Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([N:67]5[C@H:72]([CH3:73])[CH2:71][CH2:70][CH2:69][C@@H:68]5[CH3:74])=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][O:36]C3CCCCO3)[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]>CO>[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([N:67]5[C@H:72]([CH3:73])[CH2:71][CH2:70][CH2:69][C@@H:68]5[CH3:74])=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][OH:36])[CH:28]=2)[N:26]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 99 %

Procedure:
Pyridinium p-toluenesulfonate (65.0 mg, 0.26 mmol) was added to a solution of Intermediate 96d in MeOH (2.0 mL). The reaction was heated to 60° C. for 3.5 h then cooled and solvent volume reduced in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound (89.0 mg, 99%). LCMS (Method 4): Rt 3.49 min, m/z 693 [MH+].
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]2[S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:20]2[C:19]1=[O:36].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]4[S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:20]4[C:19]3=[O:36])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCCl)CCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCS2(=O)=O
Reaction time: 0.17 h

Procedure:
To a suspension of 60 mg (1.5 mmol) of 60% oily sodium hydride in 10 ml of N,N-dimethylformamide, 225 mg (1.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 10 minutes. To this mixture, 480 mg (1.3 mmol) of 6-(4-chlorobutyl)-1,1-dioxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione and 225 mg (1.5 mmol) of sodium iodide were added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1) to yield 400 mg (65.7%, white foamy substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c(=O)sc2cc(F)ccc21
Agent: O=S(=O)(O)O
Product: CC(C)n1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
6-Fluoro-3-(1-methylethyl)-2-(3H)-benzothiazolone (299 g) was dissolved in concentrated sulfuric acid (8750 g), and the resultant mixture was cooled to a temperature of -5° to 0° C. 98% fuming nitric acid (d=1.52) (94.68 g) was dropwise added thereto while maintaining the temperature at 0° C., followed by stirring for 1 hour. The reaction mixture was poured into ice-water (16 kg), and the precipitated crystals were collected by filtration. Crystals were washed with water and dried to give 325 g of 6-fluoro-3-(1-methylethyl)-5-nitro-2(3H)-benzothiazolone. m.p., 153°-153.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Mg].[C:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl>O1CCCC1.C(OCC)C>[OH:22][C:19]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]1
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N1CCC(O)(c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
2-Bromonaphthalene (24.75 g, 0.12 mol) in tetrahydrofuran (180 ml) was slowly added to magnesium (2.9 g, 0.12 mol) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for one hour. The resultant solution was slowly added to 1-acetyl-4-piperidone (16.9 g, 0.12 mol) in tetrahydrofuran (200 ml) at -78° C., and then allowed to stir to room temperature. The white suspension formed was hydrolysed with hydrochloric acid (120 ml, 1M) and the organic layer removed and concentrated in vacuo. The residue was taken up in dichloromethane, dried (MgSO4), and concentrated to leave a clear oil. Trituration of this oil with diethyl ether gave 1-(4-hydroxy-4-naphthalen-2-yl-piperidin-1-yl)ethanone (13.92 g, 43%) as a white solid; δH (CDCl3) 1.90 (4H, m, 2× piperidinyl CH2), 2.10 (2H, m, piperidinyl CH2), 2.15 (3H, s, COCH3), 3.20 (1H, m, piperidinyl H), 3.70 (1H, m, piperidinyl H), 4.60 (1H, br m, OH), 7.50 (2H, m, ArH), 7.60 (1H, dd, J 9.6, 1.6 Hz, ArH), and 7.90 (4H, m, ArH).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@@H:20]([NH2:22])[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl>[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@@H:20]([NH:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: N[C@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@H](NCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
Step (b) Benzyl bromide (0.131 mL, 1.10 mmol) was added to a flask charged with (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.465 g, 1.10 mmol), DMF (10 mL), and K2CO3 (0.607 g, 4.40 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with 1N hydrochloric acid (30 mL). The dilution was washed with ethyl acetate (30 mL). The aqueous layer was basified with 2N sodium hydroxide (40 mL) and then extracted with methylene chloride (40 mL). The extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 80, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (126 mg, 0.245 mmol, 22%), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 12.08 (br. s, 1H), 11.13 (s, 1H), 9.05 (s, 1H), 8.24-8.16 (m, 1H), 7.99-7.94 (m, 1H), 7.41-7.20 (m, 4H), 7.04-6.82 (m, 7H), 5.21 (d, J=16.0 Hz, 1H), 5.00 (s, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.74-4.57 (m, 1H), 3.96-5.59 (m, 3H), 3.14-3.07 (m, 2H), 2.62-2.00 (m, 2H). MS (EI) for C28H27FN6O3. found 515.2 (MH+).
Reaction SMILES: [C:1]([CH:4]([C:11](=[O:13])[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].Cl.[NH2:15]O.CC([O-])=O.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[O:13][N:15]=1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)noc1C
Yield: 3.4 %

