Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:33].[Na+]>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:33])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A slurry of 4-[3-(2-benzyloxy-5-methylthiophenyl)-propyl]-N-(2-hydroxyethyl)benzenecarboxamide (0.22 g) in methanol (10 ml) was added to a stirred solution of sodium metaperiodate (0.113 g) in water (1 ml) maintained at 0° C. by external cooling. The reaction mixture was stirred at 0° C. for 2 hours, then concentrated to a volume of approximately 2 ml. This residue was dissolved in ethyl acetate (10 ml), the ethyl acetate solution was dried (anhydrous magnesium sulphate) and the solution evaporated to dryness. The residue was subjected to chromatography on silica (Merck) eluted with a mixture of methanol/ethyl acetate (1:9 v/v). The only porduct obtained was triturated with ethyl acetate (2 ml) to give 4-[3-(2-benzyloxy-5-methylsulphinylphenyl)propyl]-N-(2-hydroxyethyl)-benzenecarboxamide (mp. 105°-108° C.; 43% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)=[O:6])[CH3:3].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:32][CH2:33][CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:36][CH2:35]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([CH2:32][CH2:33][CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH2:10][CH2:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 52.3 %

Procedure:
First 2.1 g (11 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride and then 4.53 g (35 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.32 g (10 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 1.65 g (52.3%) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether and melts at 177°-178°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O.O.Cl>[Cl:15][CH2:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 25 °C

Procedure:
2-Fluoroaniline (2 g, 17.99 mmol) was stirred in acetone (30 mL) and pyridine (2.91 mL, 35.99 mmol) and allowed to dissolve. To this solution was added 3-chloropropanoyl chloride (3.42 g, 26.99 mmol), slowly. The reaction mixture began to reflux, and when the mixture had cooled to room temperature (˜30 min) TLC analysis showed that the reaction was complete. The reaction mixture was then diluted with water and HCl(aq) (1N) and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated, then chromatographed on silica gel in 30% EtOAc in hexanes. Yield: 3.5 g, 97%. 1H NMR (CDCl3) δ 2.87 (t, 2H, J=6.7 Hz), 3.89 (t, 2H, J=6.7 Hz), 7.10 (m, 3H), 7.52 (brs, 1H), 8.30 (t, 1H, J=7.5 Hz). EI-MS (m/z, %): 201.1 (M+, 22), 111.1 (100).
Reaction SMILES: [OH-].[Li+].O.C([O:7][CH2:8][C:9]([NH:11][C:12]1[C:20]2[C:15](=[N:16][C:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:19]=2)[O:14][C:13]=1[C:36](=[O:41])[C:37]([OH:40])([CH3:39])[CH3:38])=[O:10])(=O)C.CO>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[C:20]3[C:12]([NH:11][C:9](=[O:10])[CH2:8][OH:7])=[C:13]([C:36](=[O:41])[C:37]([OH:40])([CH3:38])[CH3:39])[O:14][C:15]3=[N:16][C:17]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:22][CH:23]=1
Reactant: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(O)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)CO
Temperature: 25 °C

