Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].O.[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:10]([N+:27]([O-])=O)[CH:9]=1)(=[O:7])=[O:6]>[Fe].C(O)(C)C>[NH2:27][C:10]1[CH:9]=[C:8]([S:5]([CH3:4])(=[O:6])=[O:7])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCOc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(S(C)(=O)=O)cc1N

Procedure:
A mixture of 25.2 g of iron powder, 1 g of ammonium chloride, 25 ml of water and 250 ml of isopropanol was heated and stirred in a nitrogen stream. To the mixture 23.1 g of dodecyl 4-methylsulfonyl-2-nitrophenyl ether was added. After the conclusion of the addition and a 1-hour stirring, the resulting solution was filtrated out by a Nusche coated sellaite therein. The reaction mixture was concentrated, and to the mixture methanol was added to deposit 17.5 g of dodecyl 2-amino-4-methylsulfonylphenyl ether crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH2:14]1[O:32][C:31]2[CH:30]=[CH:29][C:18]([CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=3)=[CH:17][C:16]=2[O:15]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:18]3[CH:29]=[CH:30][C:31]4[O:32][CH2:14][O:15][C:16]=4[CH:17]=3)=[CH:25][N:24]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CSc1ncc(Cc2ccc3c(c2)OCO3)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc3c(c2)OCO3)c(=O)[nH]1
Yield: 77.7 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.88 g) and 5-(3,4-methylenedioxybenzyl)-2-methylthio-4-pyrimidone (0.83 g) were refluxed in pyridine (3 ml) for 24 hours. The pyridine was removed in vacuo and the resulting brown oil triturated with ethanol giving a cream solid which was recrystallised from dimethylformamide/ethanol giving 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(3,4-methylenedioxybenzyl)-4-pyrimidone (1.1 g) as a colourless solid m.p. 145°-6° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.CC1C=CC(S(O[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=2[CH:14]=1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCOCCOc1ccc2c(c1)OC(C)(C)OC2=O
Yield: 74.2 %

Procedure:
A solution of 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one, (19.4 g, 100 mmol), 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (27.4 g, 100 mmol) and K2CO3 (41 g, 300 mmol) in CH3CN (500 mL) was refluxed for 4.5 hours. The mixture was poured in H2O (1000 mL) and extracted twice with CH2Cl2 (500 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc=9/1) to give the title compound (22 g) as white solid. LC-MS (ES, m/z): 297 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:6][C:5]=2[O:4]1.[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][CH:12]([C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:15]([F:16])([F:17])[F:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCC(c1ccc2c(c1)OCO2)C(F)(F)F
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.5 %

Procedure:
Under a nitrogen atmosphere, 0.18 g of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 1.0 g of 2-(3,4-methylenedioxyphenyl)-3,3,3-trifluoropropanol and 1.17 g of 3-phenoxybenzyl bromide in 10 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred at room temperature for 14 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 1.2 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].I[CH3:25].[OH-].[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH3:25])[C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CI
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2c1c(=O)c1ccccc1n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.11 g, 4.0 mmol) in N,N-dimethylformamide (16 mL), sodium hydride (oiliness, content 60%, 0.19 g, 4.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, iodomethane (2.5 mL, 40.2 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for additional 16 hours. To the mixture was added iced water, and the mixture was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (0.47 g, 40% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([CH:16]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:17](OC(=O)C)(=[O:19])[CH3:18].S(=O)(=O)(O)O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2cn3ccsc3n2)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1c(-c2cccc(C#N)c2)nc2sccn12
Temperature: 135 °C
Yield: 74 %

Procedure:
To a mixture of 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (5.50 g, 24.4 mmol) and acetic anhydride (50 mL) was added 0.6 mL of concentrated sulfuric acid. The reaction mixture was heated at 135° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL×2), saturated aqueous sodium bicarbonate solution (50 mL×2), water (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Product was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in hexane to yield 4.8 g (74%) of the title compound as a light yellow solid. LCMS: 268 [M+H].
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>[Ni].O>[C:1](#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN
Agent: [Ni]
Solvent: O
Product: CCCCCCCCC#N
Temperature: 90 °C
Yield: 98 %

Procedure:
50 g of nonylamine and 50 g of water are introduced into a 750-ml autoclave equipped with a self-aspirating turbine. 5 g of basified Raney nickel doped with 2% by weight of Cr are added. The reactor is flushed with twice 10 bar of nitrogen and then with twice 10 bar of hydrogen. The autoclave is placed under 20 bar of hydrogen, and stirring and heating to 90° C. are carried out. The nonanenitrile resulting from example 5 is then injected using a pump, while keeping the hydrogen pressure constant in the reactor. 350 g of nonanenitrile are injected over the course of 4 h. After the end of the injection, the reaction medium is maintained under the same conditions for 30 min. The temperature is then brought back to 20° C., the reactor is flushed with nitrogen and the catalyst is filtered off. The reaction medium is then distilled under reduced pressure: in this way, the nonylamine is recovered with a yield of 98% (boiling point 201° C. under 760 mmHg).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[CH3:22][O:21][C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:23]([O-:25])=[O:24])[C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Dimethyl malonate (6.0 mL) was added to the ice-cold suspension of 2.1 g of sodium hydride in 16 mL of DMSO. The reaction mixture was then stirred at 100° C. for 1 hour and cooled to room temperature. 2-chloro-3-methoxycarbonyl-nitrobenzene (2.15 g) was added to the above mixture in one portion and the mixture was heated to 100° C. for 1.5 hours. The reaction mixture was then cooled to room temperature and poured into ice water, acidified to pH of 5, and extracted with ethyl acetate. The organic layer was then washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3.0 g of the dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:19])=[CH:9][C:10]=3[N+]([O-])=O)[C:5](=[O:20])[C:4]=2[CH:3]=1.[F-:21].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:19])=[CH:9][C:10]=3[F:21])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc(Cl)nc12
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2oc2c(F)cc(Cl)nc12
Reaction time: 0.25 h