Procedure:
A mixture of ethyl 3-acetyl-4-oxopentanoate (37.24 g, 0.2 mol), hydroxylamine hydrochloride (14.6 g, 0.21 mol), NaOAc (17.23 g, 0.21 mol) and ethanol (500 mL) was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was heated in acetic acid (12.61 g, 0.21 mol) and toluene (300 mL) for 6 to 6.5 hours with the removal of water. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford a tan oil which crystallized on cooling. The product was collected by filtration and washed with ether to afford 1.26 g of ethyl 3,5-dimethyl-4-isoxazolylacetate, m.p. 180°-182° C. Additional product was obtained by concentration of the ether filtrate and distillation of the residue at 69°-81.5° C. and 0.05 mm Hg to afford a total of 31.18 g (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C1C=CC(N)=CC=1N1CCOCC1)(=O)=O.[CH3:46][O:47][CH2:48][CH2:49][OH:50]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([O:50][CH2:49][CH2:48][O:47][CH3:46])=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Reactant: COCCO
Agent: CS(=O)(=O)c1ccc(N)cc1N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ncc2ccc(-c3cccc(Cl)c3)n2n1

Procedure:
7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (126.9 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-Methanesulfonyl-3-morpholin-4-yl-phenylamine (223 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. LC/MS and NMR data showed that the solvent underwent addition to the sulfoxide rather than the aniline. The reaction mixture was then reduced en vacuo and 7.48 mg of 7-(3-Chloro-phenyl)-2-(2-methoxy-ethoxy)-pyrrolo[2,1-f][1,2,4]triazine was isolated and purified by Gilson prep HPLC. The product was then lyophilized to a powder. (M+H)=304.08. 1H NMR (400 MHz, DMSO, d6) δ 9.09 (s, 1H), 8.36 (s, 1H), 8.19 (d, 1H, J=7.88 Hz), 7.55 (t, 1H, J=7.97 Hz), 7.45 (m, 2H), 7.10 (d, 1H, J=4.84 Hz), 4.47 (m, 2H), 3.75 (m, 2H), 3.64 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(Cl)Cl.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>Cl>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
4-(methylthio)aniline (500 mg, 3.59 mmol) was dissolved in DCM (10 ml, 155 mmol). Pyridine (1 ml, 12.36 mmol) and methanesulfonyl chloride (0.336 ml, 4.31 mmol) were added, and the reaction was stirred at RT for 3 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was triturated in Petroleum Ether to give N-(4-(methylthio)phenyl)methanesulfonamide (550 mg, 70.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[O:9][CH3:10].Br[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=[O:21].[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:14]2[CH:15]=[C:16]([F:18])[CH:17]=[CH:12][C:13]=2[CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Reactant: COc1cc(S)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(Sc2cc(F)ccc2CC(=O)O)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-3-methoxythiophenol (see Example 30) (36.2 g), 2-bromo-4-fluorophenylacetic acid (see the preceding Example) (39.6 g), potassium hydroxide (20 g) and dimethylformamide (250 ml) is heated to 100° C. while stirring until formation of a homogeneous solution. The greatest part of the dimethylformamide is distilled off under normal pressure, removing also the water arising by neutralization. Dimethylformamide (250 ml), anhydrous potassium carbonate (10 g) and copper (6 g) are added to the residue and the mixture is stirred for 14 hours in a bath heated to 170° C. The solvent is evaporated in vacuo, the residue dissolved in water, filtered and the filtrate made acidic by addition of hydrochloric acid. The separated oily acid is extracted with a large volume of warm benzene. The extract is then worked up, yielding 40 g of the crude 2-(4-chloro-3-methoxyphenylthio)-4-fluorophenylacetic acid which is crystallized from aqueous ethanol or cyclohexane. The pure compound melts at 118°-119° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]([CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH2:15][CH:16]=[CH2:17].[OH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]=[CH:16][CH2:15][CH2:14][CH:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1)[CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCC(CCC=C)OCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCC(CCC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reaction time: 10 h
Yield: 64 %

Procedure:
3 g of the compound (7), 1.5 g of methyl 4-hydroxybenzoate and 4.1 g of potassium carbonate were dissolved in 50 ml of 2-butanone, and reflux was carried out for 10 hours in an atmosphere of argon. After the precipitated solid matter was filtered off, the solvent was evaporated, and the residue was purified by a chromatography using a column filled with alumina and silica gel, to obtain 2.3 g of the compound (8). (Yield: 64%)
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>ClCCl>[OH:9][CH2:8][CH:3]([NH:2][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=1)=[O:24])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(N)CO
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-amino-3-hydroxypropanoate hydrochloride (L-serine methyl ester hydrochloride, 1.71 g, 11 mmol) was stirred in dichloromethane (20 ml) at 0° C., and triethylamine (2.79 ml, 20 mmol) added, followed by dropwise addition of 4-trifluoromethylbenzoyl chloride (1.486 ml, 11 mmol). The mixture was stirred at 0° C. for 30 minutes, then partitioned between dichloromethane and water, dried over magnesium sulfate, and filtered. Solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography, to yield methyl 3-hydroxy-2-{[4-(trifluoromethyl)phenyl]carbonylamino}propanoate, a compound of formula (13). B. Preparation of a Compound of Formula (14)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:12][C:11]=1[N+:29]([O-:31])=[O:30]>O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:12][C:11]=2[N+:29]([O-:31])=[O:30])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1

