Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH2:29][CH3:30])[CH:25]=[C:24]4[CH2:31][CH2:32][C:33]([O:35]CCC)=[O:34])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH2:29][CH3:30])[CH:25]=[C:24]4[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCCOC(=O)CCc1cn(CCC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCCn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Sodium hydroxide (130 mg) was added to a solution of propyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-propyl-1H-indol-3-yl]propanoate (D121) (166 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-propyl-1H-indol-3-yl]propanoic acid (E27) (98 mg). δH (DMSO-d6, 400 MHz): 0.54 (3H, t), 1.39 (8H, m), 2.62 (2H, t), 2.98 (2H, t), 4.08 (2H, t), 4.90 (1H, m), 7.17 (1H, t), 7.25 (1H, s), 7.44 (2H, m), 7.81 (1H, dd), 8.13 (1H, dd), 8.19 (1H, d), 12.07 (1H, br s); MS (ES): C26H26ClN3O4 requires 467; found 468.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[CH2:19][CH2:20][C:21](O)=[O:22].S(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][OH:22]
Reactant: CCOc1ccc(Cc2cc(Br)c(CCC(=O)O)cc2Cl)cc1
Solvent: C1CCOC1
Solvent: CSC
Product: CCOc1ccc(Cc2cc(Br)c(CCCO)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a stirred 0° C. solution of 3-(2-bromo-5-chloro-4-(4-ethoxybenzyl)phenyl) propanoic acid (BK) (0.5 g, 1.26 mmol) in 8 mL of THF was added BH3 in Me2S (2M, 3.15 mL, 6.29 mmol). After stirring for 30 min at 0° C., the mixture was warmed to room temperature and stirred overnight. The reaction solution was slowly quenched with dropwise addition of water until no more gas evolved. The reaction mixture was taken up in 20 mL of ethyl acetate, washed with saturated Na2CO3, water and brine, and then dried over Na2SO4, filtered and concentrated to obtain 0.268 g of crude intermediate BL, which was used in the next step without further purification.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[CH:24]=[N:23][C:22]([NH2:29])=[CH:21]2.[CH3:30][C:31]1[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[C:34]([NH2:42])[N:35]=[CH:36]2>ClCCl>[N:29]([C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([CH3:17])=[C:27]([CH3:28])[CH:26]=2)=[C:1]=[S:2].[N:42]([C:34]1[N:35]=[CH:36][C:37]2[C:32]([CH:33]=1)=[C:31]([CH3:30])[C:40]([CH3:41])=[CH:39][CH:38]=2)=[C:1]=[S:2]
Reactant: Cc1cc2cnc(N)cc2cc1C
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ccc2cnc(N)cc2c1C
Solvent: ClCCl
Product: Cc1cc2cnc(N=C=S)cc2cc1C
Product: Cc1ccc2cnc(N=C=S)cc2c1C
Temperature: 40 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.35 g, 5.81 mmol) in dichloromethane (19 mL) at ambient temperature was added a mixture (2:1) of 6,7-dimethylisoquinolin-3-amine and 5,6-dimethylisoquinolin-3-amine (1.00 g, 5.81 mmol). The reaction mixture was placed into a preheated oil-bath and stirred at 40° C. for 18 h, then cooled, concentrated, and purified by silica gel chromatography (10-35% ethyl acetate in hexanes) to afford a mixture (2:1) of 3-isothiocyanato-6,7-dimethylisoquinoline and 3-isothiocyanato-5,6-dimethylisoquinoline (186 mg, 0.869 mmol, 15%) as a yellow solid. MS (LC/MS) R.T.=2.06; [M+H]+=215.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH2:15]([S:19]Cl)[CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH3:1][N:2]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4]
Reactant: CCCCSCl
Reactant: CNC(=O)Nc1cc(C(C)(C)C)on1
Solvent: c1ccncc1
Product: CCCCSN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h
Yield: 10.9 %

Procedure:
To a solution of 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (1.97 g) in pyridine (30 ml), butylsulfenyl chloride (1.08 mol equivalent) is added at -30° to -40° C. The resultant mixture is allowed to stand at -30° to -40° C. for 6 hours and at room temperature overnight. The reaction mixture is chromatographed on a column of silica gel, whereby 1-methyl-1-butylthio-3-(5-t-butyl-3-isoxazolyl)urea (0.31 g) is obtained as an oil. I.R.: 1698, 1606 cm-1 (CCl4).
