.8 mg), HOBt (25 mg) and triethylamine (26 μL) in DMF (3 mL) was added EDCI hydrochloride (36 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (57 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>O>[O:13]=[C:11](/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=1)/[CH:12]=[CH:17]/[C:16]([OH:19])=[O:18]
Reactant: CC(=O)O
Reactant: CC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Solvent: O
Product: O=C(O)/C=C/C(=O)/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 12 g (56 mmol) of (E)-4-(4-trifluoromethylphenyl)but-3-en-2-one and 5.15 g (56 mmol) of glyoxlic acid monohydrate in 14 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded (E,E)-4-oxo-6-(4-trifluoromethylphenyl)-2,5-hexadienoic acid of melting point 192°-195°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)=[O:8].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)ccc1OC(=O)N1CCOCC1
Yield: 83.2 %

Procedure:
Using 5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[C:6]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:5][CH:4]=1.[CH3:19][NH:20][C:21]([C:23]1[N:24]([CH3:29])[N:25]=[CH:26][C:27]=1[NH2:28])=[O:22]>>[CH3:29][N:24]1[C:23]([C:21](=[O:22])[NH:20][CH3:19])=[C:27]([NH:28][C:9]([C:7]2[C:6]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[N:17][CH:18]=3)=[N:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[CH:26]=[N:25]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: COc1cnc(Nc2cncnc2)c(C(=O)O)n1
Product: CNC(=O)c1c(NC(=O)c2nc(OC)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 6-methoxy-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid (50 mg, 0.18 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (36 mg, 0.23 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (16 mg, 22%).
Reaction SMILES: [Hg:1](OC(C)=O)OC(C)=O.[CH2:10]([O:17][CH2:18][C@@H:19]([OH:49])[C@@H:20]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:22]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]=[CH2:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-:50].[K+]>C1COCC1.CCOC(C)=O>[CH2:26]([O:25][C@H:22]1[C@@H:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:20]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:19]([CH2:18][O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:49][C@@H:23]1[CH2:24][Hg:1][Cl:50])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)O[Hg]OC(C)=O
Reactant: C=C[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cl[Hg]C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a suspension of Hg(OAc)2 (0.88 g, 2.8 mmol, 1.0 equiv) in dry THF (50 mL) under nitrogen atmosphere was added (2R,3R,4R,5R)-1,3,4,5-tetrakis(benzyloxy)hept-6-en-2-ol (1.5 g, 2.78 mmol, 1.0 equiv) dissolved in 20 mL of dry THF. The reaction was stirred at room temperature for 16 hours and then a saturated aqueous solution of potassium chloride (0.50 g, 4.5 mmol, 1.6 equiv) was added. After 30 minutes, the reaction mixture was diluted with EtOAc (80 mL), washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)mercury(II) chloride as a pale yellow oil (1.5 g, 72%). 1H NMR (300 MHz, CDCl3) δ 7.45-7.15 (m, 20H), 4.62-4.39 (m, 7H), 4.33 (d, J=11.9 Hz, 1H), 4.24-4.11 (m, 1H), 4.08 (ddd, J=7.7, 5.9, 2.2 Hz, 1H), 3.89-3.76 (m, 2H), 3.72 (dd, J=4.2, 2.3 Hz, 1H), 3.68-3.57 (m, 1H), 3.39 (dd, J=8.5, 2.9 Hz, 1H), 2.18-1.96 (m, 2H). ESI (M+H2O) 792.0; calc for C35H37ClHgO5 774.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1(CO)c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.6 %

Procedure:
To 2-(4-fluoro-phenyl)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.9 g) in a round bottom flask was added Dess-Martin periodinane solution (47 mL of a 15% solution in DCM, CAS [87413-09-0]) and the reaction mixture was stirred for 5 hours at RT. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate solution (25 mL) and stirred a further 20 minutes. The phases were separated and the aqueous was extracted with further DCM (25 mL). The combined organic phases were washed with saturated sodium bicarbonate solution and dried over sodium sulfate. Filtration of the drying agent and evaporation of the volatiles in vacuo afforded the desired 2-(4-fluoro-phenyl)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.13 g, MS (ES+): 294.1 (MH+)) as a brown solid which was taken into the next step without further purification.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14].[C:24]1(C)C=CC=CC=1>S(=O)(=O)(O)O>[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C@H:7]2[C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:9][O:10][CH2:24][O:8]2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccccc1
Reactant: C=CCCCC(CO)CO
Reactant: CCCCOc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Product: C=CCCC[C@@H]1COCO[C@H]1c1ccc(OCCCC)cc1
Reaction time: 2.5 h

