Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@H:6]([C:8]#[CH:9])[CH3:7])(=O)=O.[C:10]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH2:19][NH2:20])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][C@H:6]([NH:20][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])[C:8]#[CH:9]
Reactant: C#C[C@@H](C)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#C[C@H](C)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
A solution of (R)-but-3-yn-2-yl methanesulfonate (2189 mg, 14.77 mmol) in ACN (10 ml) was added dropwise to a suspension of tert-butyl(3-aminopropyl)carbamate (2831 mg, 16.25 mmol) and potassium carbonate (2446 mg, 17.72 mmol) in ACN (50 ml). The reaction mixture was stirred at room temperature for 24 h, whereupon the slurry was filtered and the filtrate was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-8%) to afford the title compound (570 mg, 17%) as a light orange oil. LCMS: R=0.43 min, m/z=227.0 (M+1) Method 2m_acidic.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:42])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:41]=[S:37]1(=[O:40])[CH2:38][CH2:39][N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=4[O:14][C:15]([F:18])([F:16])[F:17])=[CH:20][CH:21]=3)=[O:42])=[CH:32][CH:31]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Yield: 89.5 %

Procedure:
{4′-[4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-trifluoromethoxy-biphenyl-3-yl}-carbamic acid tert-butyl ester (140 mg) was stirred in 1:1 trifluoroacetic acid:dichloromethane (6 ml) at 20 C for 1 h. The mixture was then basified and extracted with ethyl acetate. The dried extracts were then evaporated giving a dark gum (105 mg).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:29].[CH:30]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[Na].C(=O)([O-])O.[Na+].C(O)C.Cl>C(OCC)(=O)C.C(O)C.ClCCCl.C(N(CC)CC)C>[ClH:1].[ClH:1].[CH:30]1([CH2:36][N:20]([CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:4]([CH3:3])[C:5](=[O:29])[CH:6]=[CH:7]3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=CC1CCCCC1
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCCc3cccnc3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)CC3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine(0.15 ml) was added to a 1,2-dichloroethane solution (2.5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride(219 mg). The mixture was stirred at room temperature for 30 minutes. Cyclohexane carboxaldehyde(0.073 ml) and sodium triacetoxyborohydrate(159 mg) were added thereto, and the mixture was stirred at room temperature overnight. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate=1:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution(1.0 ml) was added to an ethanol solution(20 ml) of the residue, which was stirred at room temperature. The reaction mixture was condensed under reduced pressure and ethyl acetate was added to the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound(100 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[CH:26]([N:29](CC)C(C)C)(C)C.CN>C(#N)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:29][CH3:26])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Agent: CN
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC)n(C)c(=O)c1OCc1ccccc1
Reaction time: 0.5 h
Yield: 303.5 %

Procedure:
A solution of 2-methanesulfonyl-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.180 g, 3.22 mmol) in acetonitrile (20 ml) was treated at 25° C. with N,N-diisopropylethylamine (1.5 ml, 0.87 mmol) followed by 4.8 ml (9.6 mmol) of a 2M solution of methylamine in tetrahydrofuran. After 30 min, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate, 25:75) to give 0.838 g (82% yield) of the title ester as a clear syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.30 (3H, t, J=7.1 Hz, CH3), 3.04 (3H, d, J=5.1 Hz, NCH3), 3.42 (3H, s, NCH3), 4.32 (2H, q, J=7.1 Hz, OCH2), 4.58 (1H, broad q, NH), 5.07 (2H, s, OCH2), 7.3–7.37 (3H, m, aromatics), 7.47 (2H, m, aromatics). HRMS (FAB POS) calculated for C16H20N3O4 [M+H+]: 318.145381. found: 318.144860.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20].[CH3:21][S:22]SC>[Cu]>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([S:22][CH3:21])=[C:11]([S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20]
Reactant: CSSC
Reactant: Cc1c(Br)ccc(N)c1S(C)(=O)=O
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1S(C)(=O)=O
Reaction time: 7 h

Procedure:
75 g of copper powder and 100 ml of dimethyl disulfide were added to 92 g (0.8 mol) of tert-butyl nitrite. At 50–52° C., a solution of 142 g (0.54 mol) of 4-bromo-3-methyl-2-methylsulfonyl aniline in 600 ml of dimethyl disulfide was added dropwise, and the mixture was stirred at 50–55° C. for 7 hours. After cooling, the mixture was filtered off with suction through kieselguhr, and dichloromethane was added to the filtrate. The organic phase was washed with dilute hydrochloric acid and then with water. After drying over sodium sulfate, the organic phase was concentrated under high vacuum. This gave 170 g of the title compound as a black oil which was used for the next reaction step without further purification.
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:11](=[O:12])[CH2:10][O:9][C:8]2[N:13]=[C:14]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:7]1=2)(=[O:4])=[O:3]>C(O)(C(F)(F)F)=O>[NH2:33][C:29]1([C:26]2[CH:27]=[CH:28][C:23]([C:14]3[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:7]4[N:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11](=[O:12])[CH2:10][O:9][C:8]=4[N:13]=3)=[CH:24][CH:25]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CS(C)(=O)=O)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 0.01 h
Yield: 120.8 %

