Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][NH:12][S:13]([C:16]3[CH:36]=[CH:35][C:19]4[O:20]C(C5C=CC=CC=5)(C5C=CC=CC=5)[O:22][C:18]=4[CH:17]=3)(=[O:15])=[O:14])[N:10]=[C:6]2[N:5]=[C:4]([CH3:37])[CH:3]=1.CC(O[CH2:42][C:43]1[CH2:52][S:51][C@@H:46]2[C@H:47]([NH2:50])[C:48](=[O:49])[N:45]2[C:44]=1[C:53]([OH:55])=[O:54])=O.B(F)(F)F>C(#N)C>[NH2:50][C@@H:47]1[C:48](=[O:49])[N:45]2[C@@H:46]1[S:51][CH2:52][C:43]([CH2:42][S:1][C:2]1[N:7]3[N:8]=[C:9]([CH2:11][NH:12][S:13]([C:16]4[CH:36]=[CH:35][C:19]([OH:20])=[C:18]([OH:22])[CH:17]=4)(=[O:14])=[O:15])[N:10]=[C:6]3[N:5]=[C:4]([CH3:37])[CH:3]=1)=[C:44]2[C:53]([OH:55])=[O:54]
Reactant: Cc1cc(S)n2nc(CNS(=O)(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(CNS(=O)(=O)c3ccc(O)c(O)c3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
N-[[7-Mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl]methyl]-2,2-diphenyl-1,3-benzodioxol-5-sulphonamide (0.27 g) and 0.14 g of 7-aminocephalosporanic acid are stirred at room temperature for 4 hours with 3.0 ml of a 20% solution of boron trifluoride in acetonitrile. After the addition of 5 ml of ice-water the reaction mixture is partitioned between water and ethyl acetate. The pH value is adjusted to 7.0 with 3N aqueous sodium hydroxide solution. The phases are separated. The aqueous phase is adjusted to pH 2.0 with concentrated aqueous hydrochloric acid. The precipitate formed is filtered off. The still moist precipitate is dissolved in trifluoroacetic acid and stirred at room temperature for 2 hours. The trifluoroacetic acid is evaporated in a water-jet vacuum and the residue is treated with ethyl acetate. The precipitate is filtered off and dried under a high vacuum. There is obtained 0.2 g of (6R,7R)-7-amino-3-[[[2-[(3,4-dihydroxybenzenesulphonamido)methyl]-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a pale beige powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:28]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[OH:36])[CH2:29]1>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:33]1[CH2:34][CH2:35][C:30]2([CH2:28][CH2:29]2)[C@H:31]([OH:36])[CH2:32]1
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2ccc(C(F)(F)F)cc2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(C(F)(F)F)cc2)CCC1=O
Yield: 75 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-[7-oxo-4-(4-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 75% yield as light yellow foam. MS: 484.4 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:6])[CH2:3][CH2:2]1>C(O)C.C(O)(=O)C.[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C=Cc2cccc(F)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2cccc(F)c2)cc1
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a mixed solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[2-(3-fluorophenyl)vinyl]-1H-1,2,3-triazole-4-carboxamide (140 mg) obtained in Example 419 in ethanol/acetic acid (1/3, 8 ml) was added Pd/C (80 mg), and the mixture was stirred under a hydrogen stream for 15 hr. The catalyst was removed by filtration through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (110 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:11][C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)=[O:32])[CH2:29][CH2:30]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: O=C(Cl)N1CCN(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Oc1n[nH]c2cc(F)ccc12)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were dissolved in 5 ml of pyridine. Addition of 365 μl (2.63 mmol) of triethylamine and 355 mg (1.56 mmol) of 4-phenyl-piperazine-1-carbonyl chloride was followed by stirring at room temperature for 3 h. Addition of 730 μl of triethylamine and 177 mg of 4-phenylpiperazine-1-carbonyl chloride was followed by stirring for a further 20 h. The reaction mixture was concentrated and mixed with water and ethyl acetate, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 12 mg (2%), M+H+: 529.34, 6-fluoro-1-(4-phenylpiperazine-1-carbonyl)-1H-indazol-3-yl 4-phenylpiperazine-1-carboxylate; 30 mg, (4%), M+H+: 529.40, 6-fluoro-1,2-bis(4-phenylpiperazine-1-carbonyl)-1,2-dihydroindazol-3-one. It was additionally possible to isolate 6-fluoro-1H-indazol-3-yl 4-phenylpiperazine-1-carboxylate as compound not of the invention.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
