Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28](O)=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a suspension of methanesulfonamide (480 mg, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.0 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A36. A solution of 2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (310 mg, 1.0 mmol) and 1,1′-carbonyldiimidazole (320 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B36. Solution B36 was added to Solution A36 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (116 mg, 30%) as a white solid: MS (ESI) M+1=389.3.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(/[CH:15]=[CH:16]/[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(/[CH:16]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(/C=C/c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)(/C=C/c1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.04 g (5 mmol) of (E)-chalcone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.44 g of the desired product (yield 97%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[N:15]=[CH:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:10]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: Oc1ccc(Br)cc1C=Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 5-bromosalicylaldehyde (1.01 g, 5 mmol), 3,5-dichloroaniline (810 mg, 5 mmol) and ethanol (25 mL) was refluxed for 1 hour under argon atmosphere. After the reaction mixture was cooled to room temperature, the separated crystal was filtered to give 3,5-dichloro-N-(5-bromo-2-hydroxybenzylidene)aniline (1.52 g, 88.2%) as an orange crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1

Procedure:
Ethyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 3-b, (150 g, 0.46 mol) in THF (1.5 L) was treated with LiOH monohydrate (58 g, 1.39 mol) in water (60 ml) at room temperature for 3 hours. The mixture was concentrated under vacuum and diluted with water (200 ml) followed by extraction with ethyl acetate. The aqueous layer was acidified to pH=2 with 10% HCl and solid crushed out from the solution which was then filtered and washed with water to afford the compound, 3-c. (40 g, 29%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:55][CH:56]([S:58][C:59]1[CH:65]=[CH:64][C:62]([NH2:63])=[CH:61][CH:60]=1)[F:57]>CN(C=O)C.CCOC(C)=O>[F:57][CH:56]([F:55])[S:58][C:59]1[CH:60]=[CH:61][C:62]([NH:63][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:21]=[N:20][CH:19]=[N:18][CH:17]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:64][CH:65]=1
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reactant: Nc1ccc(SC(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(SC(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reaction time: 48 h

Procedure:
A mixture of (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1, 60 mg, 0.21 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 88 mg, 0.231 mmol) and DIPEA (73.2 μL, 0.419 mmol), in DMF (419 μL), was stirred at RT for 10 min. 4-Difluoromethylsulfanyl-aniline (60 mg, 0.21 mmol) was added and the RM was stirred for 2 days. The RM was diluted with EtOAc and washed with brine. The organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to obtain the title compound as a solid. UPLC-MS (Condition 3), tR=0.86 min, m/z=444.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm (TFA), 1.82 (br. s, 1H) 1.90 (d, J=8.60 Hz, 1H) 2.97 (d, J=10.95 Hz, 1H) 3.28 (d, J=7.04 Hz, 2H) 3.35-3.47 (m, 1H) 4.26 (br. s, 1H) 7.49-7.63 (m, 2H) 7.79-7.90 (m, 2H) 8.25 (br. s, 1H) 8.74 (br. s, 1H) 8.89-8.98 (m, 2H) 9.20-9.28 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCCC1.C(O)(=O)C>C(O)C>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:1][C:3]3[NH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[C:11]=3[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(Cl)ccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.7 g of 6-chloro-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.5 g (80%) of 3-[2-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](S(C)=O)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34]>>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([NH:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34])=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2]
Reactant: NCCOCCO
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(NCCOCCO)nc21

