Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(=O)C.C(O[C:10]([N:12]1[CH2:17][CH2:16][C:15]([O:21][CH3:22])([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].ClC1[N:35]=[CH:34][C:33]([B:36]([OH:38])[OH:37])=[CH:32][N:31]=1>CO.C(O)C>[ClH:4].[CH3:22][O:21][C:15]1([C:18]([O:20][CH3:1])=[O:19])[CH2:14][CH2:13][N:12]([C:10]2[N:35]=[CH:34][C:33]([B:36]([OH:38])[OH:37])=[CH:32][N:31]=2)[CH2:17][CH2:16]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CC(=O)Cl
Reactant: COC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COC(=O)C1(OC)CCN(c2ncc(B(O)O)cn2)CC1
Product: Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A 2% solution of HCl in MeOH was prepared by adding acetyl chloride (1.1 mL) to MeOH (25 mL). To this solution was added 1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-4-carboxylic acid (1 g, 3.6637 mmol) and the solution was heated under reflux for 6 h. The reaction mixture was evaporated to dryness and left on a vacuum line for 30 minutes. The material thus obtained was dissolved in ethanol (8 mL) and stirred with sodium carbonate (0.96 g, 9.1 mmol) for 10 minutes, then (2-chloropyrimidin-5-yl)-boronic acid (0.57 g, 3.61 mmol) was added and the mixture was stirred at 60° C. for 6 h. The reaction mixture was filtered through celite and the solvents removed in vacuo to give the title compound (0.8 g, 71%) as a white foam, which was used without further purification. LCMS (pH 10) MH+ 296, RT 0.86 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2Cl)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 26.7 g of ethyl 2-aminothiazol-4-ylglyoxylate, 23 g of o-chlorophenyl isocyanate and 300 ml of dimethylformamide. The resulting product was a white powder having the following physical properties.
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[OH2:4].[OH2:5].O.O.[N+]([O-])([O-])=O.[Ca+2:12].[N+]([O-])([O-])=O>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[Ca+2:12]
Reactant: O=[PH2]O
Reactant: O
Agent: *CC*
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
An aqueous solution of 8.51 g 50 wt % hypophosphorous acid, H3PO2 (Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt % [PO4]−3 was combined with 8.00 g distilled water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 22.85 g calcium nitrate tetrahydrate salt, Ca(NO3)2.4H2O (ACS reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4), equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in this mixture was 3/2 and the equivalent solids level [as Ca3(PO4)2] was 25.4 wt %. Endothermic dissolution of the calcium nitrate tetrahydrate proceeded under ambient temperature conditions, eventually forming a homogeneous solution. Warming of this solution above 25° C. initiated a reaction in which the solution vigorously bubbled while evolving red-brown acrid fumes characteristic of NOx(g). The sample turned into a white, pasty mass which foamed and pulsed with periodic expulsion of NOx(g). After approximately two minutes, the reaction was essentially complete, leaving a white, pasty mass which was warm to the touch. After cooling to room temperature, the solid (A) was stored in a polyethylene vial.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[OH:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:41][CH:42]1[CH2:47][CH2:46][N:45]([C:4](=[O:5])[CH2:3][S@:7](=[O:8])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[N:9][C:10](=[O:11])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)[CH2:44][CH2:43]1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: OC1CCNCC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CC(=O)N3CCC(O)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and 4-hydroxypiperidine were reacted to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:6]2[CH:5]=[C:4]([CH3:13])[O:3][C:2]=2[CH3:1])[N:8]=1)(=[O:25])=[O:24]
Reactant: Cc1cc(-c2csc(N)n2)c(C)o1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(-c2csc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)n2)c(C)o1

Procedure:
The title compound was prepared from 4-(2,5-dimethyl-3-furyl)-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 (11.6 mg) with purity >90%. MS (pos) m/z 417.1, 419.1.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:23][O:24][CH:25]([O:43][CH3:44])[C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1>ClCCCl>[CH:1]1([CH2:7][NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][C:28]3[CH:37]=[CH:38][C:39]([N+:40]([O-:42])=[O:41])=[C:26]([CH:25]([O:24][CH3:23])[O:43][CH3:44])[CH:27]=3)[CH:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(OC)c1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction was completed under N2. Cyclohexanecarboxaldehyde (0.01 mol) and then NaBH(OAc)3 (0.015 mol) were added to a solution of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.01 mol) in DCE (130 mL). The reaction mixture was stirred overnight at room temperature and washed with a saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]#[CH:28])[N:24]=[N:23][N:22]=4)[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)Cl>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]#[CH:28])[N:24]=[N:23][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: O
