Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(N)c2[nH]cnc2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.5 %

Procedure:
2,6-Diaminopurine (5.00 g, 33.3 mmol) and potassium carbonate (6.91 g, 50.0 mmol) were suspended in DMF (250 ml). Benzyl bromide (8.55 g, 50 mmol) was added thereto and the mixture was stirred at room temperature for 5 hours. After condensing the reaction mixture in vacuo, to the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (5% methanol/chloroform) to give the subject compound (1.56 g, yield 19%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30.5 mmol (6.42 g) of 2-naphthylsulphonyl chloride and 15 ml of 4M aqueous sodium hydroxide are added in succession to a solution of 15.2 mmol (2 g) of 6-aminocaproic acid in 15 ml of 4M aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours. The solution is then rendered acidic to pH=2 with concentrated hydrochloric acid, and extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated, and the resulting residue is recrystallised from hexane to yield the expected compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:24]=[S:25]1(=[O:35])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]O)[CH2:27][CH2:26]1>>[O:35]=[S:25]1(=[O:24])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26]1
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Product: O=C(NC1=Nc2c(OCCCN3CCS(=O)(=O)CC3)cccc2C2=NCCN12)c1cccnc1

Procedure:
The procedure used for the preparation of Example 4 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 3-(1,1-dioxidothiomorpholin-4-yl)propan-1-ol. High vacuum drying at 60° C. gave the title compound (105 mg, 45%): HPLC MS RT=1.16 min, MH+=483.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.32-2.33 (2H, m), 3.53-3.58 (2H, m), 3.66 (4H, bs), 3.87 (4H, bs), 4.27-4.40 (2H, m), 4.58-4.65 (2H, m), 7.60 (1H, t), 7.70 (1H, d), 7.93 (1H, dd), 8.89 (1H, d), 8.99 (1H, dd), 9.50 (1H, s).
Reaction SMILES: CO[NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[NH:5].[Cl-].[NH4+]>CCO.O>[CH3:12][C:8]1[N:7]=[C:6]([C:4]([NH2:5])=[NH:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CONC(=N)c1cccc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=N)N)n1
Temperature: 80 °C