Procedure:
To a solution of 8-bromo-2-chloro-4-nitro-10H-chromeno[3,2-b]pyridin-10-one (80 mg, 0.225 mmol) in 0.8 mL of DMF at 0° C. was added tetrabutylammonium fluoride (1M in THF, 0.45 mL, 0.450 mmol) dropwise. After 15 minutes, the reaction was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (SiO2, CH2Cl2 to CH2Cl2/EA=100:3) gave 8-bromo-2-chloro-4-fluoro-10H-chromeno[3,2-b]pyridin-10-one as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[CH3:2].[C:27]1(=[O:32])[CH2:31][CH2:30][CH:29]=[CH:28]1>F[B-](F)(F)F>[O:32]=[C:27]1[CH2:31][CH2:30][C@@H:29]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=2)[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH2:28]1
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Product: CCOC(=O)COc1cc([C@@H]2CCC(=O)C2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-phenoxy]-acetic acid ethyl ester and 2-cyclopenten-1-one with Rh(R-BINAP)(nbd)]BF4 as catalyst in a manner similar to the one described for Preparation 6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[N:3]=1.C[Si]([N:30]=[N+:31]=[N-:32])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:4]1[N:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]3[NH:32][N:31]=[N:30][N:12]=3)=[CH:13][CH:14]=2)[N:5]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)c(OC)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2nc(N)n(-c3ccc(-c4nnn[nH]4)cc3)n2)c(OC)c1
Temperature: 110 °C
Yield: 22.8 %

Procedure:
4-[5-Amino-3-(2,4-dimethoxy-phenylamino)-[1,2,4]triazol-1-yl]-benzonitrile (52 mg, 0.15 mmol) and trimethylsilyl azide (20 mg, 0.165 mol) were suspended in 1 mL toluene with a catalytic amount of di-butyltin oxide and heated to 110° C. for 18 hours. The toluene was evaporated and the residue purified by preparative HPLC affording 13 mg product as the TFA salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]1[C:16](=[O:24])[CH:17]=[C:18]([C:20]([O:22]C)=[O:21])[NH:19][C:9]=1[C:8]=2[Cl:25])=[O:4].[OH-].[Na+].Cl>O>[Cl:25][C:8]1[C:7]2[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13](=[O:15])[C:12]=2[CH:11]=[C:10]2[C:9]=1[NH:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16]2=[O:24]
Reactant: COC(=O)c1cc(=O)c2cc3c(=O)cc(C(=O)OC)[nH]c3c(Cl)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(=O)c2cc3c(=O)cc(C(=O)O)[nH]c3c(Cl)c2[nH]1

Procedure:
1.05 g. of the diester compound prepared in Example 6 is heated at reflux for 1 hour in 20 ml. of 5% sodium hydroxide. The mixture is cooled, 10 ml. of water added, and the pH adjusted to 3 with concentrated hydrochloric acid. The bright yellow diacid is collected by filtration. It has a melting point greater than 310° C.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[NH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=2)[CH2:9]1.[Cl-].[Cl-].[Ca+2]>O1CCCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]2[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:11][CH2:12][N:8]([CH2:7][CH2:6][NH:5][C:2]([NH:1][CH3:4])=[O:3])[CH2:9]2)=[CH:21][CH:22]=1
Reactant: CN=C=O
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CNC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A mixture of 0.9 parts of isocyanatomethane, 5.3 parts of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and 63 parts of tetrahydrofuran was stirred for 1.5 hour at room temperature using a CaCl2 -tube. Another portion of 0.9 parts of isocyanatomethane was added and stirring was continued for 1.5 hour at room temperature. The precipitated product was filtered off, washed with tetrahydrofuran and dried in vacuo at room temperature, yielding 5.0 parts (81%) of N-[2-[3-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-pyrrolidinyl]ethyl]-N'-methylurea; mp. 161.1° C. (compound 188).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([S-:14])[CH3:13].[Na+]>CN(C)C=O>[CH2:12]([S:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:13]
Reactant: CC[S-]
Reactant: Brc1cnc2ccccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cnc2ccccc2c1

