Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([NH2:21])=[N:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1>CO>[NH2:21][C:10]1[C:9]([OH:8])=[CH:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: Nc1ncc(-c2ccccc2)cc1OCc1ccccc1
Solvent: CO
Product: Nc1ncc(-c2ccccc2)cc1O
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example I-87, 3.27 g, 11.8 mmol) in methanol (30 mL) was added Pd(CH)2 (2.5 g, 2.37 mmol). The mixture was degassed and charged with hydrogen three times, and then stirred under hydrogen balloon for 5 h. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, 2-amino-5-phenyl-pyridin-3-ol was obtained (2.04 g, 93% yield). MS m/z 187 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:30])[CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH2:44]([NH2:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:49][CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])=[CH:3][C:4]=3[CH3:30])[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CN
Reactant: Cc1cc(N)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCC(C)(C)C)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
3-((4-(4-Amino-2-methylbenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (100 mg, 0.24 mmol) and 4-nitrophenylchloroformate (49 mg, 0.24 mmol) were stirred in dichloromethane (2 mL) for 30 minutes. Neopentylamine (64 mg, 0.73 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC to afford the title compound (31 mg). MS (ESI) m/z 522.7 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[NH2:33][C:34]1[S:35][C:36]([C:39]([NH2:41])=[O:40])=[CH:37][N:38]=1.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:33][C:34]2[S:35][C:36]([C:39]([NH2:41])=[O:40])=[CH:37][N:38]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: NC(=O)c1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), N,N-diisopropylethylamine (163 μL, 0.94 mmol) and 2-amino-thiazole-5-carboxylic acid amide (54 mg, 0.38 mmol) were combined in methylene chloride (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the cooling bath was removed. After stirring 16 h, thin layer chromatography analysis showed no reaction. N,N-dimethylformamide (1 mL) was added and the methylene chloride was removed in vacuo. The reaction mixture was stirred 20 h more then concentrated in vacuo and purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 2% methanol/chloroform) to afford (E)-2-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-acetylamino]-thiazole-5-carboxylic acid amide (33 mg, 22%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C19H21ClN4O5S2 [M+] 484.06, found 485 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.26-1.79 (m, 8H, 4×CH2), 2.00 (m, 2H, 2×CH of CH2), 3.32 (s, 3 H, SO2CH3), 4.40 (m, 1 H, OCH), 5.82 (brs, 2 H, NH2), 7.64 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.74 (d, Jm=1.5 Hz, 1 H, Ar), 7.96 (s, 1H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.23 (s, 1 H, NH).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl>C1COCC1.C(Cl)Cl.O.[Cl-].[Na+].O>[C:36]1([O:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: BrCc1ccccc1Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccccc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28)(3.08 g, 14.4 mmol) in THF (30 ml) under nitrogen, was treated with 1.0 M lithium bis(trimethylsilyl)amide in THF (15.9 ml, 15.9 mmol, Aldrich) and stirred at room temperature for 15 min. 1-(Bromomethyl)-2-(phenyloxy)benzene (3.8 g, 14.4 mmol, Maybridge) in THF (10 ml) was added and the mixture stirred overnight. The mixture was diluted with DCM (50 ml) and water (50 ml). To the emulsion was added brine (30 ml) and diluted aqueous HCl (15 ml). The resulting phases were separated and the aqueous layer was further extracted with DCM (50 ml). The combined organic extracts were filtered through a hydrophobic frit and the filtrate concentrated under reduced pressure. The residue was loaded in dichloromethane and purified on silica 330 g using 0-50% ethyl acetate-dichloromethane. The appropriate fractions were combined and evaporated in vacuo to give 2-(1-{[2-(phenyloxy)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione as an off-white gum (2.35 g).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[OH:5][CH2:6][CH:7]([CH2:9]O)[OH:8]>>[B:1]([O:4][CH2:9][CH:7]([CH2:6][OH:5])[OH:8])([OH:3])[OH:2]
Reactant: OCC(O)CO
Reactant: OB(O)O
Product: OCC(O)COB(O)O

Procedure:
The glycerol borate acid salt of TEDA was prepared according to U.S. Pat. No. 3,113,515. Boric acid was combined with 2 molar equivalents of glycerol and hested to 180° F. to afford a glycerol borate acid. The reaction mixture was then cooled to 100° F. and treated with 1 molar equivalent of TEDA. Further cooling afforded a viscous material containing 30 wt % TEDA which had a measured Brookfield viscosity of 14,800 centipoise at 25° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
3-Chloro-2-hydroxy-5-nitropyridine (4.8 g) was added to phosphorus oxychloride (11 ml) and phosphorus pentachloride (4.45 g) and the mixture refluxed overnight. The mixture was then cooled to room temperature and evaporated under reduced pressure. Iced water was added to the mixture and a solid product formed. The solid was removed by filtration, washed with water and air-dried to give 2,3-dichloro-5-nitropyridine (3.94 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[NH2:32][CH2:31][C:30]1[C:25]([CH:22]2[CH2:23][CH2:24][N:20]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:21]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCc1cccnc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: NCc1cccnc1C1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 86 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.80 g, 3.0 mmol) and 2-(3-pyrrolidinyl)-3-pyridinemethanamine, a procedure analogous to that given in Example 1 provided the title compound(1.09 g, 86%) as an off-white solid, mp 246°-248° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=3[CH3:32])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][CH:36]([O:51][CH2:52][CH3:53])[C@@H:37]([NH:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[CH:48][CH:47]=[CH:46]2)[CH3:38])[CH3:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>ClCCl.C(OCC)(=O)C>[CH2:33]([O:35][CH:36]([O:51][CH2:52][CH3:53])[C@@H:37]([N:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[CH:48][CH:47]=[CH:46]2)[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=1[CH3:32])[CH3:38])[CH3:34]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.2 %

