Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:50]CCCl>>[CH:3]1[C:4]2[C:13](=[CH:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:14]=[CH:15][C:2]=1[NH:1][CH:21]1[CH2:20][CH2:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([N:17]([CH3:31])[CH3:16])[CH2:23][CH2:22]1.[ClH:50].[CH:3]1[C:4]2[C:13](=[CH:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:14]=[CH:15][C:2]=1[NH:1][CH:21]1[CH2:20][CH2:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([N:17]([CH3:31])[CH3:16])[CH2:23][CH2:22]1
Reactant: Nc1ccc2cc3ccccc3cc2c1
Reactant: ClCCCl
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(Nc2ccc3cc4ccccc4cc3c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
386 mg 2-Aminoanthracene and 434 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude products was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 132 mg of the nonpolar diastereomer of N′-anthracen-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a green solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.46 ml) in 2-butanone (5 ml) (104 mg; m.p. 169-172° C.).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:40]=[CH:39][C:18]([C:19]([NH:21][C:22]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:23]=3[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:38][C:35]1[CH:36]=[CH:37][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[CH:40][CH:39]=2)=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[4-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)benzoylamino]-5-fluoro-N-(5-chloropyridin-2-yl)benzamide (Example P1, 0.59 g) in methylene chloride (3 mL) and anisole (1 mL) was added trifluoroacetic acid (3 mL) dropwise. The mixture was stirred overnight at room temperature before the solvent was evaporated. The residue was purified by using an SCX column. Yield 0.337 g.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]([CH3:36])[CH:13]([CH2:15][C:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH3:14]>C(Cl)Cl.O>[CH3:36][N:12]([CH3:11])[CH:13]([CH2:15][C:16]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH3:14]
Reactant: C=CCCCC(O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: C=CCCCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50.3 %

Procedure:
Anhydrous dimethyl sulfoxide (DMSO, 8.8 ml) was carefully added by syringe to a stirred solution of oxalyl chloride (4.8 ml) in methylene chloride (40 ml), maintained at -50° C. to -60° C. The mixture was then stirred 2 min. A solution of 2-dimethylamino-4,4-diphenyl-9-decene-5-ol (1 g) in methylene chloride (2 ml) was added, and stirring continued for 5 min. The mixture was allowed to warm to room temperature, diluted with water, and washed with sodium bicarbonate solution. Rotary evaporation of the solution gave a crude product which was flash-chromatographed over silica gel. Elution with chloroform/methanol (20:1) yielded 0.5 g of 2-dimethylamino-4,4-diphenyl-9-decene-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.Cl.C(=O)([O-])[OH:29].[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37](Cl)=[O:38]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]1[CH2:10][NH:9][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:42]([Cl:43])=[C:34]([Cl:33])[CH:35]=1)=[O:29]
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(s1)-n1c(nnc1C(F)(F)F)CN=C2c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CNC(=O)c3ccc(Cl)c(Cl)c3)nnc2C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-9-trifluoromethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.0 g) was added to 10% hydrochloric acid (20 ml), and the mixture was stirred at 70° C. overnight. Then, sodium hydrogencarbonate was added to the reaction mixture to make the mixture alkaline. Chloroform (20 ml) and 3,4-dichlorobenzoyl chloride (0.58 g) were added, and the mixture was stirred under ice-cooling for 1 hour. Then, the organic layer was washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 0.60 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-trifluoromethyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:11])([F:10])[C:7](O)=[O:8].[NH2:12][CH2:13][C:14]([OH:16])=O.[NH2:17][C:18]1[C:19]([I:32])=[C:20]([C:29]([Cl:31])=[O:30])[C:21]([I:28])=[C:22]([C:26]=1[I:27])[C:23]([Cl:25])=[O:24]>CC(N(C)C)=O>[I:28][C:21]1[C:20]([C:29]([Cl:31])=[O:30])=[C:19]([I:32])[C:18]([NH:17][C:14](=[O:16])[CH2:13][NH:12][C:7](=[O:8])[C:6]([F:11])([F:10])[F:5])=[C:26]([I:27])[C:22]=1[C:23]([Cl:25])=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: NCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(CNC(=O)C(F)(F)F)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 96 h

