Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].F[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].Cl>CN(C)C=O>[CH3:3][O:4][C:5](=[O:9])[CH:6]([C:7]#[N:8])[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)CC#N
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1cc(C)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
To a suspension of sodium hydride (0.86 g) in N,N-dimethylformamide (5 mL) was added dropwise a solution of cyano acetic acid methyl ester (0.35 g) in N,N-dimethylformamide (3 mL) under ice cooling and this mixture was stirred for 15 minutes. To this reaction mixture was added dropwise a solution of 1-fluoro-4-methoxy-5-methyl-2-nitrobenzene (0.44 g) under ice cooling and this mixture was stirred at room temperature for 30 minutes, and then stirred at 70° C. overnight. After cooling to ambient temperature, 1 mol/L hydrochloric acid (5 mL) was added to this reaction mixture. This resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.45 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[OH:11].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(Br)cc1O
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a mixture of 4-bromo-2-hydroxy-benzoic acid methyl ester (Mori, N. et al, Bull Chem. Soc. Jpn. 1969, 42(2), 488-491) (29.3 g, 127 mmol) and dimethylthiocarbamoyl chloride (17.2 g, 140 mmol) in DMF at room temperature was added DABCO (21.3 g, 190 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH of around 4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide 4-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid (36.8 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.84 (d, J=8.2 Hz, 1H), 7.43 (dd, J=8.6, 2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 3.83 (s, 3H), 3.45 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].Cl[Si:19]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:20][Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>N1C=CC=CC=1>[OH:3][C@@H:2]1[C@@H:4]2[O:5][Si:19]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:34])[CH3:33])[O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[O:8][CH2:7][C@H:6]2[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′,3′,4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](O)([CH3:9])[CH3:8].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C([O-])(O)=O.[Na+]>CCOCC.O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: Sc1ccccc1Br
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)Sc1ccccc1Br
Temperature: -10 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a 50 mL round-bottomed flask were added a stirbar, water (3.5 mL) and H2SO4 (5.0 mL, 18 M). The flask was then cooled to approximately −10° Celsius and treated with t-BuOH (0.70 mL, 7.5 mmol) followed by 2-bromo-thiophenol (0.60 mL, 5.0 mmol) (drop-wise over three minutes). The resulting mixture was stirred for 24 hours with gradual warming to rt. The reaction mixture was then added to a separatory funnel containing Et2O and sat. NaHCO3. The layers were mixed thoroughly and then separated. The organic layer was washed with 1 N NaOH, dried over MgSO4, filtered and concentrated to dryness. The resulting residue was subjected to FCC gave the title compound (686 mg, 56%). 1H NMR (500 MHz, DMSO-d6) δ 7.75 (dd, J=7.8, 1.4, 1H), 7.68 (dd, J=7.6, 1.6, 1H), 7.43-7.37 (m, 1H), 7.36-7.29 (m, 1H), 1.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:13][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: C[Mg]Cl
Reactant: O=C1CCCc2nc(Cl)ccc21
Solvent: C1CCOC1
Product: CC1(O)CCCc2nc(Cl)ccc21

Procedure:
To a solution of 2-chloro-7,8-dihydroquinolin-5(6H)-one (500 mg, 2.75 mmol) in tetrahydrofuran (20 mL) at 0° C. was added methylmagnesium chloride (3.0 M in tetrahydrofuran, 0.92 ml, 2.8 mmol) over 2 minutes dropwise. Additional methylmagnesium chloride (3.0 M in tetrahydrofuran) were added at the following time intervals after the initial addition: 40 minutes (0.46 ml, 1.4 mmol); 60 minutes (0.46 ml, 1.4 mmol); and 120 minutes (0.92 ml, 2.8 mmol). At 1 hour after the final addition, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), and diluted with ethyl acetate (30 mL). The organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-50% ethyl acetate/hexanes, linear gradient) to give 2-chloro-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol. MS ESI calc'd. for C10H13ClNO [M+H]+ 198. found 198.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:41]1(O)[CH2:45]C[CH2:43][CH2:42]1>O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH:16]2[CH2:43][CH2:42][CH2:41][CH2:45]2)=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)OC3CCCC3)c(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.30 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.06 g of sodium carbonate, and 3.0 ml of cyclopentanol was stirred at 100° C. for 1.5 hours and then at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and then poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of cyclopentyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-28).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH2:24])=[O:23]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](=[O:23])[NH2:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1C(N)=O

