Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[C:19]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:43]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])=[C:19]([N:33]([CH3:43])[S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3ccccc3)c(NS(=O)(=O)c3ccccc3)c2)CC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1NS(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeI (45 μL, 0.72 mmol) was added to a mixture of N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide (0.189 g, 0.36 mmol) and K2CO3 (0.124, 0.90 mmol) in acetone (25 mL). The mixture was stirred at r.t. for 2 h, filtered and the solvent was removed. Purification by column chromatography (DCM/MeOH/heptane 4:1:15) gave N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)-amino]phenyl}benzenesulfonamide as a colourless oil. Boc-deprotection was carried out by dissolving the compound in small amount of MeOH and adding HCl/ether. The solvent was removed and the residue was recrystallized from MeOH/ether to give 62.7 mg of product M+ 1 501.3 Calcd 501.16.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNC(=O)COc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
11 g of 2,4-dichlorophenoxy-acetic acid chloride in solution in 40 ml of methylene chloride were added without exceeding 25° C. to a mixture of 8.6 g of N-(tert-butoxycarbonyl)-1,4-diamino-butane, 120 ml of methylene chloride and 7 ml of triethylamine and the mixture was stirred for 30 minutes, then concentrated to dryness under reduced pressure. The residue was taken up in 200 ml of tetrahydrofuran and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure to obtain 18.53 g of crude product melting at 107° C. which was crystallized from 740 ml of isopropyl ether to obtain 17.43 g of the expected product melting at 110° C. 5.39 g were chromatographed on silica (eluant: hexane-ethyl acetate (6-4)) to obtain 4.48 g of the sought product melting at 114° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: O=C1CNCCN1
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 170 °C
Reaction time: 3 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 50 mg, 0.144 mmol), KF, 42.6 mg, 0.719 mmol) and piperazin-2-one (44.5 mg, 0.431 mmol) were suspended in NMP (0.3 mL). The RM was stirred at 170° C. for 3 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in EtOAc/Pentane to afford the title compound as a light brown solid (tR 3.63 min (conditions 5), (tR 10.82 min (conditions 2), MH+=412.2, 1H-NMR in DMSO-d6: 8.07 (s, 1H); 8.03 (s, 1H); 7.79 (d, 1H); 7.52 (s, 1H); 7.36 (d, 1H); 7.02 (d, 1H); 4.85 (m, 1H); 3.95 (d, 1H); 3.95 (s, 3H); 3.73 (d, 1H); 3.54 (m, 2H); 3.17 (m, 2H); 1.79 (d, 3H)).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:8]=1.[BrH:13]>>[BrH:13].[NH2:12][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][N:7]2[N:9]=1
Reactant: COc1ccc2nc(N)nn2c1
Agent: Br
Product: Nc1nc2ccc(O)cn2n1
Reaction time: 7 h
Yield: 89 %

Procedure:
A mixture of 6-methoxy[1,2,4]triazolo[1,5-a]pyridin-2-amine (780 mg, 4.75 mmol) and 48% hydrobromic acid (3 mL) was stirred under refluxing conditions for 7 hr. 48% Hydrobromic acid (2 mL) was further added, and the mixture was stirred with heating under reflux for 3 hr. The mixture was concentrated under reduced pressure, and diisopropyl ether (2 mL) and ethanol (1 mL) were added to the residue. The precipitate was collected by filtration and washed with diisopropyl ether to give the title compound (984 mg, 89%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[S:27]([NH2:30])(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.C(O)(C)(C)C.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:30][S:27]([C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[Cl:18])(=[O:29])=[O:28])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To the carboxylic acid from Step C (243 mg, 0.92 mmol) was added a solution of 4-(dimethylamino)pyridine (340 mg, 2.76 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (232 mg, 2.3 mmol) in t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 min, 2-chloro-5-methoxybenzenesulfonamide (190 mg, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 240 mg of the title compound, a compound of the present invention, as a white solid, m.p. 211-212° C. 1H NMR (CDCl3) δ 10.10 (br s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.86 (d, 1H), 7.54 (s, 1H), 7.38 (d, 1H), 7.09 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:18]>CC(C)=O>[CH3:23][O:22][C:20]([CH2:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18])=[O:21]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: COC(=O)CC(=O)Cl
Solvent: CC(C)=O
Product: COC(=O)CC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 51.4 %