Procedure:
14.5 ml (200 mmol) of thionyl chloride is added in drops at 0° C. within 1 hour to a solution of 34.2 g (200 mmol) of glycine trifluoroacetate in 200 ml of dimethylacetamide. Then, 23.8 g (40 mmol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride (DE 2943777, Schering AG, (priority: Oct. 26, 1979)) is added at 0° C. and stirred for 4 days at room temperature. The reaction mixture is poured into 5liters of ice water and the solid that accumulates is filtered off. For further purification, the filter residue is dissolved in 1000 ml of ethyl acetate, shaken out twice with saturated sodium bicarbonate solution, the organic phase is dried on sodium sulfate, and the solvent is concentrated by evaporation in a vacuum.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.CO.[Cl:27]Cl.C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[Cl:27][C:14]1[CH2:13][C@H:12]2[C@H:11]3[C@:2]([F:1])([C@@H:19]([OH:20])[CH2:18][C@:16]2([CH3:17])[C:15]=1[S:21][CH3:22])[C@:3]1([CH3:24])[C:8](=[CH:7][C:6](=[O:23])[CH:5]=[CH:4]1)[CH2:9][CH2:10]3
Reactant: ClCl
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSC1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C

Procedure:
To a solution of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one (100 mg) in a mixture of dry dichloromethane (10 ml) and methanol (8 ml) is added a 0.31 molar solution of chlorine in dichloromethane (1.0 ml). After a few hours, the solution is poured into a dilute sodium bicarbonate solution. The product is isolated by extraction with chloroform and the chloroform solution is washed with water, dried (anhydrous MgSO4) evaporated and the residue is purified by preparative thin layer chromatography to afford the title compound (35 mg), melting point 262°-268° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.S(Cl)([Cl:11])=O.[CH2:13](O)[CH3:14]>>[ClH:11].[CH2:13]([O:7][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:8])[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nc[nH]n1
Reactant: CCO
Product: CCOC(=O)c1nc[nH]n1
Product: Cl
Temperature: 5 °C
Yield: 63.7 %

Procedure:
To 10 ml of a solution of 1.00 g (8.85 mmol) of 1H-1,2,4-triazole-3-carboxylic acid in 99.5% ethanol was added dropwise under stirring and cooling at 5° C. 1.58 g (13.2 mmol) of thionylchloride. The mixture was stirred under heating at 70° C. for 4 hours. Then, the solvent was removed under reduced pressure and the obtained residue was washed with 18 ml of ethylacetate. The obtained crystal was dried at room temperature under reduced pressure to give 1.00 g of 1H-1,2,4-triazole-3-carboxylic acid ethyl ester hydrochloride. Yield: 63.7%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:22]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[O:22])=[CH:24][CH:25]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1cccs1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccs4)cc3)c2cc1OC
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 17.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and 4-hydroxyphenyl 2-thienyl ketone (102 mg) obtained in Example 39 were mixed and stirred at 160° C. for 40 minutes. The reaction mixture was purified in the same manner as described in Example 24 to obtain 34 mg of the title compound (yield: 17%).
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][N:10]=1)=[O:8]>C1COCC1>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:1])=[N:10][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(C(=O)N(C)OC)nc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C(C)=O)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
MeMgBr (1.98 ml, 5.94 mmol) was added to a solution of 5-butyl-pyridine-2-carboxylic acid methoxy-methyl-amide (I-2A-38a; 880 mg, 3.96 mmol) in THF (10 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1.5 h, quenched with saturated aqueous NH4Cl (1 ml), and saturated aqueous NaCl. The aqueous THF solution was extracted with EtOAc (2×), and the combined organic extracts were washed with saturated aqueous NaCl, dried, and concentrated under vacuum to yield the product I-2A-38b as an oil (680 mg): APcl MS 178.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H, J=1.6 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.60 (dd, 1H, J=1.6, 8.3 Hz), 2.69 (s, 3H), 2.67 (t, 2H, J=7.9 Hz), 1.65–1.56 (m, 2H), 1.40–1.30 (m, 2H), 0.92 (t, 3H, J=7.4 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.Cl>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16])(=[O:21])[CH3:20]
Reactant: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C(=O)O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-carboxylic acid (25.03 g, 100 mmol) in pyridine (200 mL) is added acetic anhydride (100 mL) and the mixture is stirred at room temperature for 24 hrs. Water and ice are added and the mixture is stirred at about 30° C. for 30 min. The mixture is cooled in ice and 6N hydrochloric acid (450 mL) is added. The resulting solid is collected, washed with water, taken up in ethyl acetate. The organic layer is washed with 2N hydrochloric acid and water, dried (sodium sulfate) and evaporated to dryness. Recrystallization from ethyl acetate gave 23.6 g (81%) of 5-acetoxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-carboxylic acid (mp=187° C.-188° C.).
Reaction SMILES: I[C:2]1[S:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.[OH:15][N:16]([C@@H:20]([C:22]#[CH:23])[CH3:21])[C:17]([NH2:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl.[Cu]I>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:4]2[S:3][C:2]([C:23]#[C:22][C@H:20]([N:16]([OH:15])[C:17]([NH2:19])=[O:18])[CH3:21])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: C#C[C@@H](C)N(O)C(N)=O
Reactant: Fc1ccc(Cc2ccc(I)s2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 17.8 %