Procedure:
3-Ethylthioquinoline is prepared starting from 2.1 g of 3-bromoquinoline and 4.2 g of sodium ethanethiolate in 30 ml of dimethylformamide analogously to Example 52d) and is purified by means of FC over 30 g of silica gel with a 1:2 mixture of diethyl ether and petroleum ether as the mobile phase. This gives the title compound: Rf (F)=0.31.
Reaction SMILES: O1CCCC1.[H-].[Na+].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[C:18]([O:36][CH2:37][CH2:38][OH:39])=[N:19][N:20]([CH3:35])[C:21]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:16][C:11]=2[O:10][CH2:9]1.[Cl:40][C:41]1[CH:42]=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1>CC(N(C)C)=O>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[C:18]([O:36][CH2:37][CH2:38][O:39][C:44]4[N:45]=[CH:46][C:41]([Cl:40])=[CH:42][N:43]=4)=[N:19][N:20]([CH3:35])[C:21]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
In an oven-dried flask a solution of tetrahydrofuran (50 ml) and dimethylacetamide (3 ml) was treated with sodium hydride as a 60% dispersion in oil (460 mg) under an atmosphere of nitrogen. The reaction was stirred for 5 min and then treated with N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (1.0 g) (Preparation 13). The reaction was stirred for 3 h and was then treated with 5-chloro-2(methylsulfonyl)pyrimidine (460 mg). After stirring for a further 3 h the reaction mixture was concentrated and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous was extracted with ethyl acetate (3×75 ml) and the combined organics were dried over sodium sulfate. The solvent was removed and the crude residue was purified on a silica (40 g) column eluting with 20% ether in dichloromethane rising to 45% ether in dichloromethane to yield the title compound as an off-white foam (560 mg).
Reaction SMILES: Cl.Cl.[C@H]1(CN2C[CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.NC1C=C[C:48]([CH2:51][CH2:52][OH:53])=[CH:47]C=1>>[OH:53][CH2:52][CH2:51][C:48]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[C:29]([O:32][CH2:33][C:34]2[C:38]4[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=4[O:36][CH:35]=2)[CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:18][CH:47]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Agent: Cl
Product: O=C(Nc1ccc(CCO)cc1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 42 from 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97) and 2-(4-amino-phenyl)-ethanol.
Reaction SMILES: O.Cl.[C:3]12([CH2:13][CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=3[F:25])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>CO.[Fe]>[C:3]12([CH2:13][CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:25])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: O=[N+]([O-])c1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
To a mixture of water (50 mL) and iron powder (0.88 g, 15.8 mmol) at 65° C. was added concentrated hydrochloric acid (1 mL) dropwise and the mixture was stirred for 15 min. The aqueous layer of the mixture was poured out, and a solution of N-(2-(adamantan-1-yl)ethyl)-2-fluoro-4-nitroaniline (0.5 g, 1.57 mmol) in MeOH (50 mL) was added to the above processed iron powder. The mixture was further stirred at 65° C. for 30 min. The mixture was then cooled to rt and filtered. The filtrate was concentrated and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a white solid (382 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(F)c1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of 3-fluorophenol (3.36 g, 30.0 mmol), ethyl 2-bromo-2-methylpropanoate (8.78 g, 45.0 mmol) and K2CO3 (6.22 g, 45.0 mmol) in acetone (50 mL) was refluxed overnight. The mixture was cooled to rt and 60 mL of water was added. The resulting mixture was extracted with DCM (40 mL×2). The combined organic phases were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as colorless liquid (3.20 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(N)cc2s1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirring solution of 6-nitro -benzo[b]thiophene-2-carboxylic acid methyl ester (3.9 g, 15.8 mmol) in DMF (120 mL) was added 10% Pd/C (700 mg, 10 %). The reaction was charged with H2, degassed and refilled with hydrogen three times. The slurry was stirred at RT for 4 days at balloon pressure, then filtered through a plug of Celite, and solvent was removed under reduced pressure. The solid was washed with EtOAc, and filtered to yield the desired amine. 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 6.78 (d, J=8.4 Hz, 1H), 3.92 (s, 3H). MS (EI): cal'd (MH+) 208.04, exp (MH+) 208.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@:14](CC2C=CC=CC=2)(O)[C@@H:13](O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@](O)(Cc2ccccc2)[C@@H](O)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 43.0 g (126 mmol) (3R,4R) and (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester and 23.1 g (189 mmol) DMAP in 600 ml CH2Cl2 were added dropwise under argon 500 ml (340 mmol, 0.70 N) (S)-N-trifluoroacetyl-prolinechloride. The reaction mixture was stirred for 16 hours at r.t. and then sat. NaHCO3 solution was added. The aqueous phase was extracted three times with CH2Cl2 and the combined organic layers were washed with sat. NaHCO3 and 1N HCl, dried over MgSO4 and the solvent was removed under reduced pressure to give the crude product. Purification by chromatography on silica gel (hexane:ethyl acetate 4:1 to 1:1) and crystallization from diethylether yielded 17.9 g (33 mmol, 27%) (3R,4R), 4-benzyl-4-hydroxy-3-(2S)-trifluoroacetyl-cyclopentanecarbonyloxy)-piperidine-1-carboxylic acid benzyl ester.