Procedure:
tert-Butyl 1-(4-(1-(methylsulfonylmethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (28 mg, 0.050 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried over the weekend to give the desired product as an off-white solid (28 mg, 98% yield). 1H-NMR (500 MHz, MeOD) δ 7.78 (1H, s), 7.32 (2H, d), 7.28 (2H, d), 7.13-7.23 (3H, m), 7.08-7.13 (2H, m), 5.43 (2H, s), 5.01 (2H, s), 2.86 (3H, s), 2.58-2.70 (2H, m), 2.40-2.52 (2H, m), 2.03-2.17 (1H, m), 1.76-1.90 (1H, m). LCMS (Method D) RT=0.87 min, M+H+=464.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([O:24]CC)=[O:23])=[N:10]1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([OH:24])=[O:23])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(I)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1

Procedure:
The ester (10 g, 19.9 mmoles) obtained from step C was taken in 500 ml 1 neck flask and to it 300 ml of 7:2:1 mixture of THF-methanol-water along with solid lithium hydroxide (2.5 g, 104.6 mol) was added. The mixture was refluxed for 12 hours. The solvents were removed totally and to the residue 200 ml of DCM was added. To that 100 ml of water was added and the mixture was acidified to pH ˜2 using concentrated HCl. The organic layer was separated, washed with 100 ml of brine, dried over sodium sulphate and concentrated to give the acid. This was taken directly to the next step (9.4 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[O:20])[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].[Cl:25][C:26]([Cl:31])([Cl:30])C(O)=O.FF.C([O-])(=O)C=C>CO.CN(C)P(N(C)C)(N(C)C)=O>[Cl:25][C:26]([Cl:31])([Cl:30])[C:8]([C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])([C:7]1[C:2]([F:1])=[C:3]([F:24])[C:4]([F:23])=[C:5]([F:22])[C:6]=1[F:21])[OH:20]
Reactant: O=C(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: C=CC(=O)[O-]
Agent: FF
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: OC(c1c(F)c(F)c(F)c(F)c1F)(c1c(F)c(F)c(F)c(F)c1F)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 4.9 g of decafluorobenzophenone and 2.7 g of trichloroacetic acid was added to 15 mL of hexamethylphosphoramide. The stirred reaction mixture was maintained at about 0° C. for about 2 hours and then allowed to warm to room temperature and continue stirring at ambient temperature for the next 15 hours. The reaction mixture was characterized by GC and fluorine NMR to show a conversion of approximately 20% to the desired carbinol. This carbinol can be converted to the corresponding acrylate by methods previously described (cf. Example 24).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[N:25][CH:24]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][N:25]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)Cc1ccncn1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Cc3ccncn3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(pyrimidin-4-yl)acetic acid (Example 33a) (44% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.35 (m, 1H), 1.54-1.68 (m, 4H), 1.79 (m, 1H), 3.21 (t, 1H, J=12.3 Hz), 3.84 (m, 1H), 3.98 (m, 2H), 4.16 (dd, 1H, J=10.0, 4.6 Hz), 4.29-4.75 (m, 1H), 5.16 (m, 1H), 6.60 (d, 1H, J=8.6 Hz), 6.81 (br d, 1H, J=7.9 Hz), 7.43 (d, 1H, J=11.0 Hz), 7.45 (d, 1H, J=8.3 Hz), 7.72 (br s, 1H), 8.07 (br s, 1H), 8.70 (d, 1H, J=5.0 Hz), 9.08 (m, 1H), 10.91 (br s, 1H). MS 431 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][CH2:11][C@@H:12]([OH:14])[CH3:13].C(N(C(C)C)CC)(C)C.C(Cl)Cl.CO>CN(C)C=O>[OH:14][C@@H:12]([CH3:13])[CH2:11][NH:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C[C@H](O)CN
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.91 ml of tert-butyl bromoacetate is added dropwise within 30 minutes to a mixture of 15.00 g of (S)-(+)-1-amino-2-propanol and 6.97 ml of diisopropylethylamine in 100 ml of N,N-dimethylformamide, while cooling with an ice bath. Then the cooling bath is removed and the reaction mixture is stirred overnight at ambient temperature. For working up, the solvent is distilled off in vacuo, the flask residue is dissolved in 50 ml water and saturated with 15 g of sodium chloride. The aqueous phase is extracted several times with ethyl acetate. The extracts are combined, washed with 20 ml of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation. The oily yellowish crude product is reacted further without any more purification. Yield: 7.80 g (103% of theory); Rf value: 0.42 (silica gel, methylene chloride/methanol=9:1); mass spectrum (ESI+): m/z=190 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:25](=[O:34])[C:24]3=[O:35])[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1.[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)[O:32][C:31](=[O:33])[CH2:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([N:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:29][CH:28]=2)[C:24](=[O:35])[C:25]1=[O:34]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.3 %