Procedure:
To the solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid 907 mg (2.1 mmol) and (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-3) 577 mg (2.0 mmol) in dichloromethane 10 ml, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 660 mg (2.1 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound 775 mg (55%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[N:6]=1.[CH2:26](O)[CH2:27][CH:28]=[CH2:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:29][CH2:28][CH:27]=[CH2:26])[CH:8]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[CH:16][CH:15]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(O)c2)N=C1N
Reactant: C=CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCOc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a solution of 2-amino-4-(4-(difluoromethoxy)phenyl)-4-(3-hydroxyphenyl)-1-methyl-1H-imidazol-5(4H)-one (0.070 g, 0.20 mmol), but-3-en-1-ol (0.023 g, 0.32 mmol), and PS—PPh3 (0.145 g, 0.32 mmol, 2.2 mmol/g) in THF (2 mL) is added diethylazodicarboxylate (0.058 g, 0.38 mmol) in THF (0.5 mL) dropwise. The mixture is stirred at 60° C. for 4 h. The solution is cooled to RT and the PPh3 is filtered and washed with CH2Cl2 and MeOH. The solvent is removed, the remaining material is absorbed onto Celite and purified by Flash Chromatography (15:1 CH2CL2:MeOH) to yield 2-amino-4-(3-(but-3-enyloxy)phenyl)-4-(4-(difluoromethoxy)phenyl)-1-methyl-1H-imidazol-5(4H)-one (0.051 g, 73%) as an off white foam.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:5]1[CH2:4][CH2:3][CH2:2][C:1]1[O:9][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: O=C(O)CCCC(=O)O
Reactant: Nc1ccccc1O
Product: c1ccc2oc(CCCc3nc4ccccc4o3)nc2c1
Yield: 80.8 %