1.57 g (10 mmol) of bromobenzene and 4.15 g (30 mmol) of K2CO3 are added to a solution of 1.83 g (15 mmol) of phenylboronic acid in 20 ml of tetrahydrofuran. After the mixture has been stirred at room temperature for 15 minutes, 0.21 g (0.15 mmol) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is added, and the reaction mixture is heated under reflux for 3 hours. After cooling and addition of 100 ml of water, the reaction mixture is extracted with 200 ml of hexane. The organic phase is washed with water and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 0.99 g of biphenyl is isolated as a white solid. The yield is 64%, based on the bromobenzene employed.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12].[O-]CC.[Na+]>C(O)C>[C:11]([NH:14][C:15]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC=Cc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Yield: 32.2 %

Procedure:
A solution of 5.42 g of cinnamyl bromide, 5.43 g of diethyl 2-acetamidomalonate and 1.87 g of sodium ethoxide in 70 ml of ethanol was refluxed under heating for 2 hours under a nitrogen atmosphere. The mixture was poured into 200 ml of ice water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:3) to give 2.68 g of diethyl 2-acetamido-2-(3-phenyl-2-propenyl)malonate as white crystals.
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:8]=[CH:7][C:6]=1[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23]>O1CCOCC1>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[N:9]1[C:5]([NH:2][NH2:3])=[C:6]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:7]=[N:8]1
Reactant: O=S(=O)(c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1c(S(=O)(=O)C(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
2.5 ml (0.065 mole) of hydrazine hydrate are added to 10 g (0.02 mole) of 5-bromo-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylsulphonyl-pyrazole in 140 ml of dioxane at room temperature and the mixture is warmed at 60° C. with stirring for 4 hours. For work-up, the solvent is removed in vacuo and the oil remaining is purified by chromatography (silica gel, eluent: dichloromethane). 6.5 g (72% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-hydrazino-4-trifluoromethylsulphonyl-pyrazole of melting point 154° C. are obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][C:14](=[CH:17]NC1C=CC=CC=1)[C:15]#[N:16])[CH3:2].Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C[O-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][C:14]1[C:15]([NH2:16])=[N:28][C:27]([NH2:29])=[N:26][CH:17]=1)[CH3:2]
Reactant: N=C(N)N
Reactant: CCc1c(OC(C#N)=CNc2ccccc2)cc(C)c2sccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1c(Oc2cnc(N)nc2N)cc(C)c2sccc12
Yield: 80.2 %

Procedure:
2-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-3-phenylamino-acrylonitrile (360 mg, 1 mmol), guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 5 mL absolute ethanol were heated to reflux in 5 ml absolute ethanol for 2 hours. Premixed guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 1 ml EtOH was added via pipette, and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled, diluted with water, extracted twice with EtOAc, washed with brine, and dried over magnesium sulfate. Solvent was removed in vacuo to give 241 mg of 5-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-pyrimidine-2,4-diamine as a white solid (74% ). Mass Spec M+H=301, M.P.=181 OC. Recrystallization of 175 mg of this product from MeOH and HCl/diethyl ether afforded 98 mg of the corresponding HCl salt 49% ., Mass Spec M+H=301, M.P.>300 C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7]>CO.O=[Pt]=O>[CH3:9][O:8][C:6](=[O:7])[CH2:5][C@@H:4]1[C:3](=[O:2])[NH:17][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:10]1
Reactant: COC(=O)C[C@@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)C[C@H]1Nc2ccccc2NC1=O
Reaction time: 6 h

Procedure:
A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared below), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80–6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:12][CH2:13][C:14]#[CH:15])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:12][CH2:13][C:14]#[CH:15])=[N:4][C:5]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[N:6][C:7]=1[Cl:8]
Reactant: c1ccc2[nH]ncc2c1
Reactant: C#CCNc1nc(S(C)=O)nc(Cl)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 0.5 g (1.62 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)-N-(prop-2-ynyl)pyrimidine-4-amine (intermediate 31) in 2 ml of DMSO, 0.19 g (1.62 mmol) indazole and 0.32 g of cesium carbonate were added. The slightly yellow solution was stirred at room temperature for 20 minutes. The reaction mixture was poured onto 10 ml of cold water. The resulting precipitate was filtered, washed with cold water and dried. The desired product was obtained as a white solid 0.31 g (52.8%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:7]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cncc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of ethyl {4-[((2-methoxyethyl){6-[4-(trifluoromethyl)phenyl]pyrazin-2-yl}amino)methyl]-2-methylphenoxy}acetate (160 mg, 0.32 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 2M sodium hydroxide (2 mL). The resulting mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was diluted with water (10 mL) acidified with 2M HCl and extracted with ethyl acetate (2×30 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as a bright yellow solid (140 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+]>CN(C)C=O.O>[F:18][CH:14]([F:19])[O:12][C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[OH:3]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
Sodium hydroxide (4.8 g, 120 mmoles) is added to a solution of 3,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and sodium chlorodifluoroacetate (18.3 g, 120 mmol) in dimethylformamide (150 mL) and water (3 mL). The mixture is heated to 120° C. and stirred at this temperature for 2 hours. The solvent is removed by vacuum distillation and aqueous hydrochloric acid (20 mL) is added to the residue. The mixture is extracted with diethyl ether (2×50 ml), the combined organic layers are washed with water and brine and the solvent removed under reduced pressure. The crude product is purified by chromatography on silica gel (hexane/ethyl acetate 8:2) to furnish 4-difluoromethoxy-3-hydroxybenzaldehyde as a colourless solid (10 g).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]1([CH2:32][C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C[O-].[Na+].Cl>CN(C=O)C.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]2([CH2:32][C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC1(CC(=O)O)CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(C(=O)NC2(CC(=O)O)CCCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 20000 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.3 μmol) and (1-amino-cyclohexyl)-acetic acid (245 mg, 1.56 mmol) (Matrix Scientific, Columbia S.C.) in 3 mL of DMF was added NaOMe solid (67 mg, 1.25 mmol). The resultant mixture was heated in a 150° C. oil bath for 7 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, dried and the purified by silica gel chromatography, eluting with 10-70% EtOAc/hexanes to provide the title compound 27 mg (0.06 mmol) in 19% yield. LC-MS ESI−: 443.95 (M−1)−.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH2:20])[C:17]=3[C:7]1=2.C(N(CC)CC)C>CN(C)C=O>[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH:20][C:1](=[O:3])[CH3:2])[C:17]=3[C:7]1=2
Reactant: CC(=O)Cl
