Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH:26]1([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][N:30]=2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=NO)C1C(=CC=CC=1)O>[Cu-]=O.O.CC#N>[CH:26]1([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=4)[CH3:13])=[O:10])=[CH:4][CH:3]=3)[N:30]=2)[CH2:28][CH2:27]1
Reactant: c1ccc2c(C3CC3)n[nH]c2c1
Reactant: C[C@@H](NC(=O)Cc1ccc(I)cc1)c1ccc(NCC(F)(F)F)cn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Solvent: O
Product: C[C@@H](NC(=O)Cc1ccc(-n2nc(C3CC3)c3ccccc32)cc1)c1ccc(NCC(F)(F)F)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
The starting 2-(4-iodophenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide (130 mg, 0.280 mmol), 3-cyclopropyl-1H-indazole (66.5 mg, 0.420 mmol), copper (I) oxide (2.004 mg, 0.014 mmol), cesium carbonate (146 mg, 0.448 mmol), and salicylaldoxime (7.68 mg, 0.056 mmol) were mixed into 1.0 ml of CH3CN in a sealed bottle. The mixture was stirred at 150° C. overnight. After cooled, water (25 mL) was added and the mixture. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient, 30-100% EtOAc in hexanes) to give 2-[4-(3-cyclopropyl-1H-indazole-1-yl)phenyl]-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a light yellow solid (94 mg, 68%). 1H NMR (CDCl3, 400 MHz) δ 8.206 (d, J=2.57 Hz, 1H); 7.816 (d, J=8.06 Hz, 1H); 7.683 (m, 3H); 7.407 (m, 3H); 7.208 (m, 3H); 6.726 (d, J=7.14 Hz, 1H); 5.128 (quintet, J=6.96 Hz, 1H); 4.361 (dd, J=15.93, 7.96 Hz, 2H); 3.645 (s, 2H); 2.288 (m, 1H); 1.413 (d, J=6.77 Hz, 3H); 1.175 (m, 2H); 1.085 (m, 2H); MS (ES): m/z 495.2 (M+H). FLIPR alpha1I IP=73 nM.
Reaction SMILES: CO[Na].[Na].[Cl:5][C:6]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:7]=1[CH2:8][NH:9][C:10]([NH:12][N:13]=[C:14]([CH3:19])[C:15](OC)=[O:16])=[S:11]>CO>[Cl:5][C:6]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:7]=1[CH2:8][N:9]1[C:15](=[O:16])[C:14]([CH3:19])=[N:13][NH:12][C:10]1=[S:11]
Reactant: COC(=O)C(C)=NNC(=S)NCc1cc(F)ccc1Cl
Agent: CO[Na]
Agent: [Na]
Solvent: CO
Product: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Cl)c1=O

Procedure:
To a solution of MeONa (0.82 M) in methanol (200 mL), freshly prepared from sodium (3.80 g, 165 mmol) and dry methanol (200 mL), was added methyl 2-(2-(2-chloro-5-fluorobenzylcarbamothioyl)hydrazono)propanoate (28, 10.00 g, 31.5 mmol). The mixture was heated at reflux for 36 h. Most of the solvent was evaporated. The resulting residue was diluted with water (300 mL), acidified with 2 N HCl to pH=1˜2, and then extracted with EtOAc (250 mL×2). The extracts were washed with brine, dried over MgSO4, and concentrated to give a mixture, which was separated by silica gel column, and eluted with 20-30% ethyl acetate in petroleum ether to give 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (29).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[C:4]([C:12]#[C:13][Si](C)(C)C)[CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[C:4]([C:12]#[CH:13])[CH:3]=1
Reactant: CC(C#N)c1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#Cc1cc(Cl)ccc1C(C)C#N
Reaction time: 1 h

Procedure:
To a solution of 2-(4-chloro-2-(2-(trimethylsilyl)ethynyl)phenyl)-propanenitrile (0.550 g, 2.1 mmol) in THF (25 mL) was added 5N NaOH (15 mL). After one hour, the reaction was complete as determined by LC-MS and TLC. The solution was acidified with 5N HCl until the pH was about 2. The solution was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (2×30 mL) and brine (2×30 mL), dried with MgSO4, and concentrated in vacuo. The resulting orange oil was purified using silica flash chromatography on the ISCO with 0-20% EtOAc/hexanes. MS m/e=190 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:38][CH2:39]SC)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][C@H:17]1[CH2:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:33])=[O:32])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:38][CH2:39][N:15]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][C@H:17]2[CH2:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:33])[C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1CS(=O)(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
Tert-butyl (1R,3R,4S)-4-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-3-(tert-butylsulfonylmethyl)cyclohexylcarbamate (6.2 g) was dissolved in iodomethane (60 mL) and CH2Cl2 (15 mL). The resulting solution was stirred at rt for 72 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. This material was dissolved in DMF (60 mL) and the solution was charged with Cs2CO3 (13.2 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(tert-butylsulfonylmethyl)cyclohexylcarbamate (5.5 g). MS found: (M+H)+=566.5.