Procedure:
A mixture of 3.6 g of 2-(4-pentenyl)-1,3-propanediol, 4.4 g of p-butoxybenzaldehyde, 75 ml of toluene and 3 drops of 10% sulphuric acid was heated to boiling for 2.5 hours, whereby about 50 ml of wet solvent were distilled off and were replaced by the dropwise addition of 50 ml of fresh toluene. Thereafter, the mixture was neutralized with 4 drops of triethylamine and, after cooling, was extracted twice with 50 ml of 5% sodium hydrogen carbonate solution each time and twice with 50 ml of water each time. The organic phase was dried over sodium sulphate and concentrated. The residue (7.5 g) was chromatographed on silica gel with hexane/ethyl acetate (vol. 92:8), whereby 4.2 g of trans-4-(p-butoxyphenyl)-5-(4-pentenyl)-m-dioxane were obtained. Two-fold recrystallization from hexane gave 2.2 g of pure product with m.p. (C-N) 29.5° C. and cl.p. (N-I) 30.7° C.
Reaction SMILES: [F:1][C:2]([CH3:37])([CH3:36])[CH2:3][CH2:4][CH:5]([C:33](=[S:35])[NH2:34])[CH2:6][CH:7]([O:29]C(=O)C)[CH:8]([NH:16][C:17]([C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:9]([CH:8]([NH:16][C:17]([C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)=[O:18])[CH:7]([OH:29])[CH2:6][CH:5]([C:33](=[S:35])[NH2:34])[CH2:4][CH2:3][C:2]([F:1])([CH3:37])[CH3:36])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(N)=S)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=S
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of acetic acid 6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-3-thiocarbamoyl-heptyl ester in methanol is added 2.0 equivalents of potassium carbonate, stirred for approximately 5 hours, and concentrated. The crude product is dissolved in ethyl acetate and water. The organic layer is then washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gives the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.Br[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CC([O-])=O.[Na+]>CC(N(C)C)=O>[CH:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[C:2](=[CH:1][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: N#Cc1ccccc1Br
Reactant: C=C1c2ccccc2CCc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Sparge a mixture of 5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.0 g, 9.7 mmol) (prepared as described in Journal of Organic Chemistry, 53 (8) 1768-1774 (1988)), 2-bromobenzonitrile ((1.77 g, 9.7 mmol), NaOAc (1 g, 12 mmol) and dimethylacetamide (100 mL) with nitrogen for 15 minutes. Add Hermann catalyst (320 mg, 0.46 mmol)(Chem. Eur. J. 1357-1364 (1997)) and heat at 150° C. for 6 days. Cool the reaction and partition between water (1 L) and EtOAc (500 mL). Wash the organic layer with water (3×1L). Dry (MgSO4) and concentrate under reduced pressure to give 3.3 g brown oil. Purify on silica gel using EtOAc/hexane 500 mg nitrile that is 81% pure by glc. Recrystallize (EtOH) to give 213 mg (7%) pale yellow plates, mp 185.4° C. 1H NMR (CDCl3) δ 3.04 (br d, 2H), 3.47 (br s, 2H), 6.82-7.34 (m, 11H), 7.62 (m, 2H); MS (ES) 308 (M+1). HPLC shows 98% purity.
Reaction SMILES: [NH:1]([C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1)[C:2]([NH2:4])=[NH:3].[ClH:16].[CH3:17][OH:18]>C(Cl)(Cl)Cl>[ClH:16].[NH:1]([C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:15])[O:18][CH3:17])[N:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N#CCCCCn1ncc(NC(=N)N)n1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCCn1ncc(NC(=N)N)n1
Reaction time: 72 h

Procedure:
A solution of 5-(4-guanidino-1,2,3-triazol-2-yl)valeronitrile (0.41 g.) in chloroform (15 ml.) and MeOH (4 ml.) was saturated at 0° with gaseous hydrogen chloride and the solution kept at 0° for 3 days. Lvaporation gave methyl 5-(4-guanidino-1,2,3-triazol-2-yl)valerimidate hydrochloride which was used without further purification.