Procedure:
20.3 g (100 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 16.4 g (120 millimoles) of methyl chloroformylacetate and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 15.6 g (52%) of 6-[p-(methoxycarbonylacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 228°-230° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 500 mg 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (2.57 mmol), 550 mg benzyl bromide (3.22 mmol), and 922 mg cesium carbonate (2.8 mmol) in 8.6 mL of anhydrous DMF were stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, and brine solutions. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was further purified by column chromatography, eluting from silica gel with a gradient of 10 to 50% ethyl acetate in hexanes, to give the desired product as a pale yellow solid. MS: (+) m/z 285.10 (M+1)
Reaction SMILES: [N:1]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[Br:31][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of tert-butyl 4-(3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate (0.85 g, 2.69 mmol) in 15 mL of DMF was cooled to 0° C. then treated dropwise with NBS (478 mg, 2.69 mmol) in 12 mL DMF. The reaction was stirred at 0° C. for 1 hour then treated with 100 mL H2O. The suspension was extracted with 2×75 mL of ethyl acetate. The combined organic layer was rinsed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to give a light brown oil. This residue was subjected to silica gel chromatography using the Biotage purification system (25+M column, 0-20% ethyl acetate/hexanes over 10 column volumes) to give a viscous oil which solidified to give a white solid (852 mg, 80.4%). 1H-NMR (CDCl3) δ 7.10 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.05-7.04 (m, 1H), 6.51 (d, J=9.0 Hz, 1H), 4.33-4.19 (m, 2H), 3.71-3.64 (m, 1H), 3.14 (t, J=6.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.69 (t, J=6.3 Hz, 2H), 1.91-1.77 (m, 2H), 1.61-1.57 (m, 4H), 1.47 (s, 9H). MS (ESI): 395.1 and 377.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[C@@H:30]1[CH2:32][O:31]1>C(O)C>[OH:31][C@H:30]([C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:29])[O:26][CH2:27][C:28]=2[C:20]=1[CH3:19])[CH2:32][N:15]1[CH2:16][CH2:17][C:10]2([C:9](=[O:18])[N:8]([C:3]3[CH2:4][O:5][C:6](=[O:7])[C:2]=3[CH3:1])[CH2:12][CH2:11]2)[CH2:13][CH2:14]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: CCO
Product: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O

Procedure:
A solution of 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17, 6.00 g, 24.0 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (1-4B, 5.93 g, 31.2 mmol) in ethanol (20 mL) in a sealed tube was heated at 95° C. overnight. After concentration, the residue was purified on silica gel column using methanol/dichloromethane, then precipitated from methanol to give the title compound. LC/MS, (M+1)+: 440.93. 1HNMR (500 MHz, CDCl3), δ7.845-7.809 (m, 2H), 5.290-5.278 (m, 4H), 5.139-5.112 (m, 1H), 4.072-4.044 (t, J=7.1 Hz, 2H), 3.190-3.167 (m, 1H), 2.876-2.859 (m, 1H), 2.636-2.604 (m, 2H), 2.468-2.421 (m, 1H), 2.311 (s, 3H), 2.350-2.328 (m, 1H), 2.193-2.165 (t, J=7.1 Hz, 2H), 2.101-2.039 (m, 5H), 1.668-1.618 (m, 2H).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.O.[NH2:14][NH2:15]>C(O)C>[C:9]1(=[O:11])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=[N:15][NH:14]1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(Br)Br
Solvent: O
Solvent: CCO
Product: O=c1[nH]ncc2ccccc12
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 29.4 g (0.1 mole) of α,α-dibromo-o-toluic acid and 16 g (0.32 mole) of hydrazine hydrate in 200 ml of ethanol was heated under reflux with stirring for 1 hour. The solvent was evaporated under reduced pressure, and the residue recrystallized from ethanol to give 12.8 g (yield: 88%) of 1-phthalazinone having a melting point of 181°-182° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:23][C@@:16]2([C:20](=[O:21])[NH:19][C:18](=[O:22])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:24])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:26][CH2:27][CH2:28][Cl:29].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:23][C@@:16]2([C:20](=[O:21])[N:19]([CH2:26][CH2:27][CH2:28][Cl:29])[C:18](=[O:22])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:24])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reaction time: 5 h
Yield: 80.4 %

Procedure:
To a solution of (2S,4S)-N-butyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (25.0 g, 74.6 mmol) in N,N-dimethylformamide (125 ml, 1.62 mmol) was added 1-bromo-3-chloropropane (23.5 g, 149 mmol). After adding 60% NaH (3.00 g, 75.0 mmol) over 30 minutes at 15°-22° C., the mixture was stirred for 5 hours at 25°-28° C. The reaction mixture was poured into iced water (500 ml), extracted with AcOEt (1000 ml×3), dried over MgSO4. The solvent was distilled off, the residue was chromatographed on silica gel, eluted with CH2Cl2 -CH2Cl2 /MeOH (9/1), and recrystallized from AcOEt to give the desired compound (24.7 g, 80.5%) as colorless prism crystals.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:25]>>[Cl:25][C:1]1[NH:2][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2F)[nH]c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate (19.3 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=10:1→3:1) to give the title compound as a brown solid (yield 8.76 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2](=[NH:1])[N:3]([CH3:19])[C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=N)c(F)cn(S(=O)(=O)c2ccccc2)c1=O
Temperature: 60 °C
Yield: 50.6 %