Procedure:
Lithium hydroxide-H2O (0.004 g; 0.174 mmol), the product of Step C (0.100 g; 0.174 mmol), and methanol (0.3 mL) were combined in 2 mL of THF and stirred at room temperature. The reaction was monitored by TLC until complete at which point the reaction was quenched by addition of 0.50 mL of acetic acid. The reaction was diluted with ethyl acetate and then washed two times with aqueous sodium bicarbonate. The solution was concentrated and purified via MPLC chromatography on silica gel with a gradient elution of 0 to 50% ethyl acetate/hexanes. The product was further purified by recrystallization from ethanol to afford the title compound. HPLC/MS 534.8 (M+2); Rt=4.09 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[F:31].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[CH2:5][C:4]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=2[O:2][CH3:1])(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2OC)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of bis(2,4-dimethoxybenzyl)amine (12 g) and 3-chloro-4-fluorobenzene-1-sulfonyl chloride (8.66 g) in dichloromethane (120 mL) was added N,N-diisopropylethylamine (13.5 mL) and catalytic amount of 4-dimethylaminopyridine. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (600 mL) and washed with 5% aqueous HCl, water and brine. After drying over Na2SO4, the mixture was filtered and the filtrate was concentrated under vacuum to give crude product which was loaded on a 400 g silica gel column and eluted with 30% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([OH:10])[CH3:9])=[O:5].[NH2:15][CH2:16][CH:17](O)C.[C:20]12[C:26](=CC=CC=1)[NH:25]C(=O)OC2=O>>[NH:15]1[CH2:16][CH2:17][N:25]=[C:26]1[CH2:20][NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([OH:10])[CH3:9])=[O:5]
Reactant: CC(O)CNC(=O)c1ccccc1N
Reactant: CC(O)CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CC(O)CNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-(2-hydroxypropyl)benzamide (prepared from 1-amino-2-propanol and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino)-N-(2-hydroxypropyl)benzamide, isolated as the hydrochloride salt.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][O:33][CH3:34].C(OCC)(=O)C>CN(C=O)C.O>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:31][CH2:32][O:33][CH3:34])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])[CH2:4][CH2:3]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65 mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to it was added 1-bromo-2-methoxyethane (0.306 g, 2.20 mmol). The resulting mixture was stirred at rt for 72 h. LCMS indicated incomplete conversion, so additional 1-bromo-2-methoxyethane (0.306 g, 2.20 mmol) and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture was heated to 70° C. for 1 h. Dilution with ethyl acetate (60 mL) and water (40 mL) followed by shaking gave a separation of phases. The organic phase was isolated, washed with water (2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. Purification by silica gel chromatography (gradient 100% DCM to 60:1 DCM:MeOH) gave the title compound as a yellow oil (0.486 g, 105% yield). LCMS: m/z 422 (M+H+), retention time 1.35 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.72 (t, J=6.41 Hz, 2H) 3.01 (s, 8H) 3.21 (s, 3H) 3.39-3.52 (m, 6H) 7.62-7.66 (m, 1H) 7.66-7.74 (m, J=7.48, 7.32, 7.32, 7.32, 1.68 Hz, 2H) 8.01 (dd, J=7.78, 1.68 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[CH3:33][C:32]1[C:27]([NH2:26])=[N:28][CH:29]=[C:30]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromo-3-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (140 mg, 30%). MS (ISP) 462.2 [(M+H)+]; mp 233–234° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[NH2:9])=[CH:5][N:4]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: NC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(N)=O)cc2Cl)CC1

Procedure:
The nicotinamide from step (b) above (1.3 g, 6.8 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.27 g, 6.8 mmol, Aldrich) reacted under the conditions Example 3a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 341 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[O:11][CH3:12])C.[Cl:21]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:21].[CH3:12][O:11][C:6]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[CH2:4][NH:2][CH3:1]
Reactant: COC1(c2cccc(C#N)c2)CCCCC1CN(C)C
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CNCC1CCCCC1(OC)c1cccc(C#N)c1
Product: Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of (+/−)-3-(2-dimethylaminomethyl-1-methoxy-cyclohexyl)-benzonitrile (0.10 g, 0.367 mmol) in anhydrous dichloroethane (2 mL) at room temperature under Ar atmosphere was added 1-chloroethyl chloroformate (0.059 mL, 0.825 mmol). After stirring at 100° C. for 2 hours, the reaction was concentrated in vacuo to a crude solid. MeOH (5 mL) was added and the reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated in vacuo to a crude oil. The pure amine was obtained by column chromatography over silica gel (0.5:100 TEA/EtOAc as eluent) which gave the free base (0.10 g, 94%). 1H NMR (CDCl3) 1.64-2.09 (m, 11H), 2.17 (s, 3H), 2.33 (m, 1H), 3.16 (s, 3H), 7.47 (d, J=7.6 Hz, 1H), 7.55 (m, 2H), 7.61 (m, 1H). 13C NMR (75 MHz, CDCl3) 21.6, 25.9, 26.6, 32.4, 36.7, 48.3, 50.3, 52.9, 80.7, 112.4, 119.2, 129.1, 130.3, 130.4, 131.1, 145.9.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@@H:10]1[CH3:14])=[O:24])[CH3:27]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
To a solution of 1.50 g (S)-4-N-Boc-2-methyl-piperazine in 10 ml dichloromethane were added at 0° C. 2.29 ml triethylamine and 0.72 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: C[O-]
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 1 h