Procedure:
To a solution of N-Methoxy-6-methyl-pyridine-2-carboxamidine (1 eq, 32.9 mmol, 4.94 g) in EtOH (40 ml) and water (10 ml) at room temperature is added ammonium chloride (1 eq, 32.9 mmol, 1.76 g). The resulting mixture is heated to 80° C. for 4 hours and then allowed to cool to room temperature overnight. The solvent is removed in vacuo to afford the title compound which is used in subsequent steps without further purification. [2M+H]+=271
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH2:10]Br)=[CH:4][C:3]=1[Cl:13].[C:14]1([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:12])=[CH:4][C:3]=1[Cl:13]
Reactant: c1ccc(CCCOCCOCCCNCc2ccccc2)cc1
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CN(CCCOCCOCCCc2ccccc2)Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
1-[4-Amino-3,5-dichlorophenyl]-2-bromoethanone (0.86 g), N-[3-[2-(3-phenylpropoxy)ethoxy]propyl]benzenemethanamine (1 g) and DEA (0.43 g) were stirred together in THF (30 ml) at room temperature under nitrogen for 22 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (40 ml), treated portionwise with sodium borohydride (0.31 g) at 0° C. under nitrogen, stirred at room temperature under nitrogen for 2 h, diluted with water (150 ml) and extracted with ethyl acetate (2×150 ml). The dried extract was evaporated in vacuo to give an oil. Purification by FCC eluting with System F (1:1) gave the title compound (1.22 g) as an oil. T.l.c. (System F 1:1) Rf 0.19
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][O:16][C:17]=2[CH3:18])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]([F:19])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])/[C:13](/[C:14]#[N:15])=[C:17](\[OH:16])/[CH3:18])=[CH:6][CH:5]=1
Reactant: Cc1oncc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
0.1 mol (28.6 g) of N-(4-trifluoromethoxyphenyl)-5-methylisoxazole-4-carboxamide is dissolved in 100 ml of ethanol and a solution of 0.11 mol (4.4 g) of sodium hydroxide solution in 100 ml of water is added at 20° C. The mixture is stirred for 30 minutes and acidified with concentrated hydrochloric acid after diluting with water. The precipitated crystal magma is filtered off with suction, washed with water and dried in the air. 27.7 g (9.1% of theory) of N-(4-trifluoromethoxyphenyl)-2-cyano-3-hydroxycrotonamide of melting point 171°-176° C. (from ethanol) are thus obtained.
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH2:10]1[O:13][CH:11]1[CH3:12].C(N(CC)CC)C>>[CH3:10][CH:11]([OH:13])[CH2:12][O:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1
Reactant: CC1CO1
Reactant: Cc1cc(C)cc(O)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(OCC(C)O)c1
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A 500 ml three-necked flask was charged with 51.88 g (425 mmol) of 3,5-xylenol, 29.6 g (510 mmol) of propylene oxide and 4.25 g (42 mmol) of triethylamine, and the resultant mixture was refluxed under heat at 90° C. for 1 hour and at 110° C. for 4 hours. The reaction product was recrystallized from hexane to give 1-methyl-2-(3,5-dimethylphenoxy)ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9]O)=[CH:4][N:3]=1.[BH4-].[Na+]>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1
Reactant: ON=Cc1ccc(Br)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: NCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Add dropwise a solution of 2-bromo-pyridine-5-carbaldehyde oxime (0.5 g, 2.487 mmol) in DME (10 mL) to a solution of titanium(IV) chloride (0.573 mL, 5.223 mmol) and sodium borohydride (395 mg, 10.445 mmol) in DME (20 mL) at 0° C. Allow the mixture to warm to room temperature and stir for 3 h. Add water and remove the solvent in vacuo. Basify the mixture to pH 12 with 1N aqueous NaOH and extract with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to afford the desired intermediate (340 mg, 73%) that was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:24][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:21]
Reactant: O=c1c2ccccc2c(-c2ccccc2)cn1CCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=c1c2ccccc2c(-c2ccccc2)cn1CCCCl

Procedure:
Then, 23 of 2-(3-hydroxypropyl)-4-phenyl-1-(2H)-isoquinolone was added to a mixture of 60 ml of benzene and 25 ml of thionyl chloride and the mixture was heated at reflux for 1 hour. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water and dried, and then the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 23.3 g of 2-(3-chloropropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 138° C. as colorless prisms.
Reaction SMILES: C([S:8][C:9]([CH2:22][O:23][CH3:24])([CH2:19][O:20][CH3:21])[CH2:10][N:11]([CH2:13][CH2:14][P:15]([CH3:18])([CH3:17])=S)[CH3:12])C1C=CC=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:18][P:15]([CH3:17])[CH2:14][CH2:13][N:11]([CH2:10][C:9]([CH2:19][O:20][CH3:21])([CH2:22][O:23][CH3:24])[SH:8])[CH3:12]
Reactant: COCC(COC)(CN(C)CCP(C)(C)=S)SCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COCC(S)(COC)CN(C)CCP(C)C
Temperature: -50 °C