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2].[H-].[Na+].[C:29](Cl)(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(Cl)(Cl)Cl>O1CCCC1.CC(C)=O>[C:29]([O:25][C:7]1[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:26])[NH2:2])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:20](=[O:22])[CH3:21])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Reactant: CCCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCCCCC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(C)=O
Reaction time: 1 h

Procedure:
11-Acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg) was dissolved in tetrahydrofuran (2.5 ml) and the solution was added to a suspension of sodium hydride (60% in oil, 3 mg) in tetrahydrofuran (0.5 ml). To this mixture was added a solution of octanoyl chloride (12 μl) in tetrahydrofuran (108 μl) in an ice-water bath and the mixture was stirred for 1 hour in an ice-water bath. After stirring for 36 hours at room temperature, an additional amount of octanoyl chloride (50 μl) was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture was then directly subjected to a preparative thin layer chromatography. Development was carried out with a mixture of chloroform and acetone (1:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-9-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl octanoate (7 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: NC1CCCCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Product: Nc1nc(Cl)cc(NC2CCCCC2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 108.5 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and cyclohexylamine (0.87 mL, 7.62 mmol) and CH3OH (10 mL). The vial was sealed, and the reaction mixture was stirred for 2 days at 50° C. The reaction was cooled to room temperature and concentrated. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (750 mg, 99%) as an orange oil. LC-MS (ES) m/z=227 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=O)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:22])[C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:20])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)N3CCOCC3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoic acid (Example 1, Step H, 180 mg, 0.46 mmol), morpholine (Wako Pure Chemical Industries, Ltd., 48 mg, 0.55 mmol), N,N′-diisopropylethylamine (71 mg, 0.55 mmol) in N,N′-dimethylformamide (3 mL) was added diethyl cyanophosphonate (Aldrich, 90 mg, 0.55 mmol) at room temperature. The mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4 as eluent) to afford the title compound (102 mg, 48%) as a white solid.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:4]([CH2:13][CH2:14][NH2:15])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:16](=[O:19])([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:6]1[N:5]=[C:4]([CH3:13])[CH:3]=[CH:8][C:7]=1[C:16]([NH:15][CH2:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Reactant: Cl
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NCCc2ncc(C(F)(F)F)cc2Cl)c(Cl)n1

Procedure:
A solution of 161 mg (0.7 mmol) 2-chloro-6-methylnictotinyl chloride, 160 mg (0.7 mmol) 2-(3-chloro-5-trifluormethyl-pyridin-2-yl)-ethylamine hydrochloride and 236 mg (1.7 mmol) sodium carbonate in 8 ml acetonitrile is stirred for 3 days at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1.CCN(C(C)C)C(C)C.CCOC(C)=O>[C:28]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.062 g) in THF (2.5 mL) and DIEA (0.030 mL) was added acetyl chloride (0.015 mL). After 30 minutes, the reaction mixture was diluted with EtOAc and the solution washed with NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: CH2Cl2/MeOH: 99/1, Chromatotron) afforded the titled compound (0.046 g,). MS (m/z) 510 (MH+). mp 89.6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]([CH3:7])=[O:6].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:7][Cl:17])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCON=C(C(C)=O)C(=O)OC
Solvent: CC(=O)O
Product: CCCON=C(C(=O)CCl)C(=O)OC