Procedure:
9.1 g (0.05 mol) of 30% strength sodium methylate were added to a mixture of 10 g (0.05 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 100 ml of methanol at 0° C. in the course of 15 minutes while stirring. Stirring was continued for one hour at 0° C., after which the mixture was evaporated down under reduced pressure, the residue was taken up in methylene chloride and the solution was extracted with water. Drying and evaporating down gave 10.5 g (99% of theory) of the title compound of melting point 96°-101° C.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(OCC)=O>CCOCC>[Cl:7][CH:8]([CH:2]=[O:4])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC=O
Solvent: CCOCC
Product: O=CC(Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To potassium tert-butoxide (141 mL, 141 mmol) at 0° C. was added dropwise a solution of benzyl 2-chloroacetate (26.8 g, 141 mmol) and ethyl formate (11.6 mL, 141 mmol) in Et2O (45 mL). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was filtered and washed with cold ether (100 mL). The potassium salt was dissolved in H2O (50 mL) and the solution was acidified with concentrated HCl to pH=4 in a cold bath. The solution was extracted with ether and the organic phase was dried (MgSO4) and concentrated to give the crude product. A lower boiling point impurity was removed by vacuum distillation (90° C., 5 mm Hg) and the residue was taken directly to the next step.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([CH:15]=O)=[O:14]>C(O)(=O)C>[OH:12][C:10]1[C:9]([C:13](=[O:14])[CH3:15])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)c1nn(-c2ccccc2)cc1O
Yield: 43.4 %

Procedure:
To 2-oxopropanal phenylhydrazone (5.00 g, 30.8 mmol) in acetic acid (60 mL) was added a 40% aqueous solution of glyoxal (5.9 g, 4.6 mL, 30.8 mmol) and the mixture was heated at reflux for 45 minutes. The acetic acid was removed under reduced pressure. The resultant mixture was diluted with ethyl acetate (100 mL), washed with NaHCO3 and sat. aq. NaCl. Solids were removed by filtration, the filtrate was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (180 g column, 0-20 EtOAc/heptane gradient) to afford 1-(4-hydroxy-1-phenyl-1H-pyrazol-3-yl)ethanone as a yellow solid (2.70 g, 43%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH2:20][Br:22])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
The ketone from step 1 (0.310 g, 1.02 mmol) was dissolved in THF (3 ml), and phenyltrimethylammonium tribromide (PTT) (0.386 g, 1.02 mmol) was added as a solid leaving an orange solution which began to deposit a white solid immediately. Stirring for 1.5 hours leaves a colorless mixture to which water (5 ml) was added. THF was then evaporated and the resulting aqueous mixture was extracted with ethyl acetate. Drying over Na2SO4 and evaporation leaves a white crystalline solid (85% desired mono-brominated material by LC-MS, 5% starting material, 10% dibrominated) suitable for the next step. LC-MS (ES+): 381, 379 m/e.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1COCC1.C(N(CC)CC)C.[F:23][C:24]1[CH:34]=[C:33](F)[C:32]([N+:36]([O-:38])=[O:37])=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:33]1[CH:34]=[C:24]([F:23])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][C:32]=1[N+:36]([O-:38])=[O:37])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)cc1F
Yield: 86.7 %

Procedure:
By using 3.63 g of glycine tert-butyl ester hydrochloride, 25 ml of THF, 3.03 g of triethylamine, 5 ml of DMF and 5.0 g (21.6 mmol) of ethyl 2,4-difluoro-5-nitrobenzoate, 6.41 g (87%) of N-(4-ethoxycarbonyl-5-fluoro-2-nitrophenyl)glycine tert-butyl ester was obtained.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15](=[O:22])[CH:16]([C:18]([F:21])([F:20])[F:19])[OH:17].C(N(CC)C(C)C)(C)C.[CH3:32][NH:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[CH:16]([O:17][C:5](=[O:11])[N:33]([CH3:32])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:15]([O:14][CH3:13])=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(O)C(F)(F)F
Reactant: CNCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC(=O)N(C)CCc1ccccc1)C(F)(F)F
Reaction time: 2 h
Yield: 210.3 %