Procedure:
To a solution of 2-iodo-5-(4-fluorophenylmethyl)thiophene (5.30 g, 16.6 mmol), prepared as in step 2, in anhydrous DMF (5.0 mL) was added (R)-N-hydroxy-N-(3-butyn-2-yl)urea (2.12 g, 16.6 mmol), triphenylphosphine (84 mg, 0.32 mmol), bis(acetonitrile)palladium(II) chloride (40 mg, 0.16 mmol), copper (I) iodide (16 rag, 0.08 mmol), and diethylamine (5.6 ml). The mixture was stirred under nitrogen at ambient temperature for 22 hours and concentrated in vacuo at 32° C. The residue was subjected to chromatography on silica eluting with 2-7% MeOH in CH2Cl2, crystallization from ethyl acetate-hexane and trituration in CH2Cl2 to afford (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea as a cream-colored solid 0.94 g (18%). m.p. 135°-136° C.(dec). 1H NMR (DMSO-d6, 300 MHz) δ1.32 (d, J=6.0 Hz, 3H), 4.11 (s, 2H), 5.10 (q, J=6.0Hz, 1H), 6.54 (s, 2H), 6.81 (d, J=3.0Hz, 1H), 7.08 (d, J=3.0Hz, 1H), 7.10-7.18 (m, 2H), 7.25-7.32 (m, 2H), 9.33 (s, 1H). MS (DCI/NH3) m/e 319 (M+H)+. [a]D23° =+47.8° (C=1, MeOH). Anal calcd for C16H15FN2O2S: C, 60.36; H, 4.75; N, 8.80. Found: C, 60.31; H, 4.79; N, 8.50.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:35])[CH:30]1[O:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:34]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:29][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCC1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC3CCCO3)ccc21
Yield: 60.7 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide (73 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), tetrahydrofurfurylamine (27 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 492.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 4.03-3.94 (m, 1H), 3.78 (q, 1H), 3.74-3.57 (m, 5H), 3.38-3.31 (m, 1H), 2.00-1.73 (m, 3H), 1.68-1.53 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]([CH3:17])[CH2:15][OH:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[C:25]([O:24][C:22]([CH2:21][O:16][CH2:15][CH:14]([NH:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[Cl:1])[CH3:17])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1ccc(NC(C)CO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(C)COCC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.12 g (4.35 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are combined in 10 ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride dispersion and stirred for 5 min at ambient temperature. Then 0.67 ml tert.-butyl bromoacetate are added and the mixture is stirred for a further 16 h at ambient temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=95:5->80:20)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.OC[C@H]1CCCN1C(OC(C)(C)C)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 140, starting from tert-butyl (R)-2-hydroxymethylpyrrolidine-1-carboxylate and used without further characterisation.
Reaction SMILES: Cl.Cl[S:3]([CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].[CH3:13][O:14][C:15](=[O:37])[C@H:16]([CH2:33][CH2:34][S:35][CH3:36])[NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:13][O:14][C:15](=[O:37])[C@H:16]([CH2:33][CH2:34][S:35][CH3:36])[NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:8]2[C:7]([CH:6]=[S:3](=[O:5])=[O:4])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:21][C:20]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=S(=O)(Cl)Cc1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(Nc2ncccc2C=S(=O)=O)cc1-c1ccccc1