Reaction SMILES: [C:1]([CH:6]1[N:9](C2C=CC(OC)=CC=2)[C:8](=[O:18])[CH:7]1[O:19][CH3:20])([O:3][CH2:4][CH3:5])=[O:2].[N+]([O-])([O-])=O.[NH4+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[C:1]([CH:6]1[NH:9][C:8](=[O:18])[CH:7]1[O:19][CH3:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1C(OC)C(=O)N1c1ccc(OC)cc1
Agent: O=S([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1NC(=O)C1OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 1.4 g of 4-carboethoxy-3-methoxy-1-(p-methoxyphenyl)azetidine-2-one in 50 ml acetonitrile at 0° was added a solution of 8.23 g of cerric ammonium nitrate in 50 ml H2O over 3 minutes. After stirring at 0° for 1 hour the solution was poured into 200 ml of 10% sodium sulfite and extracted with 3×75 ml of ethyl acetate. The combined organic extracts were washed with 10% sodium sulfite and saturated sodium chloride solutions and dried over sodium sulfate. Filtration and evaporation gave an amber oil which was recrystallized from methylene chloride/hexane to give 700 mg of 4-carboethoxy-3-methoxyazetidine-2-one; m.p. 91°-92°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH2:30][C@H:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][C:28]=1[Cl:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:22][C:23]1[CH:24]=[C:25]([CH2:30][C@H:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][C:28]=1[Cl:29])=[O:21])[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](C)Cc1ccc(Cl)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)Cc1ccc(Cl)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (purity 76%, about 3.14 mmol) of (3R)—N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 0.91 g (3.76 mmol) of (+)-ethyl (2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate were dissolved in a mixture of 10 ml of DMF and 4 ml of pyridine, and 1.55 g (4.08 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were then washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The resulting solid was stirred in a mixture of cyclohexane and diethyl ether (about 3:1), filtered off with suction and dried under high vacuum. This gave 0.99 g of the target product (59.9% of theory, diastereomer ratio about 7:1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Temperature: 80 °C
Yield: 26.6 %

Procedure:
To a solution of 9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Example 31) (260 mg, 0.62 mmol) in acetonitrile (15 ml) was added N,N-diisopropylethylamine (0.214 ml, 1.23 mmol) followed by ethyl 3-bromopropanoate (0.158 ml, 1.231 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equiv. of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography, eluting with 50-65% ethyl acetate in cyclohexane to give the title compound as a yellow oil (80 mg).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:32])=[O:5])[CH2:3][CH2:2]1.[N+:33]([C:36]1[CH:37]=[N:38][NH:39][CH:40]=1)([O-:35])=[O:34].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12]([N:38]4[CH:37]=[C:36]([N+:33]([O-:35])=[O:34])[CH:40]=[N:39]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:32])=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]1CCc2c(ccc(-n3cc([N+](=O)[O-])cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A 100-mL round-bottom flask equipped with a balloon filled with air was charged with (5)-cyclopropyl(2-methyl-5-phenoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.240 g, 0.55 mmol), 4-nitro-1H-pyrazole (0.188 g, 1.66 mmol), copper (II) acetate (0.301 g, 1.66 mmol), pyridine (0.2 mL), and N,N-dimethylformamide (5 mL), and the resulting mixture stirred overnight at 90° C. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (eluting with 1:3, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.060 g, 26%) as yellow oil. MS (ESI, pos. ion) m/z 419 [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O>C(OC(=O)C)(=O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)CNC(=O)c2ccncc2)cc1
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2cnc(-c3ccncc3)o2)cc1

Procedure:
Isonicotinic acid (24.93 g., 0.0938 mole) and thionyl chloride (50 ml) is refluxed for 1 hour. The crude acid chloride which remains after removal of excess thionyl chloride at diminished pressure is dissolved in dry pyridine (200 ml) and p-methoxy phenacylammonium chloride (19.00 g, 0.938 mole) is added portion wise to the stirred solution. The addition is exothermic.. After the addition is completed, the reaction mixture is heated and stirred on a boiling water bath for 2 hours and then poured into ice-water to precipitate the product. The solid is collected and dried under reduced pressure to give α-isonicotinamido-p-methoxyacetophenone m.p. 227°-230° C. (with decomposition). α-isonicotinamido-p-methoxyacetophenone (11.5 g., 0.043 mole) is added portion-wise to a stirred solution of 200 ml of acetic anhydride and 15 ml of 90% phosphoric acid; the addition is exothermic. After the addition is complete the reaction mixture is stirred and refluxed for 2 hours. After cooling, the supernatant liquid is decanted from the viscous precipitate, which is crystallized by titration with 350 ml of 1% aqueous sodium hydroxide. The yellow solid is filtered, washed with distilled water (200 ml), and dried in vacuo yielding 2-(4-pyridyl)-5-p-methoxyphenyloxazole, m.p. 105°-107° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]Br.[OH-].[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10%) to pH ˜8.0-9.0 under cooling and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (80 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90%). 1H-NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:5]2.C([O:21]P(OCC)OCC)C.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)([OH:21])[CH2:5]2
Reactant: O=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Reactant: CCOP(OCC)OCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccc(F)cc2CC1(O)c1ccc(F)cc1
Yield: 38.8 %

Procedure:
A solution of 7.0 g (0.029 moles) of the product obtained from Step A and 69 mL of toluene was added with stirring to a mixture of 5.7 g (0.034 moles) of triethylphosphite, 0.33 g (0.0014 moles) of benzyltriethylammonium chloride, 344 mL of toluene and 167 mL of 50% aqueous sodium hydroxide solution. A steady stream of air was introduced into the vigorously stirred reaction mixture at room temperature for I hour. The resulting mixture was partitioned between hexane/ether and water and the aqueous layer was extracted three times with ether. The combined organic layers were washed twice with water, three times with saturated aqueous sodium bisulfite solution, dried over magnesium sulfate and concentrated. The resulting crude product was triturated several times with hexanes to afford 2.93 g of a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Product: COC(=O)c1ccc(Br)cc1C
Yield: 61 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (2.0 g, 9.3 mmol) in methanol (20 mL) was added p-TsOH—H2O (90 mg, 0.50 mmol). The mixture was heated at reflux overnight. Methanol was evaporated and the residue was purified by chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford 4-bromo-2-methyl-benzoic acid methyl ester (1.3 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=8.4 Hz, 1H), 7.41-7.36 (m, 2H), 3.89 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)nn2)CC1
Yield: 45.9 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and (R)-4-methyloxazolidin-2-one (51 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (97 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH:4]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:2].Cl.C(=O)([O-])[O-].[K+].[K+]>[Fe].C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:4]2[N:3]([CH2:1][CH3:2])[CH2:8][CH2:7][NH:6][C:5]2=[O:9])=[CH:15][CH:14]=1
Reactant: CCN1CCNC(=O)C1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCN1CCNC(=O)C1c1ccc(N)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 32 (210 mg, 0.89 mmol), ethanol (6 mL), iron powder (−325 mesh, 491 mg, 8.93 mmol) and 2N hydrochloric acid (0.70 mL, 1.40 mmol), and the mixture was heated at reflux for 30 min. After this time, the reaction was cooled to room temperature, and powdered potassium carbonate (3.03 g, 22.0 mmol) was added. The resulting suspension was filtered and the filter cake washed with ethanol (4×10 mL). The filtrate was concentrated under reduced pressure to afford 33 in 100% yield (185 mg) as a white solid: mp 153-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, 1H, J=2.7 Hz), 6.90 (d, 2H, J=8.4 Hz), 6.47 (d, 2H, J=8.4 Hz), 4.95 (bs, 2H), 3.45 (m, 1H), 3.42 (s, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.44 (m, 1H), 2.02 (s, 3H); MS (ESI+) m/z 206 (M+H).