Procedure:
A solution of 2-benzylthio-N-(2-dimethylphosphinothioylethyl)-3-methoxy-2-methoxymethyl-N-methylpropylamine (450 mg) in dry tetrahydrofuran (10 cm3) was placed in a flask fitted with a low temperature condenser (-50° C.), drying tube and gas inlet. The flask was flushed with nitrogen, the solution cooled to -50° C., and then dry ammonia (40 cm3) was condensed into the flask. Small pieces of sodium were then added to this mixture until the blue colouration persisted for at least 1 hour. The blue colouration was then discharged by the addition of ammonium chloride, and the mixture allowed to warm to room temperature. As the ammonia evaporated steps were taken to ensure that no air entered the apparatus. [The flask and its contents were then transfered to a glove box containing a nitrogen atmosphere for subsequent operations.] The reaction mixture was then filtered and the solvent removed under reduced pressure to give a yellow oil containing some solid material. The oil was dissolved in chloroform, the solid removed by filtration, and the solvent removed under reduced pressure to give 2-[N-(2-dimethylphosphinoethyl)-N-methylamino]-1,1-bis(methoxymethyl)ethanethiol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH:10]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=3[CH:23]=2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647 μmol) in dichloromethane (15 mL) was added triethylamine (190 μL, 1.43 mmol) and 4-nitrobenzoyl chloride (264 mg, 1.43 mmol). The solution was stirred at room temperature for 72 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.42 min, MH+ 459].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:7]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[PH2:8]=[O:9])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)SCc1ccccc1)C([PH2]=O)(N1CCCC1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (12.55 g.; 0.033mol.) dissolved in 100 ml. of diethyl ether was added to a solution of pyrrolidine (9.3 g.; 0.13 mol.) in 100 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with water, dried with magnesium sulfate and concentrated in vacuo. To remove any remaining solvent, the residue was concentrated at 25° C. and 0.05 mm. to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(pyrrolidyl)-phosphinylmethyl]-glycinate, hemi-hydrate as an oil (nD25 =1.5424) having the following analysis:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13]I.[H-].[Na+]>>[CH3:13][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:11]=[O:12])=[C:2]1[Cl:1]
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: Cn1c(Cl)c(C=O)c2ccccc21
Yield: 93.8 %

Procedure:
Prepared from (1) (18 g), methyl iodide (17.1 g) and NaH (2.88 g) yielding (3) (18.2 g), m.p. 88°-90° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[N+]([O-])(O)=[O:12]>C(O)(=O)C.N([O-])=O.[Na+]>[CH3:9][C:4]1[C:3](=[O:10])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:12])[CH:5]=1
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 69.6 %

Procedure:
Also, in the process described in Japanese Pat. Publication No. 38063/70 (German Pat. OLS No. 1,814,652), 2,3,6-trimethylphenol is dissolved in acetic acid and oxidized with a dilute nitric acid using sodium nitrite as a catalyst to obtain trimethyl-p-benzoquinone in maximum yield of 69.6 percent. This process is simple and is considered to be a good one. However, the yield is a little low.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([NH:15][CH2:16][C:17]([OH:19])=[O:18])(=O)[CH3:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH3:13][C:12]1[O:19][C:17](=[O:18])[C:16](=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:15]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Temperature: 120 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
4-Nitrobenzaldehyde (53.7 g, 0.356 mol), N-acetylglycine (49.9 g, 0.427 mol) and sodium acetate (37.9 g, 0.463 mol) were mixed with acetic anhydride (168 g, 1.78 mol) and the resulting mixture heated with stirring to 120° C. for 6 hrs, giving a dark suspension. The mixture was then cooled to RT overnight, resulting in the formation of a precipitated solid. The reaction mixture was poured into ice-water (150 g) and the resulting suspended solid was collected by filtration. The crude solid product was washed with acetone (100 ml) then recrystallized from hot acetone (650 ml) to give a crystalline solid that was washed with 50% aqueous ethanol, then dried in vacuo to give 2-methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one (55.0 g, 66%) as pale yellow needles. The crystallisation mother liquors and washes were combined and evaporated to give a solid residue that was recrystallized from acetone to give a second crop of 2-methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one (8 g, 10%). The combined yield of 2-methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one was 63 g (76%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[N+:19]([O-])=O>[Pd].CO.CCOC(C)=O>[NH2:19][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:8]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccc(N2CCCCC2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCCCC2C)c(N)c1

