Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[N:4][N:5]([CH3:7])[CH:6]=1.O[CH:18]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([N:8]([C:9]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:16])[C@H:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])[CH2:31][CH:32]([CH3:34])[CH3:33])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C)cc2Br)cc1
Reaction time: 48 h

Procedure:
To 2,2,2-trichloroethyl 4-bromo-1-methyl-1H-pyrazol-3-ylcarbamate (2.402 g, 6.83 mmol), 4-methoxybenzyl 2-hydroxy-4-methylpentanoate (3.45 g, 13.67 mmol) and triphenyl phosphine (3.58 g, 13.67 mmol) in dry DMF (50 mL) under dry nitrogen was added dropwise diisopropyl azodicarboxylate (2.7 mL, 13.67 mmol) over 45 minutes and the reaction mixture stirred for 2 days. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford 4-methoxybenzyl N-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29](O)=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)NCCC(=O)OCc2ccccc2)N3C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
In 10 ml of anhydrous tetrahydrofuran was dissolved 0.50 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. Then, at 0-5° C., 0.22 g of benzyl 3-aminopropionate, 0.19 g of 1-hydroxybenzotriazole monohydrate and 0.26 g of dicyclohexyl carbodiimide were added successively. After stirring the resulting mixture at the same temperature as above for 30 minutes and then at ambient temperature for 5 hours, the insoluble matter was filtered off. The filtrate was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=2:1] gave 0.55 g of benzyl 3-{[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino-propionate as a colorless oily product.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CC(=O)c1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 14.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-acetylphenylboronic acid (available from ASDI Incorporated; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-acetyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (14 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 12.97 (br s, 1H), 8.44-8.50 (m, 2H), 8.34 (d, J=1.8 Hz, 1H), 8.20 (dd, J=7.9, 1.9 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.81-7.88 (m, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55-7.64 (m, 1H), 7.45-7.54 (m, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.19-7.28 (m, 1H), 6.52 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH2:13]([O:15][CH2:16][C@H:17]([O:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=3)[N:30]=[CH:31][C:24]=12)[C:18](OC)=[O:19])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:18](=[O:19])[C@@H:17]([O:22][C:23]2[C:24]3[CH:31]=[N:30][N:29]([C:32]4[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=4)[C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:16][O:15][CH2:13][CH3:14])=[N:10][CH:11]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1C(F)(F)F)C(=O)OC
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1C(F)(F)F)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
A solution of trimethylaluminium (2M in hexane) (0.322 mL, 0.64 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (CAS no. 1072-98-6) (79 mg, 0.62 mmol) in toluene (5 mL) at 0° C., over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 3-ethoxy-2-(1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate Q1) (230 mg, 0.56 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was stirred at 0° C. for 10 minutes, allowed to warm to ambient temperature and then heated at 60° C. for 20 hours. The resulting mixture was allowed to cool and 1M citric acid (10 mL) added with vigorous stirring. Ethyl acetate (35 mL) and water (10 mL) were added and the organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane and then chiral preparative HPLC to give the product (90 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t), 3.60-3.68 (2H, m), 4.06-4.15 (2H, m), 6.05 (1H, t), 7.64-7.70 (2H, m), 8.22-8.25 (2H, m), 8.29 (1H, dd), 8.43 (1H, s), 8.62 (1H, s), 8.84 (1H, s)8.89 (1H, dd); m/z (ESI+) (M+H)+=508: HPLC tR=2.35 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]3([O:17][CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH2:25]=O.[BH4-].[Na+]>CO>[CH3:18][O:17][C:11]1([C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][CH:2]=[N:7][C:6]=3[CH:8]=2)[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH2:12]1
Reactant: COC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCNCC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2cc3ncnc(N4CCOCC4)c3s2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-6-(4-methoxy-piperidin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (175 mg) in methanol (3 ml) was added formaldehyde (37% solution in water, 0.11 ml) and sodium borohydride (54 mg). The reaction mixture was stirred at room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-4-yl)-6-(4-methoxy-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4](Cl)[C:5]([F:8])([F:7])[F:6])#[N:2].FF.[SH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[K+]>O.C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:14][C:4]([C:5]([F:8])([F:7])[F:6])=[C:3]([C:10]#[N:11])[C:1]=1[NH2:2])=[O:17])[CH3:20]
Reactant: N#CC(C#N)=C(Cl)C(F)(F)F
Reactant: CCOC(=O)CS
Agent: CC(=O)[O-]
Agent: FF
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1N