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 7.4 g of 2-(n-propoxyimino)acetoacetic acid methyl ester in 7.4 ml of acetic acid is added 5.5 g of sulfuryl chloride, and the mixture is stirred for 10 minutes at 40° C., then for 6 hours at room temperature. The reaction solution is poured into 100 ml of ice-water, and subjected to extraction twice with chloroform. The extract is washed with an aqueous solution of sodium chloride, and aqueous solution of sodium bicarbonate and water in this order, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to yield 8.2 g (94%) of 4-chloro-2-(n-propoxyimino)acetoacetic acid methyl ester as a pale yellow oil product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:46](=[O:47])[C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=[N:42]2)=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:48]([C:45]2[C:46](=[O:47])[N:41]([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[N:42]=[CH:43][CH:44]=2)=[O:49])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=3)[N:9]=[C:10]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.213 g, 0.479 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.561 g, 2.40 mmol, prepared in Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.459 g, 2.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.367 g, 2.40 mmol), N-ethyl-N-isopropylpropan-2-amine (0.310 g, 2.40 mmol) and CH2Cl2 (5 mL) were charged in a 50 mL single-neck, round-bottomed flask. The reaction mixture was stirred at room temperature until LC-MS shows that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH from 100/1 to 50/1, v/v) to afford product (0.201 g, 63.5%). LRMS (APCI pos): >95% purity, 254 nm, m/e 661 (M+1). 1H NMR (400 MHz, CDCl3 δ 11.75 (s, 1H), 8.31 (d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.87 (dd, 1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.42 (s, 1H), 7.28 (m, 3H), 7.13 (m, 3H), 6.75 (m, 2H), 6.20 (d, 1H), 5.56 (s, 2H), 3.83 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][C:6]1[N:10](COC)[C:9]([C:14]2[CH:19]=[CH:18][C:17](S[Si](C(C)C)(C(C)C)C(C)C)=[CH:16][CH:15]=2)=[N:8][N:7]=1.[N+]([O-])([O-])=O.[K+].[S:39](Cl)(Cl)(=[O:41])=[O:40].[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[NH2:49]>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][C:6]1[NH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([S:39]([NH:49][C:45]3[S:44][CH:48]=[CH:47][N:46]=3)(=[O:41])=[O:40])=[CH:18][CH:19]=2)=[N:8][N:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1nccs1
Reactant: COCn1c(Cc2cccc(Cl)c2)nnc1-c1ccc(S[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1nccs1)c1ccc(-c2nnc(Cc3cccc(Cl)c3)[nH]2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(3-chloro-benzyl)-4-methoxymethyl-5-(4-triisopropylsilanylsulfanyl-phenyl)-4H-[1,2,4]triazole (0.42 mmol) in acetonitrile (5 mL) at 0° C. was added potassium nitrate (1.05 mmol) and sulfuryl chloride, and the mixture was stirred for 1 h. The inorganic precipitate was filtered and washed with acetonitrile. The organic phase was concentrated and the residue was dissolved in THF (1.3 mL). To the solution were added thiazol-2-ylamine (0.5 mmol) and excess pyridine. The mixture was stirred over weekend. After concentration, the residue in 6N HCl (1 mL) and ethanol (1 mL) was stirred at 80° C. for 16 h before the reaction mixture was concentrated, the crude product was purified by reverse phase HPLC to give 4-[5-(3-chloro-benzyl)-4H-[1,2,4]triazol-3-yl]-N-thiazol-2-yl-benzenesulfonamide (0.1 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=[O:20])[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14]([OH:18])[CH:13]=[CH:12][C:11]=3[F:19])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:18][C:14]1[CH:13]=[CH:12][C:11]([F:19])=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][CH:21]=1)[C:8](=[O:20])[NH:9]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(F)ccc(O)c12