Procedure:
4-Amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidine-2-one (200 mg, 0.74 mmol) was stirred at room temperature in dimethyl formamide (3 mL) together with anhydrous potassium carbonate (210 mg, 1.5 mmol). Iodomethane (210 mg, 1.5 mmol) was added and the mixture was heated at 60° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (EtOAc) and water. The organic phase was dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by chromatography on silica gel (gradient, 20 to 80% EtOAc in petroleum ether) to isolate 1-benzenesulfonyl-5-fluoro-4-imino-3-methyl-3,4-dihydro-1H-pyrimidin-2-one (106 mg, 50%) as a white solid: mp 144° C.; 1H NMR (600 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.03-8.00 (m, 2H), 7.97 (d, J=5.9 Hz, 1H), 7.80-7.76 (m, 1H), 7.67-7.63 (m, 2H), 3.09 (s, 3H); ESIMS m/z 284 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:27])=[CH:4][C:3]=1[F:10]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Cl)c(F)cc1I
Yield: 70.4 %

Procedure:
A round-bottom flask was charged with 2-chloro-1-fluoro-4-methoxybenzene (Alfa Aesar, Ward Hill, Mass., 2.714 g, 16.90 mmol), DCM (24.86 ml), AcOH (24.86 ml), and sulfuric acid (0.496 ml, 9.30 mmol) to give a solution. n-iodosuccinimide (3.80 g, 16.90 mmol) was added in a single portion. TLC showed what appeared to be conversion of the starting material to a slightly higher, move UV-active spot. The mixture was diluted with DCM, washed with water (2×), washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-10% EtOAc/Heptane) to give 3.409 g of a clear oil. This oil was used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:51][NH:52][O:53][CH3:54]>ClCCl>[CH3:54][O:53][N:52]([CH3:51])[C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (13.8 g, 44.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (12.8 g, 67.2 mmol) and hydroxybenzotriazole (7.2 g, 53.7 mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol). The mixture was stirred at room temperature for 1 hour, and then N,O-dimethylhydroxylamine (5 g, 53.7 mmol) was added. The reaction mixture was stirred for another 3 hours. LCMS showed the reaction was completed. The reaction mixture was directly washed with water (100 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (11.2 g, 67%) as a white solid. MS (ES+) C16H25N5O4 requires: 351, found: 296 [M-56+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methylpyridin-4-yl)propan-1-one (example 282, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=443.0 ([M+H]+).
Reaction SMILES: C(O)C.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[Sn].[CH2:17](Br)[CH:18]=[CH2:19]>O>[CH2:19]([CH:5]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:4])[CH:18]=[CH2:17]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CCBr
Agent: [Sn]
Solvent: CCO
Solvent: O
Product: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
A three liter three-necked round bottom flask, equipped with heating mantle, stirrer, nitrogen inlet, and condensor, was charged with 900 mL of ethanol, 150 mL of water, 180 g (1.00 mole) of D-glucose, 119 g (1.00 mole) of tin powder (−100 mesh), and 121 g (1.00 mole) of allyl bromide. The mixture was stirred and slowly heated to reflux—a significant exotherm and gas evolution was observed at 60° C. The gray suspension was stirred at reflux for two days, in which time the reaction mixture turned an orange/brown color. Heat was removed and the mixture was allowed to cool to room temperature. The reaction was neutralized to pH=7 by adding approximately 200 ml of 5M NaOH aqueous solution. The suspension was filtered to remove solids, and the yellow solution was decolorized with multiple treatments of activated carbon. The activated carbon was removed by filtration, and the solvent was removed by rotary evaporation to isolate a white syrup. Typical yield was 200 g with threo-erythro ratio of 6:1, based on GC-MS. The syrup was used without further purification.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#[N:7].[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH2:18][C:19](OCC)=[O:20])[CH3:14]>>[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH:5]([C:6]#[N:7])[C:19](=[O:20])[CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Na]
Product: CCOC(=O)CCC(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A clean, dry 500 ml 3-neck R.B. flask was equipped with a reflux condenser, mechanical stirrer, addition funnel, and nitrogen inlet. The flask was charged with 600 ml of ethanol (distilled from magnesium turnings and stored over type 3A molecular sieves) followed by 30.0 g (1.30 mol) of sodium, and the reaction mixture stirred and heated until all the sodium had dissolved. The temperature of the reaction mixture was then raised to the reflux point, and a mixture of 186.03 g (1.00 mol) of 2,4-dichlorobenzyl cyanide and 261.3 g (1.50 mol) of diethylsuccinate added at a rapid drop rate through the addition funnel. The reaction mixture was refluxed for 12 hours, then approximately 2/3 of the ethanol was distilled off, the reaction mixture refluxed for two additional hours, cooled to room temperature, and poured into 600 ml of ice water. The basic solution was extracted twice with 300 ml of ether, and then acidified with 6 N HCl. An oil formed, and the aqueous acid solution was extracted twice with 250 ml portions of ether. The ether extract was washed twice with water, dried (MgSO4), and the ether stripped to leave 156.61 g (50% yield) of product as a viscous red oil.