Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][OH:36])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.O[C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1>O1CCCC1.CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][O:36][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.4 %

Procedure:
A solution of 6.6 g of 1,1'-(azodicarbonyl)dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of 1-t-butoxycarbonyl-2-hydroxymethylindoline (prepared as described in Preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4-87.2° C.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.Cl.[CH:15]1([NH:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>C(O)C>[CH:15]1([N:21]2[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NNC1CCCCC1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnn(C2CCCCC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
3.96 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt was suspended in 40 ml of ethanol, and 3.13 g of cyclohexylhydrazine hydrochloride was added. The mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.01 g of methyl 1-cyclohexyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH3:30])[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH3:32][NH:33][CH2:34][CH2:35]N>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]([N:11]([CH3:30])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[N:33]([CH3:32])[CH2:34][CH2:35][N:2]=2)=[CH:8][CH:7]=1)=[O:29])(=[O:20])=[O:19]
Reactant: CN(CCc1ccc(C#N)cc1)C(=O)CCCNCS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CNCCN
Agent: [S]
Product: CN(CCc1ccc(C2=NCCN2C)cc1)C(=O)CCCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methyl-N-{2-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.62 g (1.32 mmol) of N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methylbutyramide, 48 mg (1.49 mmol) of sulphur and 3 ml of N-methylethylenediamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[SH:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:21][CH:22]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(O)CCc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]([Cl:17])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccc(C(=O)O)cc21
Reactant: O=S(Cl)Cl
Product: CC1(C)COc2ccc(C(=O)Cl)cc21
Yield: 127.7 %

Procedure:
The product of stage (a) (3 g) was boiled under reflux in thionyl chloride (3.6 g) for 3 hours. Removal of the thionyl chloride under vacuum gave crude title product (4.2 g).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21](Cl)(=[O:23])=[O:22]>>[CH2:1]([C:5]1[S:9][C:8]([NH:10][S:21]([C:14]2[C:15]([CH3:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])(=[O:23])=[O:22])=[N:7][C:6]=1[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCCCc1sc(N)nc1C
Product: CCCCc1sc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-butyl-4-methyl-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (41 mg) with purity >90%. MS (pos) m/z 393.2, 395.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:26])([F:28])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=1)=[O:38]
Reactant: O=C=Nc1ccccc1F
Reactant: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2F)c1

Procedure:
The title compound was prepared from {3-[3-(2-methylphenyl)-8 (trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluorophenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 218-220° C.; MS (EI) m/z 516 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.Cl>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C
Yield: 0 %

Procedure:
Pyridine-3-sulfonic acid (3.00 g, 18.8 mmol) and PCl5 (4.79 g, 23.0 mmol) were mixed in POCl3 (6 mL). The reaction was stirred and refluxed at 120° C. over night (15 h). Cooled to rt., diluted with CHCl3 (20 mL) and saturated with HCl (g). This gave a white precipitation, which was filtered off, washed with CHCl3 and dried under reduced pressure to give the title compound (3.36 μg, 83%) as a white powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][C:26]1[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[C:26]([Br:25])=[CH:31][CH:30]=[C:29]([CH3:32])[N:28]=4)[CH2:34][CH2:35]3)=[O:17])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: Cc1ccc(Br)c(N2CCNCC2)n1
Product: Cc1ccc(Br)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)n1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(3-bromo-6-methyl-pyridin-2-yl)-piperazine to give the title compound as a colorless solid. MS: 591.7 ([M+H]+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[NH2:29]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Nc1ccc(N2CCCCC2)c(F)c1
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCCCC2)c(F)c1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pyrid-2-yl)benzoyl chloride (1.37 mmol, prepared as described in Example 1B, and DIEA (1.2 mL, 6.9 mmol) in tetrahydrofuran (5 mL) were treated with the product from Example 10B (260 mg, 1.34 mmol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (50 mL), washed with H2O (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.72 (d, J=4.7 Hz, 1H), 8.25 (d, J=8.2 Hz, 2H), 8.05–8.10 (m, 3H), 7.94 (td, J=7.8 Hz, 1.7 Hz, 1H), 7.70 (dd, J=14.9 Hz, 2.4 Hz, 1H), 7.40–7.50 (m, 2H), 7.04 (t, J=9.4 Hz, 1H), 2.92–2.96 (m, 4H), 1.62–1.69 (m, 4H), 1.52–1.56 (m, 2H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:38]>[Pd]>[OH:18][C@H:17]1[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:29]=2)(=[O:22])=[O:23])[C@H:12]1[C:10]([OH:11])=[O:38]
Reactant: O=C(NOCc1ccccc1)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Product: O=C(O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The above compound (6) (1.68 g) was dissolved in methanol (70 mL) and 10% Pd—C (350 mg) was added, and then the mixture was stirred under a hydrogen atmosphere at 40° C. for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→9:1. 4:1) to obtain the titled compound (951 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.Cl[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:15]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccc(C)cc3)c2c1
Reactant: Clc1ccccn1
Product: COC(=O)CCCCCOc1ccc2nc(Sc3ccccn3)n(-c3ccc(C)cc3)c2c1