Product: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate-1-oxide (9.3 g) and dry N,N-dimethylformamide (93 ml) was cooled to -30° C. and thereto was added phosphorus trichloride (3.9 g). The resulting solution was stirred for 40 minutes at -30° C. The reaction mixture was allowed to warm to ambient temperature, added to water (150 ml) and then extracted with ethyl acetate (×3). The extracts were combined, washed successively with a saturated aqueous solution of sodium bicarbonate (×2) and water (×3), dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane, collected by filtration, washed with n-hexane and then dried to give benzhydryl 7-(2-phenylacetamido)-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (8.07 g).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](OC)[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(CC(C)(C)C)(C)C>[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)=[CH:10][CH:11]=1)=[O:3]
Reactant: COc1cc(C2OCCO2)ccc1O
Reactant: N#Cc1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CC(C)(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 81.8 %

Procedure:
Dissolve 4-[1,3]dioxolan-2-yl-2-phenol (Example 388, Part C2) (1.70 g, 10.2 mmol), 5-chloropyrazine-2-carbonitrile (Example 404, Part A) (1.50 g, 10.7 mmol) and K2CO3 (3.71 g, 26.9 mmol) in DMA (27.0 mL) and isooctane (13.4 mL). Beat at 110° C. for about 2.25 hours. Cool to room temperature and quench with water (100 mL). Extract with dichloromethane (3×100 mL). Wash the extract with saturated aqueous NaHCO3 (1×50 mL) and brine (1×75 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-30% ethyl acetate in hexanes. Concentrate the eluant, then take the solid up in 88% formic acid (46 mL) and stir at room temperature for 4 hours. Dilute the reaction mixture with water (50 mL). Extract with dichloromethane (2×100 mL). Wash the extract with saturated aqueous NaHCO3 (1×50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 30% ethyl acetate in hexanes to give the title compound (1.88 g, 77.7%): TOF MS ES+ 225.1 (M)+, HRMS calcd for C12H7N3O2 225.0538 (M)+, found 225.0527, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=11.5 min, 100% purity.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([N:4]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 2.12 g of 2-(trimethylsilyl)ethyl 3-(cyclopropylsulfamoyl)benzoate, 1.45 g of ethyl 4-bromobutyrate, 2.57 g of potassium carbonate, and 21 mL of DMF was stirred at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.48 g of 2-(trimethylsilyl)ethyl 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoate as a colorless oily substance. ESI+: 456
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O.S(Cl)([Cl:23])=O>>[Cl-:23].[CH:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:11]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1SSc1ccccc1C(=O)O
Product: [Cl-]
Product: c1ccc(SSc2ccccc2)cc1
Temperature: 30 °C

Procedure:
A mixture of 2,2'-dithiobisbenzoic acid (25 g, 81.6 mmol) in 350 mL of thionyl chloride was heated at reflux for 18 hours. The resulting solution was cooled to about 30° C. and excess thionyl chloride was removed in vacuo. The crude solid was slurried in hexane and the title compound was recovered by filtration to yield 21.2 g. This compound was used without further purification, mp 150°-151° C.;
Reaction SMILES: CO[CH:3]1[C:7](=[O:8])[O:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13](=[C:14]=O)[C:4]1=2.[CH3:16][C:17](C)=O.[CH2:20](NCC)C>O>[CH3:20][O:6][C:7]([C:3]1[C:4]2[C:13]([CH:12]=[CH:11][CH:10]=[CH:9][CH:5]=2)=[CH:14][C:16]=1[CH3:17])=[O:8]
Reactant: CCNCC
Reactant: COC1C(=O)OC2=C1C(=C=O)C=CC=C2
Reactant: CC(C)=O
Solvent: O
Product: COC(=O)c1c(C)cc2cccccc1-2

Procedure:
2-Methylazulene was synthesized in accordance with the method described in Japanese Laid-Open Patent Publication No. 207232/1987. Thus, 19.5 g (0.16 mol) of tropolone and 40 g (0.21 mol) of p-toluenesulfonic acid chloride were reacted with each other in pyridine to obtain 37.1 g of tosylated tropolone. This compound was then reacted with 20 g (0.15 mol) of dimethyl malonate and 9.7 g (0.18 mol) of NaOMe in methanol at room temperature for four hours to obtain 14.4 g of 3-methoxy-carbonyl-2H-cyclohepta(b)furan-2-one (compound (2)). To 12 g of the compound (2) were added 200 ml of acetone and 70 ml of diethylamine, and the mixture was refluxed for 30 hours. Water was added to this mixture, and the resulting mixture was extracted with toluene to obtain 39.2 g of methyl-2-methyl-azulenecarboxylate. To this compound was further added 25 ml of phosphoric acid, and reaction was carried out at a temperature of 85 to 90° C. for one hour. The reaction mixture was subjected to decomposition with water, and the resultant was extracted with benzene. The organic phase was dried to obtain 6.5 g of the desired compound, 2-methylazulene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][S:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH:17]1([CH2:23][NH:24][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][S:15][CH3:16])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCC1CCCCC1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