Procedure:
To a stirring solution of triphosgene (20 mg, 0.07 mmol) in CH2Cl2 (5.0 mL) was added methyl-3,3,3-trifluoro-DL-lactate (36 mg, 0.23 mmol) followed by N,N-diisopropylethylamine (120 μL, 0.69 mmol). After 2 h, N-methyl phenethylamine (31 mg, 0.23 mmol) was added as a solution in CH2Cl2 (2 mL) and stirred for another 2 h. The mixture was concentrated under reduced pressure and purified directly by SiO2 flash chromatography (25% EtOAc/hexanes) to provide the titled compound (47 mg, 64%): 1H NMR 500 MHz (CDCl3) δ 7.34-7.28 (m, 2H), 7.25-7.18 (m, 3H), 5.51-5.42 (m, 1H), 3.87 (s, 1.8H), 3.86 (s, 1.2H), 3.60-3.46 (m, 2H), 2.96-2.90 (m, 2.5H), 2.90-2.83 (m, 2.5H); HRMS m/z calc'd for [M+H]+ C14H16F3NO4: 320.1104. found 320.1109.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[S:13][C:12]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.[CH:29]([O:31][CH2:32][CH2:33][O:34][NH2:35])=[CH2:30].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH:29]([O:31][CH2:32][CH2:33][O:34][NH:35][C:20]([C:12]1[S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:30]
Reactant: C=COCCON
Reactant: CSc1ccc(Nc2c(C(=O)O)sc3ccncc23)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=COCCONC(=O)c1sc2ccncc2c1Nc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
A suspension of 3-(2-fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (0.107 g, 0.32 mmol) in dry dichloromethane (5 ml) under an atmosphere of nitrogen was cooled to 0° C. and treated with DMF (1 drop) and oxalyl chloride (0.081 ml, 0.96 mmol). The reaction mixture was stirred for 1 hour then the solvent removed in vacuo. The resultant residue was re-suspended in dry dichloromethane (1 ml) and treated dropwise with a solution of O-(2-vinyloxy-ethyl) -hydroxylamine (0.066 g, 0.64 mmol) and DIPEA (0.167 ml, 0.96 mmol) in dry dichloromethane (4 ml) before being stirred for 18 hours. The reaction mixture was washed (water, brine), dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-SPE, gradient 0-30% ethyl acetate in dichloromethane) to provide the title compound as a yellow solid (0.024 g, 18%). LCMS (method B): RT=3.17 min, M+H+ 420.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.C(O)C>CC(O)C.O>[Cl:13][C:14]1[N:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:17]([C:21]([F:24])([F:22])[F:23])=[CH:18][N:19]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2nc(Cl)ncc2C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Alternatively, 33.7 g 4-nitrophenol are dissolved in 250 mL 2-propanol. 18.3 g aqueous sodium hydroxide solution (50%) diluted with 42 mL of purified water are added. Additionally 50 mL of purified water are added. The reaction mixture is stirred for 30 minutes at 50° C. and then cooled to −15° C. 50 g 2,4-Dichloro-5-trifluoromethylpyrimidine are added at −15° C. under vigorous stirring. An additional amount of 50 mL of cooled (−15° C.). 2-propanol is added. The suspension is stirred for 2 hours at −15° C. and then warmed up to 20° C. during 2 hours. 100 mL ethanol are added. The mixture is heated to reflux. The solution is cooled to 20° C. while seeding with the title product at about 60° C. After stirring the suspension for 30 minutes at 20° C. the precipitate is filtered and washed with a mixture of 150 mL 2-propanol and 75 mL purified water and then with 150 mL purified water. The product is dried at 50° C. in a vacuum drying oven. 54.3 g (74% of theory) regioisomeric pure colorless title product is obtained.