Procedure:
Combine 1,1-dicyano-2-chloro-2-(trifluoromethyl)ethylene (0.554 mmol) (prepared by the method of Middleton, J. Fluorine Chem., 20, 1982, p 397-418) and ethanol in a 50 ml flask. Add ethyl 2-mercaptoacetate (0.554 mmol) and potassium acetate (0.831 mmol) and heat to 60-70° C. for 30-40 minutes. Cool the reaction and add water. Product crystallizes as yellowish needles. Filter crystals and wash with 1:1 ethanol/water. Dry solid under reduced pressure to give the title compound as light yellow crystals: 1H NMR (400 MHz, CDCl3) δ 5.88 (s, 2H), 4.36 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.0 Hz), MS found (M−1) 262.9.
Reaction SMILES: C1(C([Cl:6])=O)CC1.C1(C(O)=O)CC1.CC1(C(Cl)=O)CC1.CC1(C(O)=O)CC1.Cl.[C:28]([NH:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])=[C:38]([O:48][C:49]([CH:51]2[CH2:53][CH2:52]2)=[O:50])[CH:37]=1)=[O:35])([CH3:31])([CH3:30])[CH3:29]>>[ClH:6].[CH:51]1([C:49]([O:48][C:38]2[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=2[O:42][C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])[CH:34]([OH:35])[CH2:33][NH:32][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:50])[CH2:53][CH2:52]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C2CC2)c(OC(=O)C2CC2)c1
Agent: CC1(C(=O)Cl)CC1
Agent: CC1(C(=O)O)CC1
Agent: Cl
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C2CC2)c(OC(=O)C2CC2)c1

Procedure:
When cyclopropanecarbonyl chloride and cyclopropanecarboxylic acid are substituted for the 1-methylcyclopropanecarbonyl chloride and 1-methylcyclopropanecarboxylic acid, respectively, in the procedure described in Example 13A above, the acylation product obtained is 3,4-bis(cyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride; and when this product is catalytically hydrogenated using the procedure described in Example 13B above, there is obtained 3,4-bis(cyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:11]([F:12])([F:14])[F:13])[CH:4]=[N:3][C:2]=2[N:1]=1)[CH3:16]
Reactant: NC(=O)c1cc(C(F)(F)F)cnc1N
Reactant: CCSc1ccccc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A mixture of 1.0 g of 2-amino-5-trifluoromethylpyridine-3-carboxylic acid amide, 810 mg of 2-ethylsulfanylbenzaldehyde, 1.01 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 12 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 975 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([OH:32])=O)[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[CH3:37][NH:38][C:30](=[O:32])[CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C:19]1[C:18]([C:33]([F:35])([F:36])[F:34])=[CH:17][N:16]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=2)[N:20]=1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)Cc1ccccc1CCc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
2-(2-(2-(2-((3-(4-Methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (I68) (75.0 mg, 169 μmol) was dissolved in DMF (1 mL) then HATU (129 mg, 339 μmol), DIPEA (57 μL, 339 μmol) and methylamine (8.0 M in ethanol; 200 μL) were added. The resulting mixture was stirred at room temperature overnight then the volatiles were evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with 10% NaHCO3, the layers were separated and the organic layer was dried (MgSO4) then evaporated under reduced pressure to give a cream solid. The cream solid was adsorbed onto silica and chromatographed on silica gel (0-10% MeOH/DCM) to give the title compound (18) (9.0 mg, 10%) as a solid; 1H NMR (400 MHz, CD3CN) δ 8.56 (d, J=0.6 Hz, 1H), 8.36-8.28 (m, 1H), 7.39 (s, 1H), 7.20 (ddd, J=5.6, 4.4, 1.9 Hz, 6H), 6.71-6.65 (m, 1H), 6.33-6.23 (m, 1H), 3.56 (s, 2H), 3.22-3.15 (m, 4H), 3.10 (s, 2H), 3.07 (s, 2H), 2.60 (d, J=4.7 Hz, 3H), 2.49-2.43 (m, 4H). LCMS Method C: rt 4.86 min; m/z 513.3.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[N:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>O1CCCC1.N1C=CC=CC=1>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:27]([C:33]#[N:34])=[CH:28][N:29]=[C:30]3[C:25]=2[CH:24]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:32]=[N:31]3)[CH:41]=[CH:40][CH:39]=1
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1cnc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.8 %

Procedure:
To a solution of 0.85 g (10.1 mmol) of tetrolic acid and 1.8 g (17.96 mmol) of N-methyl morpholine in 18 ml of tetrahydrofuran was stirred at 0° C. as 1.35 g (9.9 mmol) of isobutyl chloroformate was slowly added. After 15 min, this mixture was added to a solution of 1.3 g (3.8 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 5 mg of 4-N,N-dimethylamino-pyridine in 10 ml pyridine. The mixture was stirred a room temperature for 2.25 hr. The tetrahydrofuran was removed, diluted sodium bicarbonate was added, and the solid was collected via filtration. The solid was air dried and chromatographed on silica gel eluting with ethyl acetate-methanol mixtures giving 0.46 g of the title compound as a tan powder: mass spectrum (electrospray, m/e): M+H 408.1, 406.0.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][O:32][CH2:33][C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:31][O:32][CH2:33][C:34]2[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=2)[C:27]([OH:29])=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1cncc1CON
Solvent: CO
Product: Cn1cncc1CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
17.4 g of (2-tritylaminothiazol-4-yl)glyoxylic acid was dissolved in 500 ml of methanol under heating and the mixture was cooled to room temperature. A mixture of 100 ml of methanol and 5.5 g of 5-aminooxymethyl-1-methylimidazole was added to the mixture and then the resulting mixture was stirred overnight at room temperature. The precipitate formed was collected by filtration and washed with methanol to give 14.9 g of 2-(2-tritylaminothiazol-4-yl)-2-((1-methylimidazol-5-yl)methoxyimino)acetic acid with mp 231°-232° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].[OH-].[Na+].[O:15]=[As]O[As]=O.Cl>O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([OH:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=[As]O[As]=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(O)c([N+](=O)[O-])c1