Procedure:
200 mg of 6-[[1-(4-methylphenyl)-2-mercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was heated to 150° C. with 80 μl of 2-chloropyridine for 14 hours. After another 200 μl of 2-chloropyridine was added, it was heated for 3 hours to 170° C. After cooling, it was purified by column chromatography on silica gel. 40 mg was obtained.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH3:17])[C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:16]=[C:15]([CH3:17])[C:5]([O:6][CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]3)=[C:4]([CH3:18])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(Br)cc(C)c1OCC1CCCN(C)C1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cc(C)c(OCC3CCCN(C)C3)c(C)c2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine (531 mg, 1.70 mmol) in toluene (10 mL) was added 3-methoxyphenylboronic acid (319 mg, 2.10 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), and 2M sodium carbonate (1.7 mL, 3.4 mmol). The mixture was stirred at 100° C. overnight and cooled to room temperature. The solution was partitioned between water and ethyl acetate. The organic layer was washed twice with water, brine, and dried. The solvent was removed and the residue purified on silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, to give 3-[4-(3-methoxyphenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17](=[S:26])[NH:16][N:15]=2)([CH3:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:35]=1[CH2:36]Cl>CC(C)=O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:35]=1[CH2:36][S:26][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:14]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:13])[CH3:12])=[N:15][N:16]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: COc1ccc(C(C)(C)c2n[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)c2nnc(SCc3c(F)cccc3Cl)n2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A mixture of 3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-1H-1,2,4-triazole-5(4H)-thione (200 mg, 0.54 mmol) and K2CO3 (111 mg, 0.80 mmol) in acetone (15 mL) was stirred for 30 min at room temperature. 2-Chloro-6-fluorobenzyl chloride (206 μL, 1.61 mmol) was added to the reaction mixture, and the resulting mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated. Purification by flash chromatography [Hex/EtOAc, 1:4 to 1:1] afforded the title product (230 mg, 0.45 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 6.95-6.91 (m, 1H), 6.84-6.80 (m, 2H), 6.68 (d, 1H), 6.54 (d, 1H), 6.50 (dd, 1H), 6.45-6.40 (m, 2H), 4.45 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.65 (s, 6H); MS (EI) m/z 516 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CC(C)=O.O>[CH2:11]([O:10][C:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:9])[CH3:12]
Reactant: NCCCCO
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NCCCCO
Reaction time: 2 h

Procedure:
In an amount of 25.5 g of 4-aminobutanol was dissolved in 255 ml of a mixed solvent of acetone/water (3:1). Under ice cooling, the mixture was added with 43.5 g of potassium carbonate, added dropwise with 27.6 ml of ethyl chloroformate over 13 minutes, and then stirred for 2 hours. The reaction mixture was added with 100 ml of water, and extracted with 100 ml of ethyl acetate, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 45.3 g of 4-ethoxycarbonylaminobutanol. Physicochemical Properties of this Compound
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:41]=[CH:40][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:41]=[CH:40][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
To a dichloromethane (120 mL) solution of di-tert-butyl (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)imidodicarbonate (11.8 g, purity about 70%) described in Manufacturing Example 3-1-2 was added trifluoracetic acid (40 mL) at 0° C., which was stirred at room temperature for 14 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate at 20° C. or less, which was then extracted with ethyl acetate and purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1). The solvent was concentrated under a reduced pressure, tert-butylmethyl ether was added to the resulting residue, and the solids were filtered out to obtain the title compound (7.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([Cl:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)cc(C)c2c1
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(=O)cc(C)c2c1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
In a 250 ml, three-necked round bottom flask equipped with a mechanical stirrer, thermowatch, and addition funnel was placed glacial acetic acid (125 ml) and 6-methoxy-4-methyl-2-quinolone (15.78 g, 0.0834 moles). This was heated to 70° C., then a solution of sulfuryl chloride (13.5 g, 0.100 moles) and glacial acetic acid (10 ml) was added over 50 minutes. Reaction temperature held between 70-75° C. and product precipitated from solution about one third through the addition. The slurry was stirred for 15 minutes , then cooled to ambient temperature. Product was isolated by suction filtration followed by two 20 ml washes with acetic acid and one 50 ml wash with ethanol. Air dried yield is 17.9 g; purity by HPLC is 76.6 area % (contains 9.8% starting material and 12.8% over chlorinated product)
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][N:23]=1.C.IC>O>[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[N:32]([CH3:2])[N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][N:23]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Solvent: CI
Solvent: O
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: -5 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (19.87 mL, 132.90 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (48 g, 102.23 mmol) in 2-methylTHF (300 mL). A dark solution was obtained after 5 minutes which was treated with charcoal and filtered through a celite pad, washing the charcoal and charcoal with additional 2-methylTHF (100 mL). The filtrate was stirred with an air stirrer at −5° C. in a 3 L jacketed fixed vessel under an atmosphere of nitrogen. 2-methylTHF (100 mL) was added to help stir the yellow suspension. Iodomethane (7.96 mL, 127.78 mmol) was added dropwise over 15 minutes. The mixture was stirred for 2 hours and the reaction mixture was warmed to room temperature. After 16 hours, additional iodomethane (6 mL) and DBU (20 mL) was added and stirring was continued for 16 hours. The mixture was poured into water and stirred for 5 minutes. The insoluble material was isolated as a beige solid and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (24.77 g, 50.1%). The mother liquors were concentrated under reduced pressure and the residue was purified by flash column chromatography on silica using MTBE as the eluant. A second crop of the desired product (13.04 g, 26%), was thus obtained as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.47 (9H, s), 1.51 (9H, s), 1.57-1.76 (2H, m), 1.94-2.1 (2H, m), 2.87-3.09 (3H, m), 3.9-4.08 (2H, m), 4.26 (3H, s), 7.97 (2H, br, s), 8.92 (1H, s); Mass Spectrum [M+H]+=484
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1nc(Cc2ccccc2)no1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-Benzyl-[1,2,4]oxadiazole-5-carboxylic acid (330 mg, 1.5 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (389 mg, 1.5 mmol), HATU (1.1 g, 3.1 mmol) and DIPEA (0.8 mL, 4.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.834 min; [M+H]+=438.1.