Reactant: NCCC1=CCc2ccc3c(c21)CCO3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1=CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Acetyl chloride (0.24 g, 3.03 mmol) was slowly added dropwise to an ice-cooled solution of 2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (0.6 g, 2.52 mmol) and triethylamine (0.64 g, 6.31 mmol) in N,N-dimethylformamide (60 mL). After overnight stirring at room temperature, the reaction mixture was concentrated and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) and further recrystallized from ethyl acetate to give 425 mg (yield: 70%) of the target compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([NH2:11])[C@@H:9]([O:12][C:13](=[O:15])[CH3:14])[C@H:8]([O:16][C:17](=[O:19])[CH3:18])[C@@H:7]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:6]1)(=[O:3])[CH3:2].[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:43]([NH:42][C:40]([O:39][CH2:38][CH:36]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:37]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:41])=[S:44])[C@@H:9]([O:12][C:13](=[O:15])[CH3:14])[C@H:8]([O:16][C:17](=[O:19])[CH3:18])[C@@H:7]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:6]1)(=[O:3])[CH3:2]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
The amine from above (220 mg) was dissolved in pyridine (5 mL) and 9-Fluorenylmethoxycarbonyl isothiocyanate (180 mg, 0.65 mmol) and triethylamine (0.02 mL) was added. Then the resulting mixture was stirred at room temperature for 16 h. The solution was concentrated and the residue taken up in CH2Cl2 (20 mL) and diluted with saturated aqueous NaHCO3 (20 mL), then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. Flash chromatography of the residue (EtOAc:hexanes 2:3) gave (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(((9H-fluoren-9-yl)methoxy)carbonyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (360 mg, 89% yield over two steps). 1H NMR (600 MHz, CDCl3) δ 2.06 (s, 3H), 2.07 (s, 3H), 2.12 (s, 3H), 2.14 (s, 3H), 3.89 (ddd, 1H, J=2.4, 4.8, 9.6 Hz), 4.17 (dd, 1H, J=2.4, 12.5 Hz), 4.24 (dd, 1H, J=6.6, 6.6 Hz), 4.33 (dd, 1H, J=4.8, 12.5 Hz), 4.52 (s, 1H), 4.54 (s, 1H), 5.08-5.12 (m, 1H), 5.22 (dd, 1H, J=9.5, 9.6 Hz), 5.34 (dd, 1H, J=6.6, 9.5 Hz), 5.88 (d, 1H, J=6.6 Hz), 7.36 (dd, 2H, J=7.2, 7.8 Hz), 7.45 (dd, 2H, J=7.2, 7.8 Hz), 7.57 (d, 2H, J=7.8 Hz), 7.80 (d, 2H, J=7.2 Hz). 13C NMR (150 MHz, CDCl3) δ 20.62, 20.72, 20.77, 21.05, 46.49, 57.59, 61.65, 67.47, 68.40, 72.21, 72.87, 92.21, 120.09, 120.29, 124.84, 124.96, 125.32, 127.30, 127.83, 128.15, 128.25, 129.06, 141.37, 142.80, 152.16, 169.27, 169.34, 170.46, 170.72, 180.22.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.O=S(Cl)[Cl:14].CN(C=O)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]([C:7]([Cl:14])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(I)ccc1O

Procedure:
5-Iodosalicylic acid (2.0 g, 7.58 mmol) in toluene was treated with SOCl2 (1.66 mL, 22.7 mmol) and catalytic DMF at reflux for 1 h. The reaction mixture was evaporated to dryness and the acid chloride used in the next step without purification.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3=[N:16][S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 3-[4-(1-methylethyl)phenyl]pyridin-2-amine (700 mg) in dehydrated THF (15 mL) was added to a mixture of sodium hydride (60%, 659 mg) and 2-chloroethanesulfonyl chloride (1613 mg) in dehydrated THF (15 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (738 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12](NCCCC)CCC.C(O)(=O)C.C=O>C1(C)C=CC=CC=1>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: CCCCNCCCC
Reactant: O=C1CCCc2ccccc21
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C1CCc2ccccc2C1=O
Temperature: 90 °C

Procedure:
A 100-ml pressure-proof glass reaction vessel was charged with 2.92 g (0.02 mole) of 1-tetralone, 2.59 g (0.02 mole) of di-n-butylamine, 1.20 g (0.02 mole) of acetic acid and 15 ml of toluene. To the mixture 0.974 g (0.012 mole) of an 37% aqueous formaldehyde solution was added and the vessel was sealed and heated up to 90° C. After maintaining the temperature at 90° C. for 30 minutes, the vessel was cooled to room temperature. The contents were separated by addition of 5 ml of water, and the water layer was washed off with a 50% aqueous acetic acid solution. The toluene layer was further washed with a 10% aqueous hydrochloric acid, saturated aqueous NaHCO3 solution and saturated aqueous sodium chloride solution, to give a solution of 2-methylene-1-tetralone in toluene. The reaction mixture was analyzed by GLC and its composition was found to be 1.45 g of 2-methylene-1-tetralone and 1.16 g of unreacted 1-tetralone (the conversion of 1-tetralone: 60.2%; selectivity: 82.1%).