Procedure:
132 G (1.0 mol) of glutaric acid was reacted with 216 g (2.0 mol) of o-aminophenol to produce 225 g of 1,3-bis-(benzoxazole-2-yl)-propane (yield was 78%) whose chemical formula is as follows: ##STR6##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cc1ccnc(-c2ccnc(C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(CC(=O)O)ccn2)ccn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2-(2′-methyl-2,4′-bipyridin-4-yl)acetate 238-2 (621 mg, 2.56 mmol) and NaOH (409 mg, 10.24 mmol) in 1,4-dioxane (6 mL) and water (6 mL) was stirred at 80° C. for 3 hours. After cooled down to room temperature, the mixture was treated with 3N HCl aqueous solution to adjust the pH to around 4, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted with 20% methanol in ethyl acetate. The organic extraction was concentrated to give 2-(2′-methyl-2,4′-bipyridin-4-yl)acetic acid 238-3 as pale white solid. MS m/z 229.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Cl)ccc1C(=O)O
Solvent: CC#N
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-chloro-2-methoxybenzoic acid (5 g, 26.8 mmol) in 200 mL of acetonitrile was added N-chlorosuccinimide (17.9 g, 134 mmol). The mixture was allowed to stir for 72 hours at ambient temperature and was quenched with 50 mL of H2O. The layers were separated and the aqueous layer was extracted with three 25 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 25% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 238 (M+NH4)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C1COCC1.[Na+].[I-].O>[N:29]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[O:6])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=C(CCCO)c1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCn1ccnc1)c1ccc2ccccc2c1
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a cooled (0° C.) solution of 4-hydroxy-1-(2-naphthyl)-1-butanone (4.32 g) in THF (60 ml) were added triethylamine (5.6 ml) and methanesulfonyl chloride (2.4 ml) successively. The mixture was stirred at 0° for 1 hour. Imidazole (2.93 g) and NaI (0.02 g) were added to the mixture and resulting mixture was refluxed for 16 hours. Water was added and the mixture was concentrated. The residue was extracted with ethyl acetate and the extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate-methanol=20:1, followed by crystallization from ethyl acetate-CH2Cl2-cyclohexane to give the titled compound (1.21 g) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:17][C:16]=3[C:27]([F:30])([F:29])[F:28])[CH2:11][N:10]2[C:31]([C:33]2([C:36]([F:39])([F:38])[F:37])[CH2:35][CH2:34]2)=[O:32])=[O:8])[CH2:5][CH2:4]1)#[N:2].[OH2:40].[OH2:41].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(#N)C.O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:17][C:16]=3[C:27]([F:30])([F:29])[F:28])(=[O:41])=[O:40])[CH2:11][N:10]2[C:31]([C:33]2([C:36]([F:39])([F:38])[F:37])[CH2:34][CH2:35]2)=[O:32])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: O
Reactant: Cn1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)cn1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cn1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)cn1
Temperature: 50 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
(2S,4R)-4-[4-(1-Methyl-1H-pyrazol-4-yl)-2-trifluoromethyl-phenylsulfanyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (crude product, 97.6% purity, 64.0 g, 109 mmol) was dissolved in acetonitrile (480 mL) and magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) was added. The resulting white suspension was stirred for 5 h at 50° C. After that, a suspension of magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) in acetonitrile (150 mL) was added and the mixture was stirred for further 16 h at 50° C. After cooling to 20° C., water (480 mL) and a solution of sodium metabisulfite in water (40% w/w, 56.8 mL, 109 mmol) were added. The mixture was basified to pH 8 by addition of an aqueous sodium hydroxide solution (3 M, ca. 290 mL), extracted with dichloromethane (1 L), the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (1 L) and concentrated in vacuo. The residue was dissolved in dichloromethane (300 mL) and filtered to remove solid impurities. The solvent of the filtrate was exchanged to ethanol by continuous distillation while keeping the volume constant (ca. 750 mL ethanol used). The desired product started to crystallize. The resulting suspension was stirred for 12 h at 0° C., filtered, the precipitate was washed with cold ethanol (50 mL) and dried in vacuo at 45° C. to obtain the title compound as white crystals (50.0 g, 74.9%). MS (ESI & APCI): m/z=604.1 [M+H]+, 621.1 [M+NH4]+. 1H NMR (CDCl3, 600 MHz): δ 1.10-1.22 (m, 2H), 1.30-1.35 (m, 1H), 1.35-1.41 (m, 1H), 1.45-1.59 (m, 4H), 2.22-2.28 (m, 1H), 2.84 (ddd, J=5.9 Hz, 8.0 Hz, 14.3 Hz, 1H), 3.84 (dd, J=7.1 Hz, 13.2 Hz, 1H), 4.00 (s, 3H), 4.08-4.14 (m, 1H), 4.81 (d, J=13.3 Hz, 1H), 4.86 (dd, J=5.8 Hz, 8.6 Hz, 1H), 7.65 (bs, 1H), 7.80-7.83 (m, 2H), 7.89 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:35])[C@H:7]([CH3:34])[N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>CCOC(C)=O.Cl>[ClH:26].[CH2:27]([N:8]([S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C@H:7]([C:6]([OH:35])=[O:5])[CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)O)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 157.9 %

Procedure:
N-Benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (100 mg, 0.19 mmol) was dissolved in a solution of EtOAc saturated with HCl (5.0 mL) and the mixture stirred at room temperature for 18 h. The mixture was concentrated in vacuo, azeotroping with EtOAc, to give N-benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine hydrochloride (77 mg, 0.15 mmol) as a white powder.
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>CC#N>[Cl:23][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
Methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate (100 mg, 0.36 mmol, 1.00 equiv) and PCl5 (220 mg, 1.07 mmol, 3.00 equiv) in CH3CN (10 mL) was allowed to react, with stifling, for 5 hrs while the temperature was maintained at reflux in an oil bath. The reaction was then quenched by the addition of 50 mL of water, and the pH value of the solution was adjusted to 9 with saturated K2CO3. The resulting solution was extracted with 3×50 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, and concentrated under vacuum, affording 60 mg (56%) of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[C:13]1([NH:19][N:20]2[C:1](=[O:12])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: NNc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Nc1ccccc1
Temperature: 25 °C
Yield: 30 %

Procedure:
Phthalic acid (1.66 gram, 0.01 mole), phenylhydrazine (1.08 gram, 0.01 mole), and zinc chloride (3.0 gram, 0.022 mole) were added into 50 ml. of dioxane. After refluxing for 2 hours, the mixture was cooled to room temperature. The solvent was then removed and the residue was poured into ice-water which precipitated a yellow solid. After recrystallization from methanol, the pure compound was obtained in 30% yield as yellow needles (0.7 grams; m.p. 180° C.).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[N:18]1([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=3)[N:17]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-n3ccnc3)n2)cc1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: O=C(O)c1ccc(Nc2nccc(-n3ccnc3)n2)cc1

Procedure:
4-(4-imidazol-1-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 18 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[N+:17]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N

Procedure:
Prepared from (4-cyclopropyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A3) by reduction with SnCl2.2H2O according to the general procedure G (method b). Obtained as a dark solid (1.96 g).