Procedure:
A mixture of 3-chlorosulfonylmethylpyridine hydrochloride (1.0 equivalent) and (4-amino-2-phenylbenzoyl)methionine methyl ester (1.0 equivalent) in dichloromethane is treated with triethylamine (2.2 equivalents). When judged complete by TLC analysis, the reaction is diluted with ethyl acetate, and then is washed with pH 4 water, saturated NaHCO3, and brine. The mixture is dried and concentrated to give the crude title compound which is purified by chromatography on silica gel.
Reaction SMILES: CCC([O-])(C)C.[Na+].[C:8]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[C:21]=1[F:30].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:30][C:21]1[C:20]([F:19])=[CH:25][CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[C:22]=1[CH:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(F)c1F
Temperature: 40 °C

Procedure:
To toluene (810 l) was charged sodium tert-pentoxide (91 kg, 2.3 eq). The mixture was heated to 40° C. and tert-butyl acetoacetate (124.3 kg, 2.2 eq) added. The mixture was heated to 70° C. and trifluoronitrobenzene (63.1 kg, 1.0 eq) added. The temperature was maintained at 70° C. for 3 hours. The mixture was cooled to 25° C. and 20% w/w sulphuric acid added to adjust the pH to 5. The lower aqueous layer was discarded and the organic layer washed twice with water (2×227 kg of water), with 2.3% w/w sodium bicarbonate (192 kg) and then water (192 kg). The organic layer was distilled under vacuum (50 mbar), removing 574 kg of distillate leaving a solution of tert-butyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in toluene.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].S(=O)(=O)(O)[OH:11].C(OC(=O)C)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[Cr](O)(O)(=O)=O>O.C(O)(=O)C>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([C:1](=[O:11])[CH3:2])=[CH:4][CH:5]=1
Reactant: CCc1ccc(C)nc1
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.6 %

Procedure:
5-Ethyl-2-methyl-pyridine (40 g, 0.33 mol) was placed in a three-necked flask immersed in an ice bath and equipped with an efficient mechanical stirrer, a thermometer and a dropping funnel. Sulfuric acid (14.9 ml, 0.26 mol) was added with vigorous stirring. Then acetic acid (47.5 ml), acetic anhydride (46.3 ml) and finally CrO3 (44 g, 0.44 mol) were added in small portions, at a rate to maintain the temperature of the reaction mixture between 20-30° C. Stirring was continued for 24 hours. Then 200 ml of water and Na2CO3 were added slowly, until the brown color of chromic acid was gone, and the product was extracted with ethyl acetate (3×200 ml). Combined organic layers were washed with water and brine and dried over magnesium sulfate and solvent was removed. The residue was distilled under reduced pressure (110° C., 19 mbar) to give 12.85 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][C:21]([C:25]([OH:27])=[O:26])=[CH:22]3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C1(C)C=CC=CC=1>[CH3:28][O:26][C:25]([C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]=3)=[CH:24]2)=[CH:19][CH:20]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3ccc(C(=O)O)cc3c2)ccn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1ccc2ccc(Oc3ccnc(C(=O)OC(C)(C)C)c3)cc2c1
Reaction time: 5 h
Yield: 58.4 %

Procedure:
To a solution of 7-{[2-(tert-butoxycarbonyl)pyridin-4-yl]oxy}-2-naphthoic acid (5.25 g, 14.3 mmol) in MeOH (50 mL) and toluene (50 mL), was added a solution of 2.0M trimethylsilyldiazomethane in hexane (14.3 mL, 28.7 mmol) dropwise. The reaction was allowed to stir for 5 h, after which time 2.0M trimethylsilyldiazomethane in hexane (7.17 mL, 14.3 mmol) was added. Stirring continued for an additional 1 h. The solvents were evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine. The organic solution was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography to give tert-butyl 4-{[7-(methoxycarbonyl)-2-naphthyl]oxy}pyridine-2-carboxylate as an off-white solid (3.18 g, 58.4%). LCMS: (FA) ES+ 380.2.