Procedure:
A solution of hydroquinone was heated under a nitrogen atmosphere. A solution of the product from Example 114A was added dropwise. The mixture was then stirred, cooled, poured into water, and adjusted the pH. The mixture was extracted, washed, and concentrated to provide N-[4-(4-Hydroxy-phenoxy)-3-nitro-phenyl]-3-trifluoromethyl-benzamide which was reduced to provide the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][F:11])[CH:9]=1)[CH:5]=O.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][F:11])[CH:9]=1)/[CH:5]=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(F)cc(CF)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(CF)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 3-fluoro-5-(fluoromethyl)benzaldehyde (890 mg, 5.70 mmol) and (R)-2-methylpropane-2-sulfinamide (760 mg, 6.27 mmol) in DCE (19.0 mL) was added copper(II) sulfate (anhydrous) (1.820 g, 11.40 mmol), the suspension was stirred under nitrogen at 60° C. in an oil bath for overnight. The suspension turned to light blue color. Cooling down, the reaction mixture was filtered though a plug of Celite and rinsed with DCM, the filtrate was concentrated to yield the crude product. The crude product was purified by flash chromatograph (0-30% EtOAc in heptane) to yield the (R,E)-N-(3-fluoro-5-(fluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (900 mg, 60.9% yield) as light yellow color oil. LCMS (m/z): 260.1 (MH+), 0.88 min. 1H NMR (400 MHz, CDCl3) δ ppm 8.57 (s, 1H), 7.60 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.26-7.22 (m, 1H), 5.50 (s, 1H), 5.38 (s, 1H), 1.29-1.23 (m, 9H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.[CH2:21]([Mg]Cl)[CH2:22][CH2:23][CH3:24].Cl>C1COCC1.C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Mg]Cl
Reactant: CON(C)C(=O)c1cccc(Br)n1
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCCCC(=O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide (5.29 g, 21.58 mmol) in dry THF (120 mL) at −78° C. (dry ice/acetone bath) under nitrogen was added nBuMgCl (15.2 mL of a 20% wt solution in THF/toluene, 25.84 mmol) drop-wise over 15 minutes. The resulting yellow mixture was stirred at this temperature for 1 hour and was then allowed to warm to 0° C. (ice/water bath) slowly over 1.5 hours and then to rt over 18 hours. The yellow cloudy mixture was then added portion-wise to a stirred solution of aqueous HCl (2M, 200 mL) and the resulting mixture partitioned with EtOAc (200 mL) and the layers separated. The aqueous was re-extracted with EtOAc (200 mL) and the combined organic layer washed with brine (300 mL), dried (MgSO4) filtered and reduced to give a yellow/orange oil. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 20:1 to 1:2) afforded the title compound (2.51 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11]1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC.O1CCCC1>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][C:18]1[S:19][C:13]2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11][N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Cc1nn(C)c(=O)c2cc(Cc3ccccc3C(F)(F)F)sc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 3.2 %

Procedure:
A solution of lithium diisopropylamide (11.3 mmol) in tetrahydrofuran/hexane (2:1, 16 ml) was added dropwise to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (Example 6 step b, 1.00 g) in tetrahydrofuran (20 ml) at −78° C. under nitrogen. After 5 minutes, 2-trifluoromethylbenzaldehyde (1.57 g) was added. The mixture was stirred at −78° C. for 3 hours, then saturated sodium hydrogen carbonate solution (50 ml) was added, and the mixture was warmed to room temperature and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with saturated sodium hydrogen carbonate solution, then with brine, then dried, filtered and evaporated. The residue was dissolved in trifluoroacetic acid (5 ml) and triethylsilane (2 ml) was added. After 24 hours, additional trifluoroacetic acid (5 ml) and triethylsilane (2 ml) were added. After a further 3 days, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with 1M sodium hydroxide solution, then with brine, and then dried, filtered and evaporated. The residue was purified by column chromatography, eluting with an ethyl acetate/isohexane gradient, followed by preparative normal-phase HPLC with gradient dichloromethane/ethanol elution and then with gradient ethyl acetate/isohexane elution to give the title compound (0.055 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[CH3:1][O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=1[NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(F)c1NC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To a suspension of caesium carbonate (1.3 g, 4.0 mmol) in DMF (5.0 ml) was added 2-tert-butoxycarbonylamino-3-fluorobenzoic acid from Example 19A (890 mg, 3.5 mmol) and iodomethane (230 μl, 3.8 mmol). The mixture was stirred for 18 h and evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc;pet. ether 25:75) to give a white solid; yield 680 mg, 72%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH2:34][OH:35])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:37])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH2:34][OH:35])(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (910 mg, 1.79 mmol) and HATU (5 eq., 3396 mg, 8.9 mmol) were initially charged in dry DMF (20 ml) at 0° C., and ammonium chloride (5 eq., 478 mg, 8.9 mmol) and DIEA (10 eq., 2309 mg, 17.9 mmol) were added after brief stirring (20 min). The mixture was stirred at RT for 16 h (HPLC control) and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (740 mg, 81% of theory).