Product: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(F)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-(4-bromobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:5]([O:8][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: COc1cc2nccc(Oc3cc(Cl)cnc3O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc(Cl)cnc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-(5-Chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxyquinoline (39 mg) was suspended in N,N-dimethylformamide (7 ml). Cyclopentyl bromide (0.3 ml) and potassium carbonate (300 mg) were added to the suspension, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (29 mg, yield 62%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]>C(#N)C.CO>[Br-:14].[N:18]1([C:16](=[O:17])[CH2:15][N+:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(CBr)N1CCCC1
Reactant: c1ccc(Cc2ccccn2)cc1
Solvent: CC#N
Solvent: CO
Product: O=C(C[n+]1ccccc1Cc1ccccc1)N1CCCC1
Product: [Br-]
Temperature: 98 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2-Benzylpyridine (1.0 g, 5.9 mmole) and 1-(bromoacetyl)pyrrolidine (1.134 g, 5.9 mmole) were heated with stirring in an oil bath at 98° C. for 2 hr. The viscous mixture was dissolved in 10 mL 4:1 acetonitrile-methanol and stored at 4° C. for 2 days. The crystals which separated were filtered out to give 1.96 g of crude product which was recrystalized from methanol-acetonitrile to give 1.45 g of the title compound, mp 224-226° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:13][O:14][C@@H:15]1[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:17]([C:30](OC)=[O:31])[CH2:16]1>C1COCC1>[CH3:13][O:14][C@@H:15]1[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:17]([C:30](=[O:31])[NH:1][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:16]1
Reactant: COC(=O)[C@@H]1C[C@H](OC)CN1C(=O)OCc1ccccc1
Reactant: Nc1cnccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](C(=O)Nc2cnccn2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of aminopyrazine (535 mg, 5.63 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M THF solution, 2.7 mL, 5.35 mmol) dropwise at 0° C. The resulting slurry was stirred at room temperature for 30 min. A solution of (2S,4S)-1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate (550 mg, 1.88 mmol) in THF (2 mL) was added to the slurry. The reaction mixture was stirred at room temperature for 4 h and quenched with methanol (3 mL). The crude product was purified by preparative HPLC to give (2S,4S)-benzyl 4-methoxy-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 18C (570 mg, 85%) as an oil. LC/MS [M+H]+: 356; Ret time (Method F): 2.32 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]1[CH:83]=[CH:82][CH:81]=[C:80]([OH:84])[C:75]=1[C:76]([O:78][CH3:79])=[O:77]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]2[CH:83]=[CH:82][CH:81]=[C:80]([OH:84])[C:75]=2[C:76]([O:78][CH3:79])=[O:77])=[O:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
(2S)-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]-propanoic acid (10.3 mg, 0.020 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10.6 mg, 0.024 mmol). After stirring 5 minutes at rt a solution of N,N-diisopropylethylamine (17.4 L, 0.10 mmol) and methyl 2-(4-aminobutoxy)-6-hydroxybenzoate hydrochloride (8.27 mg, 0.030 mmol) in DMF (1 mL) was added. The solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (9.2 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 7.96 (brs, 1H), 7.69–7.65 (m, 2H), 7.52–7.14 (m, 7H), 6.51–6.46 (m, 2H), 5.62–5.59 (m, 1H), 4.00–3.94 (m, 13H), 3.87 (s, 3H), 3.44–3.38 (m, 1H), 3.36–3.30 (m. 1H), 3.06–3.00 (m, 1H), 2.98–2.91 (m, 2H), 2.81–2.72 (m, 1H), 1.64–1.60 (m, 2H), 1.51–1.47 (m, 2H); LCMS found for C30H33BrN3O10S2 (M+H)+: m/z=738.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10](Cl)(Cl)Cl)[N:7]([CH3:14])[C:6]=2[CH:15]=1.[C:16](=O)([O-])[O-:17].[Na+].[Na+].C[OH:23]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([O:17][CH3:16])=[O:23])[N:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(Cl)(Cl)Cl)nc2ccc(Br)cc21
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2ccc(Br)cc2n1C

Procedure:
A mixture of 6-bromo-1-methyl-2-(trichloromethyl)-1H-benzimidazole (0.781 g), sodium carbonate (0.298 g), MeOH (20 ml), and water (2 ml) was refluxed overnight. After evaporation of the solvent and addition of water, the mixture was extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was washed with Et2O to give the title compound (0.315 g) as a pale brown solid.