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline amide (0.114 g, 0.57 mmol) gives the title compound.
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH2:27][CH3:28])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1.[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:27]([N:24]1[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([B:29]([OH:33])[OH:30])[C:25]1=[O:26])[CH3:28]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CCn1c(=O)c(Br)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(B(O)O)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 18.2 %

Procedure:
6-Bromo-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (5, 100 mg, 0.22 mmol), bis(pinacolato)diboron (63 mg, 0.25 mmol), potassium acetate (66 mg, 0.68 mmol) and PdCl2(PPh3)2 (16 mg, 0.02 mmol) were mixed under argon in degassed toluene (3 mL). The resulting suspension was irradiated for 30 min at 120° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue was purified by column chromatography using dichloromethane:methanol:triethylamine (4:1:0→1:1:0→0:95:5) as eluent. The crude product was dissolved in dichloromethane (10 mL), washed with water (5 mL), and the organic layer was dried over sodium sulfate, filtered and evaporated. The title compound (15 mg, 0.04 mmol, 18%) was obtained as a yellow solid. ESMS m/z 409 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (br. s., 1H) 8.85 (s, 1H) 8.52 (s, 2H) 8.28 (s, 1H) 7.64 (br. s., 2H) 6.94 (d, J=9.0 Hz, 2H) 4.33 (q, J=6.9 Hz, 2H) 3.07-3.14 (m, 4H) 2.43-2.47 (m, 4H) 2.22 (s, 3H) 1.26 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[N:17]=[C:16]2[N:33]([CH:36]([CH3:38])[CH3:37])[N:34]=[CH:35][C:15]=12)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylate (0.2 g, 0.383 mmol) was taken in DCM (3 mL), to it TFA (0.6 mL) was added at 0° C. and stirred at room temperature for 3 h. On completion of reaction, DCM was removed under reduced pressure, saturated NaHCO3 solution was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (60% yield). LCMS: 423.25 (M+1)+; HPLC: 99.121% (@ 254 nm) (Rt; 4.628); 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (t, J=4.8 Hz, 1H); 8.26 (s, 1H); 7.49 (s, 1H); 5.89 (s, 1H); 5.22-5.16 (m, 1H); 4.36 (d, J=4.8 Hz, 2H); 3.04 (d, J=12.0 Hz, 2H); 2.84-2.92 (m, 1H); 2.60 (t, J=, 8.4 Hz, 2H); 2.20 (s, 3H); 2.10 (s, 3H); 1.65-1.81 (m, 4H); 1.49 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]([CH:4]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:7]1)[CH3:5])([OH:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:7]1)[CH3:5])([OH:3])=[O:2]
Reactant: CC(C(=O)O)N1CCC=C(c2nnn[nH]2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C(=O)O)N1CCCC(c2nnn[nH]2)C1
Yield: 68.7 %

Procedure:
To a solution of 5 (14.9 g, 0.078 mol) in ethyl acetate (160 ml) acetic acid (25 ml) and 5% palladium on charcoal (1.25 g) were added. The mixture was shaken for 24 hours with 3.5 atm. of hydrogen pressure. The mixture was filtered and evaporated to yield the title compound as an oil (12.07 g, 80%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]([Cl:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[ClH:18].[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:14]=1[O:13][CH3:12])[CH2:5]2
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NC2CN3CCC2CC3)c(OC)c1
Yield: 23.7 %