Procedure:
336.4 g of 2-nitro-4-methoxyaniline was refluxed with 200 g of sodium hydroxide and 10 g of arsenic trioxide in 6500 ml of water, for 20 hours. The resulting solution was cooled on an ice-bath, acidified to pH 1 with concentrated hydrochloric acid and filtered. The solid product was washed with water, and dried under vacuum and in the presence of P2O5 to give 4-methoxy-2-nitrophenol (7A), mp: 78°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[N:39][C:5]2[O:6][C@@H:7]([CH3:38])[C:8](=[O:37])[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH2:31][C@H:32]([CH3:35])[CH2:33][OH:34])=[CH:20][C:19]=4[F:36])=[O:17])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=[O:42].Cl([O-])=O.[Na+].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[Cl:1][C:2]1[CH:40]=[N:39][C:5]2[O:6][C@@H:7]([CH3:38])[C:8](=[O:37])[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH2:31][C@H:32]([CH3:35])[C:33]([OH:42])=[O:34])=[CH:20][C:19]=4[F:36])=[O:17])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: C[C@H](CO)COc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)[C@H](C)Oc4ncc(Cl)cc43)CC2)c(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H]1Oc2ncc(Cl)cc2N(C2CCN(C(=O)c3ccc(-c4ccccc4OC[C@H](C)C(=O)O)cc3F)CC2)C1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixed solvent solution of (3S)-7-chloro-1-{1-[(3-fluoro-2′-{[(2R)-3-hydroxy-2-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (920 mg) in acetonitrile (10 ml) and a neutral phosphate pH standard solution (pH 6.86) (8 ml) were added at room temperature 2,2,6,6-tetramethyl-1-piperidyloxy radical (25.3 mg), 79% sodium chlorite (371 mg) and a 5% aqueous sodium hypochlorite solution (0.041 ml). After the reaction solution was stirred at 50° C. overnight, 2,2,6,6-tetramethyl-1-piperidyloxy radical (25.3 mg) and a 5% aqueous sodium hypochlorite solution (0.041 ml) were added, and further stirred for 4 hours. The reaction solution was brought back to room temperature, and an aqueous sodium sulfite solution and a 10% aqueous citric acid solution were added, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford (2S)-3-{[4′-({4-[(3S)-7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl]piperidin-1-yl}carbonyl)-3′-fluorobiphenyl-2-yl]oxy}-2-methylpropanoic acid (701 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7](=[O:19])[CH2:6][CH2:5]2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].N>C(O)C.CO.C(Cl)Cl>[O:19]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])[CH:3]=2)[N:8]1[CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (165 mg, 0.636 mmol) in 5 mL of ethanol was treated with methyl thiophene-2-carbimidothioate hydroiodide (363 mg, 1.27 mmol) and stirred for 18 hours at room temperature. The mixture was partitioned between CH2Cl2 (50 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was extracted with an additional 20 mL CH2Cl2. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow residue which was subjected to flash chromatography on a Biotage system using 5-10% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid. Yield: 157 mg of yellow oil (68%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.86 (br s, 2H), 4.12-4.06 (m, 2H), 2.88-2.83 (m, 2H), 2.75-2.70 (m, 2H), 2.65-2.60 (m, 6H), 1.82-1.78 (m, 4H). MS (ESI): 369.2 (M+1). ESI-HRMS calculated for C20H25N4SO (MH+): 369.1743, Observed: 369.1731.
Reaction SMILES: [C:1]([P:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[O:5]C)(=[O:3])[CH3:2].[I-].[Na+:15]>CC(CC)=O>[C:1]([P:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[O-:7])(=[O:3])[CH3:2].[Na+:15]
Reactant: COP(=O)(C(C)=O)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)P(=O)([O-])c1ccccc1

Procedure:
Methyl acetylphenylphosphinate (5.0 g, 0.025 mol) was added to a solution of sodium iodide (3.8 g, 0.025 mol) in molecular sieve dried ethyl methyl ketone (50 ml) and the resulting solution was stirred and refluxed for 15 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]([C@H:36]1[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)[CH3:35])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([N:34]([CH3:35])[C@H:36]4[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]4)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CN([C@H]1CCCN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CN([C@H]1CCCNC1)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (S)-tert-butyl 3-(2-bromo-N-methylphenylsulfonamido)-piperidine-1-carboxylate yielding 41 mg (48%) of the title compound after HPLC purification. MS (ESI): mass calcd. for C27H32FN5O4S, 541.21; m/z found, 542.1 [M+H]+.