Procedure:
Ethyl 4-(2-methylpiperidin-1-yl)-3-nitrobenzoate (5 g; 17.10 mmol) in a solution of MeOH/EtOAc 1:1 (340 mL, 0.05 M) was injected on a flow hydrogenation reactor (H-Cube), adapted with a Pd/C cartridge (44 mm), a flow of 1 mL/min, no heating and the full H2 option enabled, affording after evaporation of the solvents the title compound as a white solid (4.34 g, 96%). 1H NMR (DMSO-d6, 300 MHz) δ 7.34-7.33 (d, 1H), 7.21-7.18 (dd, J=8.2 Hz, 1.8 Hz, 1H), 7.06-7.03 (d, J=8.1 Hz 1H), 5.09 (br s, 2H), 4.28-4.26 (q, J=7.4 Hz, 2H), 3.11-3.07 (m, 1H), 2.97-2.88 (m, 1H), 2.47-2.3 (m, 1H), 1.83-1.65 (m, 6H), 1.32 (t, J=7.4 Hz, 3H). HPLC (Method A) Rt 2.60 min (Purity: 97.8%). LC/MS (Method B): 263.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 186.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2) and (S)-1-pyrrolidin-3-yl-methanol. HPLC (Condition 4) tR=6.17 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=476.2/478.2 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:3][CH:4]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:14][CH:15]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: COC(=O)CC(N)c1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COC(=O)CC(NS(=O)(=O)c1ccc(C)cc1)c1ccc(OCC2CCN(c3ccncc3)CC2)cc1

Procedure:
Using a procedure similar to that described in Example 19, but starting from the product of Example 61, step (iii) and p-toluenesulphonyl chloride, the title compound was prepared; NMR(CDCl3): 1.34-1.55(m,2H), 1.95(d,2H), 2.0-2.2(m, 1H), 2.38(s,3H), 2.62-3.05(m,4H), 3.55(s,3H), 3.78(d,2H), 3.96(d,2H), 4.65(m, 1H), 5.65(brs,1H), 6.7(d,2H), 6.72(d,2H), 7.05(d,2H), 7.2(d,2H), 7.65(d,2H), 8.25(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 524(M+H)+.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH:3]([OH:6])[CH2:4][CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH:2]([CH:3]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4][CH3:5])[CH3:1])(=[O:18])=[O:17]
Reactant: CCC(O)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Pentane-2,3-diol 1.04 g (10.0 mole) and triethylamine 2.23 g (22.0 mole) were dissolved in 40 mL of methylene chloride, and methanesulfonyl chloride 2.52 g (22.0 mole) was dropwise added thereto in a range of 0 to 5° C. and stirred at 0° C. for 30 minutes. After the raw materials were confirmed to be exhausted by gas chromatography analysis, the organic layer was washed with 20 ml of water and then 20 ml of a saturated salt solution. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was refined by column chromatography (Wako Gel C-200, hexane/ethyl acetate=2/1 eluted) to obtain 2.24 g of pentane-2,3-diyl dimethanesulfonate (pale orange liquid; novel compound) which was the targeted product (yield: 86%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:21]>ClCCl.CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH2:21])=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1
Reactant: Cc1nn(C)c(C(=O)O)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
To 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxylic acid (1.08 g, 5.84 mmol) in anhydrous dichloromethane (DCM) (25 mL) and DMF (0.5 mL) was added dropwise oxalyl chloride (0.74 mL, 8.77 mmol, 1.5 eq.) over 10 minutes. The reaction mixture was stirred at RT under N2 for 17 hours. Volatile solvent was evaporated in vacuo, and the crude material dissolved in anhydrous THF (20 mL) and acetone (10 mL). Concentrated aqueous ammonium hydroxide (5.0 mL, 128.4 mmol, 22 eq.) was added slowly, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration from ether-heptane afforded the desired product as a white solid (550.0 mg, 51.5%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.39 (broad s, 1H), 8.21 (broad s, 1H), 3.77 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:29]I>>[CH3:29][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:7]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: CI
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(C)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.412 g, 83%) from {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using MeI and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.74 (t, J=7.5 Hz, 3H), 1.07-1.27 (m, 4H), 1.47-1.65 (m, 2H), 2.68 (t, J=8.3 Hz, 2H), 3.59 (s, 3H), 5.34 (s, 2H), 7.08 (t, J=8.3 Hz, 1H), 7.19 (t, J=8.3 Hz, 1H), 7.34 (dd, J=1.5, 9.0 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.53-7.66 (m, 3H), 7.92-8.08 (m, 3H); mass spectrum [(+) ESI], m/z 383 (M+H)+.