Procedure:
A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in diethyl ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211°-212° C. The NMR analysis was satisfactory.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Na+]>CO>[C:12]([C:9]1[C:10]([Cl:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:16])[N:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (prepared as described in the previous step, 2.20 g, 9.00 mmol) and 3 N aqueous NaOH (7.50 mL, 22.5 mmol) in MeOH (40 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the residue was treated with H2O (30 mL) and washed with Et2O. The aqueous layer was then acidified to pH 7 by 2 N aqueous HCl and extracted with DCM. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed in vacuo to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.41 (br s, 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated for C9H13ClN2O2: 217.1 (M+H), Measured: 217.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[CH3:49][C@@H:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1>>[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][C@H:50]2[CH3:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@@H]1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H]1COCCN1C(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and (R)-3-methylmorpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19IN4O4S, 538.0; m/z found, 537 [M−H]−. HPLC (reverse phase): RT=8.71 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.05 (d, J=1.8 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.94 (br s, 1H), 8.54 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.92 (dd, J=8.4, 7.4 Hz, 1H), 7.90-7.89 (m, 1H), 7.37 (dd, J=8.0, 1.6 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.5-4.0 (br m, 1H), 3.90-3.82 (m, 1H), 3.66-3.64 (m, 1H), 3.47 (dd, J=11.5, 2.7 Hz, 1H), 3.35-3.25 (m, 3H), 1.31-1.21 (br m, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:37])([F:36])[CH2:24][C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([CH2:24][C:23]([F:37])([F:22])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 41 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 41%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([NH:21][C@H:22]1[CH2:47][CH2:46][C@:24]2([O:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([N:35]4[CH:39]=[CH:38][N:37]=[C:36]4[C:40]([F:43])([F:42])[F:41])[CH:32]=[CH:31][C:30]=3[O:44][CH3:45])[CH2:25]2)[C@@H:23]1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=O)C1C=CC=CC=1.IC.[C:57]([O:60][CH2:61][CH3:62])(=[O:59])[CH3:58]>C1COCC1>[CH2:61]([O:60][C:57]([CH2:58][NH:21][C@H:22]1[CH2:47][CH2:46][C@:24]2([O:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([N:35]4[CH:39]=[CH:38][N:37]=[C:36]4[C:40]([F:42])([F:43])[F:41])[CH:32]=[CH:31][C:30]=3[O:44][CH3:45])[CH2:25]2)[C@@H:23]1[C:48]1[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=1)=[O:59])[C:62]1[CH:46]=[CH:47][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NCC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsily)amide (0.059 mL, 1.0M, 0.059 mmol) was added to an ice-cooled solution of (3S,5R,6R,7S)-7-(benzyloxycarbonylamino)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane (30 mg, 0.049 mmol) in 0.50 mL of dry THF. After stirring for 15 minutes at 0° C., iodomethane (0.0037 mL, 8.4 mg, 0.059 mmol) was added. The mixture was stirred at 0° C., then allowed to warm up to RT for 3 h. The reaction was diluted in 20 mL of ethyl acetate and washed with 10 mL of saturated aqueous sodium bicarbonate, followed by 10 mL of brine. Drying over sodium sulfate and concentration afforded the crude product. Purification by preparative TLC, eluting with 30% ethyl ether in 1:1 toluene/hexane, yielded 7.5 mg of pure title compound and 15 mg of a mixture containing the title compound and recovered starting material. Mass spectrum (NH3/CI): m/z=624.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])[C:5]#[N:6].[H-].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]([C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH:18][C:19]([CH3:22])([CH3:23])[CH2:20][CH3:21])[C:26](=[O:28])[CH3:27]
Reactant: CCC(C)(C)Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(C)(C)Nc1c(N(Cc2ccc(C#N)cc2Cl)C(C)=O)c(=O)c1=O
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 3-chloro-4-{[2-(1,1-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-methyl}-benzonitrile (0.829 g, 2.50 mmol, Example 76) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was treated with sodium hydride (0.066 g, 2.75 mmol) and stirring was continued for 15 minutes. Acetic anhydride (0.281 g, 2.75 mmol) was added. After stirring 40 minutes at room temperature, solvent was removed and the residue was partitioned between ethyl acetate and brine, and the brine fraction was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with dilute, aqueous sodium carbonate solution, with brine and dried (anhydrous sodium sulfate). Removal of solvent gave a yellow solid that was chromatographed (gravity, chloroform) on silica. The appropriate fractions were freed of solvent and the foamy residue was solidified by addition-rotoevaporation of hexane (twice). Recrystallization (twice) of the solid from acetone-hexane gave 513 mg of the title compound as a white solid: mp 150.5°-151.0° C. (softens 149.5° C.); 1H NMR (DMSO-d6) δ7.90-9.22 (broad hump, 1H), 8.10 (s, 1H), 7.84 (m, 1H), 7.51 (d, 1H), 5.29 (br s, 2H), 2.16 (s, 3H), 1.71 (q, 2H), 1.35 (s, 6H), 0.85 (t, 3H) ppm. IR (KBr): 3300, 3080, 2230, 1790, 1720, 1680 cm-1. MS (m/z) 373/375 (M+). HPLC indicates a major component (>99%).