Procedure:
1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-[2-(2-hydroxy-ethoxy)-ethylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.350 g (0.887 mmol) 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.267 mL (2.66 mmol) 2-(2-amino-ethoxy)-ethanol. The final product was purified by column chromatography (20:1 dichloromethane/methanol). This gave 0.331 g (86%) of 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-[2-(2-hydroxy-ethoxy)-ethylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 143° C.–146° C.; MS (APCI) m+1/z 436.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=2)[CH:9]=1.Cl.[NH2:24][C@H:25]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][N:37]=[C:38]3[Cl:41])=[CH:33][CH:32]=2)[C:26]1=[O:42]>CC#N>[Cl:41][C:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([CH2:30][N:27]3[CH2:28][CH2:29][C@H:25]([NH:24][S:19]([C:17]4[S:18][C:14]([C:10]5[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=5)=[CH:15][CH:16]=4)(=[O:21])=[O:20])[C:26]3=[O:42])[CH:40]=2)[CH:35]=[CH:36][N:37]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3cccnc3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Triethylamine (0.35 mL, 2.5 mmol) is added dropwise to a solution of 5-pyridin-3-yl-thiophene-2-sulfonyl chloride (0.22 g, 0.85 mmol) and 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.22 g, 0.71 mmol) in CH3CN (5 mL). The suspension is stirred at room temperature overnight then concentrated to dryness. The residue is diluted with methylene chloride and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered, concentrated, and then purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the product (0.23 g, 0.45 mmol) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCC(C)Sc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(SCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(1-methylpropylthio)benzenethiol (8.79 g, 44.3 mmol) in 25 ml of DMF is added, under N2, potassium carbonate (7.05 g, 51.0 mmol) followed by dropwise addition of N-(bromoethyl)phthalimide (12.94 g, 51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solvent removed to give N-{2-[4-(1-methylpropylthio)phenylthio]ethyl)phthalimide. Following the procedures of Example 13, the above phthalimide (2.12 g, 5.7 mmol) is reacted with hydrazine hydrate (0.28 ml, 5.7 mmol) to give 2-[4-(1-methylpropylthio)phenylthio]ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([CH3:15])[CH2:9]OS(C)(=O)=O)[C:5]([F:17])=[CH:4][N:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[NH4+].[Cl-]>C(O)C.O.CC(OC)(C)C>[N:18]([CH2:9][C:8]([C:6]1[C:5]([F:17])=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)([OH:16])[CH3:15])=[N+:19]=[N-:20]
Reactant: CC(O)(COS(C)(=O)=O)c1cc(Br)ncc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: O
Product: CC(O)(CN=[N+]=[N-])c1cc(Br)ncc1F
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of methanesulfonic acid 2-(2-bromo-5-fluoro-pyridin-4-yl)-2-hydroxy-propyl ester (10.36 g, 31.6 mmol) in ethanol (160 ml) was added NaN3 (5.13 g, 79.0 mmol) and NH4Cl (8.44 g, 158.0 mmol). The reaction mixture was stirred at 80° C. for 20 h. The reaction mixture was diluted with H2O and TBME and the phases were separated. The aq. phase was twice reextracted with TBME, the combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. HPLC RtH4=0.89 min; ESIMS: 275, 277 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, 1H), 7.80 (d, 1H), 3.81 (d, 1H), 3.65 (d, 1H), 1.61 (s, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)(=O)=O.[CH2:37]([NH2:39])[CH3:38]>CO>[CH2:37]([NH:39][CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:32])([F:33])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)[CH3:38]
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CCN
Solvent: CO
Product: CCNCc1cc2ncn(-c3cc(O[C@H](C)c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1

Procedure:
In a similar manner as described for example 116, 200 mg of crude [3-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (example 49, step 1) and 0.925 ml ethylamine (2 M solution in THF) in 4 ml methanol give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH2:22][C:23]([OH:25])=O)=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:29])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:29][C:23](=[O:25])[CH2:22][CH2:21][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)O)c3cccnc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)Cl)c3cccnc23)cc1
Reaction time: 0.33 h

Procedure:
A solution of Example 201H (1.65 g, 4.92 mmol) in dichloromethane (15 mL) at room temperature was treated oxalyl chloride (344 mg, 2.71 mmol), stirred for 20 minutes, treated with toluene (25 mL), and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:47][O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30]([NH:47][O:48][CH:49]5[CH2:54][CH2:53][CH2:52][CH2:51][O:50]5)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1
Reactant: NOC1CCCCO1
Reactant: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c2ccccc21

Procedure:
A suspension of (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (150 mg, 0.348 mmol) in DCM (4 ml) was treated with TEA (0.070 ml, 0.52 mmol) and then with EDC (99 mg, 0.52 mmol), HOBt (70 mg, 0.52 mmol) and NH2OTHP (49 mg, 0.42 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)acrylamide as a white solid [LC-MS: (ES+) MH+: 531]. The solid was suspended in DCM (5 ml) and treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C to give, after purification by preparative HPLC, (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl]-N-hyroxy-acrylamide (40 mg, trifluoroacetic salt) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:24])[C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Yield: 129.5 %