Procedure:
A mixture of 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid 2,2,2-trifluoroacetic acid salt (0.319 g, 0.607 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.170 g, 0.405 mmol), EDC (0.233 g, 1.214 mmol), and DMAP (0.099 g, 0.809 mmol) in DCM (25 ml) was stirred at room temperature for 3 days. The mixture was diluted with DCM and washed with aqueous 5% NaHCO3 and with sat. NH4Cl; the organic phase was dried over sodium sulfate, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 95:5). An additional purification by chromatography on silica gel column (DCM:MeOH=98:2 to 97:3) was performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.113 g, 0.139 mmol, 34.3% yield, MS/ESI+ 813.19 [MH]+, [αD]=−26.83, c=0.24, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.69 (d, 1H), 7.68 (dd, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 7.09 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.04 (dd, 1H), 4.69 (d, 1H), 4.58 (d, 1H), 3.93 (d, 2H), 3.74 (t, 2H), 3.46-3.55 (m, 4H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (s, 3H), 2.37 (t, 2H), 2.28-2.34 (m, 4H), 1.08-1.36 (m, 1H), 0.47-0.66 (m, 2H), 0.27-0.49 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:53][NH2:54]>C(O)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:53][NH2:54])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:51])[CH:8]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Solvent: CCO
Product: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (EXAMPLE 36 Step A, 0.091 g, 0.122 mmol) was dissolved in ethanol (0.83 mL). Added hydrazine (0.117 mL, 3.65 mmol) and stirred at 85° C. in a screw cap vial (with a pressure relief cap) under a nitrogen blanket. The reaction was monitored by LCMS. Once complete, the reaction was cooled to room temperature. The solvent was removed by rotary evaporation, and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.74 (s, 2H), 7.71 (s, 1H), 7.61 (dd, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 7.32 (d, 1H), 5.67 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.71 (d, 1H), 4.44 (m, 3H), 4.31 (m, 2H), 4.00 (m, s, 4H), 2.37 (s, 3H), 1.59 (br, 2H+water), 0.74 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:33](Br)[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:33][CH3:34])[C:18]([C:22]4[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cccc(Cl)c2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(-c2c(F)cccc2Cl)nn(-c2ccc(C#Cc3cccc(Cl)c3F)cc2)c1=O

Procedure:
The title compound was prepared by following the procedure as described for Intermediate-41 by using 1-(4-((3-chloro-2-fluorophenyl)ethynyl)phenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one (Example-12, 0.070 g, 0.15 mmol), dry DMF (3 mL), NaH (0.010 g, 0.23 mmol) and ethyl bromide (0.026 g, 0.23 mmol) to afford 0.030 g of the crude product which was purified by column chromatography in basic alumina eluting with 0.2% methanol:DCM to afford 0.030 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.09 (t, 3H), 3.56 (m, 2H), 7.29 (t, 1H), 7.52-7.84 (m, 7H), 8.04 (d, J=8.1 Hz, 2H); MS (m/z): 470.06 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12](N(CC)CC)C.CI>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Br)ccc2s1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CI
Product: CSc1nc2cc(Br)ccc2s1
Yield: 78.4 %

Procedure:
To a solution of 5-bromobenzo[d]thiazole-2-thiol (24 mg, 0.098 mmol) in EtOH (1.5 mL) was added triethylamine (10 mg, 0.098 mmol) and methyliodide (14 mg, 0.098 mmol). The mixture was heated at reflux for 1.5 h. Then the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 5-bromo-2-(methylthio)benzothiazole 20 mg (80%).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:19][C:20]1[C:21](=[O:39])[N:22]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=2)[CH:25]=1.O>CN(C)C=O>[CH:36]1([CH2:35][N:22]2[C:21](=[O:39])[C:20]([CH2:19][CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=3)=[N:23]2)[CH2:38][CH2:37]1
Reactant: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)n(CC3CC3)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
After 55% sodium hydride (322 mg, 7.38 mmol) was added to a solution of di-tert-butyl malonate (970 mg, 4.48 mmol) in N,N-dimethylformamide (10 mL), 4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (1.8 g, 4.90 mmol) was added under ice-cold stirring. The reaction mixture was stirred at room temperature for 1 hour, poured into water, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was isolated and purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to yield the title compound as a yellow powder (yield: 1.39 mg, 61.8%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12]=[CH:11][C:10]=2[CH:17]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:1](=[O:4])([OH:2])[NH2:5].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13]([CH3:15])([CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]=1
Reactant: O=C([O-])[O-]
Agent: CC1(C)C=Cc2cc(N)ccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: NC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After a carbonate resin (0.80 mmol/g, 10 g, 8.0 mmol) of formula 2 was mixed with dimethylacetamide (DMA, 50 mL) by shaking at room temperature for 10 min, 6-amino-2,2-dimethyl-2H-1-benzopyran (2.80 g, 16.0 mmol) and N,N-diisopropylethylamine (DIPEA; 5.17 mg, 40.0 mmol) were successively added thereto and shaked at 25° C. for 15 hrs. After the reaction was completed, the reaction mixture was subjected to filtration and repeatedly washed with DMF, DCM, DCM/MeOH and MeOH, to obtain a solid resin (Formula 4-1; 11.5 g). (ATR-FTIR; carbamate: 1725 cm−1)