Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C([O:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:22]=[CH:21]2)=[CH2:15])CCC.O>C1COCC1>[Br:8][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:22]=[CH:21]2)=[O:15]
Reactant: C=C(OCCCC)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 117.2 %

Procedure:
NBS (51.7 mg, 0.290 mmol) was added to a solution 8-(1-butoxyvinyl)-2-(1-phenylcyclopropyl)quinazoline (100.0 mg, 0.290 mmol) in THF (2.2 mL) and water (0.084 mL, 4.65 mmol) at 0° C. and the resulting solution was stirred at 0° C. for 2 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 2-bromo-1-(2-(1-phenylcyclopropyl)quinazolin-8-yl)ethanone (124.8 mg) as a light-yellow oil. NH4OAc (90 mg, 1.161 mmol) and piperidine-2,4-dione (39.4 mg, 0.348 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (2.2 mL) and stirred under argon in a sealed flask at 50° C. for 15.5 h. The reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (2×30 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(1-phenylcyclopropyl)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (35.3 mg, 0.093 mmol, 32% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 11.24 (1H, br. s.), 9.28 (1H, s), 8.16 (1H, d, J=7.6 Hz), 7.66 (1H, d, J=7.8 Hz), 7.52-7.58 (3H, m), 7.46 (2H, t, J=7.3 Hz), 7.39 (1H, t, J=7.2 Hz), 7.11 (1H, d, J=2.2 Hz), 5.45 (1H, br. s.), 3.51 (2H, td, J=7.0, 2.1 Hz), 2.49 (2H, t, J=6.9 Hz), 1.95 (2H, q, J=3.6 Hz), 1.51 (2H, q, J=3.6 Hz). m/z (ESI, +ve) 381.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33]>ClCCl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)/[CH:8]=[N:23]/[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33])[CH3:2]
Reactant: CCOC(OCC)c1cccc(C=O)c1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(OCC)c1cccc(/C=N/c2cccc3c2COC3=O)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 60.9 %

Procedure:
To a stirred mixture of 3-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(3-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (3.1 g, yield 61%) as a white solid. LC-MS (ESI) m/z: 340 (M+1)+.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: O=Cc1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N4CCOCC4)c([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-morpholinyl)-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 467.1 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:8][C:9]([C:11]1([CH2:21]Br)[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)=[O:10])[CH3:7].O>CN(C=O)C>[CH2:6]([O:8][C:9]([C:11]1([CH2:21][S:3][C:1](=[O:4])[CH3:2])[CH2:20][CH2:19][C:14]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C1(CBr)CCC2(CC1)OCCO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CSC(C)=O)CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 101.6 %

Procedure:
Potassium thioacetate (1.0 g) was added to a solution of 8-bromomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g) in DMF (30 ml) and the solution was heated at 80° C. for 4 h. The mixture was then added to water (100 ml) and extracted with ether. The solvent was washed with water, bicarbonate solution and brine, then dried (MgSO4) and evaporated to give the title compound (1.0 g) as colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([OH:21])[CH:9]=[CH:10][C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][C:3]1=[O:4].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>N1CCCCC1>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:21][CH2:22][CH:24]3[O:26][CH2:25]3)[CH:9]=[CH:10][C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)CCc2c(O)ccc(OCc3ccccc3)c21
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: CN1C(=O)CCc2c(OCC3CO3)ccc(OCc3ccccc3)c21
Reaction time: 3 h
Yield: 53.1 %

Procedure:
5.5 g of 1-methyl-5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril was added to 15 g of epichlorohydrin, and 12 drops of piperidine were then added thereto followed by stirring at 90° to 100° C. for 3 hours. The unreacted epichlorohydrin and piperidine were evaporated under reduced pressure, and the residue was dissolved in chloroform, washed successively with a 5% aqueous solution of sodium hydroxide and water and dried over anhydrous potassium carbonate. The chloroform was evaporated under reduced pressure, and the residue was purified by silica gel chromatography and then recrystallized from ethanol to afford 3.5 g of 1-methyl-5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril as yellow needle-like crystals having a melting point of 111°-112.5° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[NH2:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>CS(C)=O>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:13])[CH:19]=3)[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc3cc[nH]c3c2)ccn1
Temperature: 160 °C
Reaction time: 8.5 h
Yield: 10.6 %