Procedure:
A solution of 7.5 grams (0.021 mole) of 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, 3.4 grams (0.025 mole) of potassium carbonate, and 3.5 grams (0.025 mole) of methyl iodide in 200 mL of acetone was stirred at ambient temperature for about 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in 200 mL of water. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 6.9 grams of crude product. The dark oil was combined with 7.0 grams of crude product prepared by a similar route to yield a total of 13.9 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 10.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([NH:16][C@H:17]([C:26]1[NH:27][C:28]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)=[CH:29][N:30]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:15].[F:41][C:42]([F:47])([F:46])[C:43]([O-:45])=[O:44].C(CCCCC[C@@H](C1[NH2+]C(C2C=CC3C(=CC=CC=3)C=2)=CN=1)NC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)(O)=O.C([O-])([O-])=O.[Na+].[Na+].C(OC(C(F)(F)F)=O)([C:96]([F:99])([F:98])[F:97])=O.N1C=CC=CC=1>CCO.O>[F:41][C:42]([F:47])([F:46])[C:43]([O-:45])=[O:44].[CH:40]1[C:39]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:33]=[CH:32][C:31]=1[C:28]1[NH2+:27][C:26]([C@@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]=2[CH3:12])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:96]([F:99])([F:98])[F:97])=[N:30][CH:29]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCCC(=O)O)c3ncc(-c4ccc5ccccc5c4)[nH]3)c2c1
Agent: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCCC(=O)O)C3=NC=C(c4ccc5ccccc5c4)[NH2+]3)c2c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCCC(=O)C(F)(F)F)C3=NC=C(c4ccc5ccccc5c4)[NH2+]3)c2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanoic acid (Free base of Example 107) (1 eq.) in EtOH (0.5 M solution) was added Na2CO3 (1 eq.). The heterogeneous mixture was stirred 40 min at RT then the solvent was removed under reduced pressure. DCM was added (0.14 M solution), the mixture was cooled at 0° C. with an ice-bath then TFAA (6 eq.) was added followed by pyridine (8 eq.). After 40 min at the same temperature some water was added and the product extracted with DCM. The collected organic phase were treated with brine and dried (Na2SO4) and after removing the solvent under reduced pressure the crude was purified by preparative RP-HPLC, using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound as a white powder as a mixture of the ketone and hydrated form 1H NMR (500 MHz, pyridine) δ: 11.65-11.55 (0.5H, m), 11.50-11.38 (0.5H, m), 9.21-9.12 (0.5H, m), 8.71-8.63 (2H, m), 8.30-8.10 (1.5H, m), 8.00-7.79 (4.5H, m), 7.56-7.30 (4H, m), 7.09-6.97 (1H, m), 5.76-5.62 (1H, m), 4.11-3.96 (1.5, m), 3.85-3.71 (2.5H, m) 2.71-2.58 (1H, m), 2.55-2.41 (3.5H, m), 2.40-2.23 (2H, m), 2.21-2.03 (2H, m), 2.10-1.79 (1.5H, m), 1.70-1.00 (6H, m). MS (ES) C33H33F3N4O3 requires: 590, found: 609 (M+H2O+H)+.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[C:31]([NH:34][NH2:35])(=[O:33])[CH3:32]>C1COCC1>[C:31]([NH:34][NH:35][C:21]([CH:18]1[CH2:19][CH2:20][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])[CH2:17]1)=[O:23])(=[O:33])[CH3:32]
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Isobutyl chloroformate (152 μL, 1.16 mmol) was added to a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (237 mg, 1.10 mmol) and 4-methylmorpholine (182 μL, 1.65 mmol) in THF (5.50 mL) at −78° C. After 15 min, added acetic hydrazide (2.0 mg, 1.10 mmol), and the resulting mixture was warmed slowly to rt. After 1 h, the reaction mixture was quenched with 0.5 M HCl and extracted with EtOAc. The combined organics were dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-8a. m/z (ES) 272 (MH)+.