A mixture of (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylthio)butanoic acid (4.57 g), cyclohexanemethylamine (2.28 g), HOBt (2.72 g), and EDCI (3.87 g) in DMF (50 mL) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with aqueous ammonium chloride, aqueous sodium hydrogen carbonate, and brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was crystallized from ethyl acetate and hexane to give tert-butyl [(1R)-1-{[(cyclohexylmethyl)amino]carbonyl}-3-(methylthio)propyl]carbamate (5.65 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([N:38]=[C:39]=[S:40])(=O)C1C=CC=CC=1.O>CC(C)=O>[NH2:38][C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1)=[S:40]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(N)=S)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a ice-cold solution of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (247.6 mg) in acetone (4.8 ml) was added benzoyl isothiocyanate (94.1 mg), and the mixture was stirred at r.t. for 1 hour. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual amorphous substance was dissolved in EtOH (5 ml), and 6N-NaOH (0.288 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and neutralized with 1N-HCl at 0° C. The mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was solidified with ethyl ether to give N-{4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (290.7 mg) as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([OH:28])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1.O>CN(C)C=O>[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([O:28][CH2:7][CH3:8])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1
Reactant: Cn1nc(O)c(CSC2=NOC(C)(C)C2)c1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(C)c(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
0.20 g (1.3 mmoles) of anhydrous potassium carbonate and 0.20 g (1.5 mmoles) of ethyl iodide were added to a solution of 0.30 g (1.0 mmoles) of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.30 g (yield: 92.0%) of intended 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](N)=[C:6]([O:8][CH3:9])[CH:7]=1.C([N:15](CC)CC)C.[C:20]([CH2:24][C:25](Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([CH:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:25]([NH2:15])=[O:26])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1N
Reactant: CCN(CC)CC
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of the crude 5-bromo-1,3-dimethoxy-2-amino-benzene from above and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butyl acetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Then the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.0 g, 91%). 1H-NMR (DMSO-d6, 400 MHz): δ 8.69 (brs, 1H, exchangeable with D20), 6.87 (s, 2H), 3.73 (s, 6H), 2.11 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:34](Cl)(=O)[O:35]C1C=CC([N+]([O-])=O)=CC=1.[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>ClCCl.CN(C)C=O>[CH:47]1([CH2:50][NH:51][C:34]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:23]=4)[CH2:15][CH2:16]3)(=[O:9])=[O:10])[CH:3]=2)=[O:35])[CH2:49][CH2:48]1
Reactant: NCC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)Nc1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
2-(4-((4-(3-Aminophenylsulfonyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.302 mmol, 150 mg) and 4-nitrophenyl carbonochloridate (0.302 mmol, 60.8 mg) were combined in a mixture of dichloromethane/dimethylformamide and stirred at room temperature for 1 hour. Cyclopropylmethanamine (0.603 mmol, 42.9 mg) was added and the reaction mixture was left to stir at room temperature for 15 minutes. The reaction mixture was purified by SCX chromatography and concentrated under vacuum. The residue was purified by silica column chromatography, eluting with 0%-4% methanol/dichloromethane gradient, to afford the title compound (52.3 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:35])[CH2:33][OH:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([O:34][CH2:33][CH:32]([C:29]1[CH:30]=[N:31][C:26]([C:24]2[NH:25][C:21]([CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)[OH:35])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)OCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 1-[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]ethane-1,2-diol (245 mg) in N,N-dimethylformamide (5 mL) were added N-(tert-butoxycarbonyl)glycine (86.0 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (80.0 mg) and N-methylmorpholine (162 μL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (110 mg, yield 34%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 654 (MH+).