Reaction SMILES: CCOC(CCC(C)=O)=O.CC1(CCCCCCCC)OC(=O)CC1.Cl.Cl[C:28]([CH3:43])([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CCOCC>[CH3:43][CH:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CCCCCCCCC(C)(Cl)CCC(=O)OC
Agent: CCCCCCCCC1(C)CCC(=O)O1
Agent: CCOC(=O)CCC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCC(C)CCC(=O)OC
Temperature: 0 °C

Procedure:
An ether solution of the Grignard compound obtained from n-chlorooctane is added dropwise, under nitrogen, to a solution of ethyl levulate in ether, cooled to 0° C. The resulting lactone, 5-methyl-5-octyltetrahydrofuran-2-one (II), is converted with methanolic hydrochloric acid to methyl 4-chloro-4-methyldodecanoate (III), which, after eliminating hydrochloric acid by heating and then carrying out hydrogenation, gives racemic methyl 4-methyldodecanoate (IV), from which 4-methyldodecanoic acid (V) is obtained by hydrolysis. At the same time, the tosylate is prepared from 2-hexanol and, when reacted with sodium malonate in ethanolic solution, forms ethyl 2-carbethoxy-3-methylheptanoate (VI). This is converted to racemic 3-methylheptanoic acid (VII) by hydrolysis and thermal decarboxylation.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C(N(C(C)C)C(C)C)C>CO>[NH2:19][C:18]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=2[CH3:10])[N:9]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1c(Br)cccc1NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1c(Br)cccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3-Bromo-2-methylphenyl)hydrazine (CAS no. 459817-67-5) (10 g, 49.74 mmol) was suspended in MeOH (100 mL) under nitrogen at 0° C. 2-(Ethoxymethylene)malononitrile (6.07 g, 49.74 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 2 hours. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. No reaction. The starting material was NMRed and found to be a salt, so N-ethyl-N-isopropylpropan-2-amine (17.33 mL, 99.47 mmol) was added and stirred for a further 16 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc, and washed sequentially with water ×2 and saturated brine. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product, 5-amino-1-(3-bromo-2-methylphenyl)-1H-pyrazole-4-carbonitrile (12.60 g, 91%). m/z (ES+) (M+H)+=279.25; HPLC tR=1.95 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCC(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCC(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(1-(2-amino-5-bromo-3-nitropyridin-4-yl)piperidin-4-yl)-N-(thiazol-2-yl)acetamide (0.110 g, 0.25 mmol) and ethanol (6 ml) was added 4-dimethylaminobenzaldehyde (0.049 g, 0.32 mmol) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (1.0 ml, 1.0 mmol). The reaction mixture was stirred at 80° C. for 18 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g silica isolute column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), 3% methanol in ethyl acetate/dichloromethane (v/v; 1:1), 3% methanol in ethyl acetate, and 3% MeOH in chloroform. The title compound was obtained as a solid after trituration with diethyl ether/methanol (0.027 g, 20%);