Procedure:
Sodium hydride (1.04 g, 26.0 mmol, 60% in oil) was suspended in dimethyl sulfoxide (2.5 ml); 6-hydroxyindole (3.46 g, 26.0 mmol) and 2-amino-4-chloropyridine (2.57 g, 20.0 mmol, WO 02/332872) were subsequently added thereto at room temperature under nitrogen stream; and the reaction mixture was stirred at 160° C. for 8.5 hours. After cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate (150 ml) and a solvent mixture of aqueous ammonia:water=1:1 (50 ml); the organic layer was washed with a solvent mixture of aqueous ammonia:water=1:1, and with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate, or ethyl acetate:methanol=93:7); and the obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (477 mg, 2.12 mmol, 10.6%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:35][C:36]1[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:23])[C:10]1([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reactant: Cc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1CC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (-78° C.) solution of N-t-butoxycarbonyl isonipecotic acid benzyl ester (13.34 g, 41.8 mmol) in 140 ml of dry THF was added a 1.0 M THF solution of sodium bis trimethysilylamide (59 ml, 59 mmol) over 15 min. The resulting orange solution was stirred at -78° C. for 1 h and then treated dropwise with α-bromo-o-xylene (6.8 ml, 50.7 mmol) and then allowed to warm slowly to room temp. overnight. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with brine (2×), and concentrated in vacuo to an orange gum. Flash chromatography on silica with 20% to 30% EtOAc/hexane as eluent, combining appropriate fractions, and concentrating in vacuo, afforded the product as a white solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C=O)C>[CH:33]1([C:36]([N:21]2[CH2:20][CH2:19][C:17]3[N:18]=[C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([C:5]5[O:1][CH:2]=[N:3][CH:4]=5)=[CH:7][CH:8]=4)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:16]=3[CH2:22]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (50 mg, 0.12 mmol, Example 1) was dissolved in DMF (3 mL). Cyclopropanecarbonyl chloride (10.59 μL, 0.12 mmol) was added and the reaction was stirred at room temperature for 4 h. An extra equivalent of cyclopropanecarbonyl chloride was added and the reaction was stirred for 2 h. The solvent was evaporated, the crude dissolved in few drops dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding cyclopropyl(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone (1.8 mg, 2.96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([CH2:32][O:33][CH2:34][C@@H:35]2[C@@H:40]3[C@H:36]2[CH2:37][O:38][C:39]3=[O:41])=[CH:30][CH:29]=1.Cl>C1COCC1.CCOC(C)=O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:37]([C@@H:36]1[C@@H:35]([CH2:34][O:33][CH2:32][C:31]2[CH:42]=[CH:43][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C@@H:40]1[CH2:39][OH:41])=[O:38]
Reactant: COc1ccc(COC[C@H]2[C@@H]3COC(=O)[C@H]23)cc1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(COC[C@H]2[C@H](CO)[C@@H]2C(=O)Nc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 850 mg (3.4 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 80 ml of THF was cooled to −78° C., treated dropwise with 4.8 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min at 78° C. To this solution were added 839 mg (4.8 mmol) of (1R,5S,6S) 6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one dissolved in 5 ml of THF. Stirring was continued at −78° C. for 1 hr and then for 3 hrs at RT. Pouring of the mixture into a 2M aqueous solution of HCl, extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent gave 1.2 g (77%) of (1S,2S,3S) 2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Yellow semisolid. 453 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.O>CN(C)C=O>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a suspension of 3-(1-cyanocyclopropyl)-N-(3-hydroxy-4-methoxyphenyl)-benzamide (1.54 mg, 5.00 mmol) and potassium carbonate (0.69 g, 5.00 mmol) in N,N-dimethylformamide (5 mL) was added 1-fluoro-4-nitrobenzene (0.78 g, 5.50 mmol), and the mixture was stirred at 60° C. for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (1.90 g, 89%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](S)=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[N+:13]([O-])([OH:15])=[O:14].OS(O)(=O)=O.O=S(=O)=O.ClC1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl>>[C:7]1([N+:13]([O-:15])=[O:14])[C:2]([Cl:1])=[C:3]([Cl:12])[C:4]([Cl:11])=[C:5]([Cl:10])[C:6]=1[Cl:9]
Reactant: Sc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 55 °C
Yield: 83.2 %

Procedure:
Pentachlorothiophenol (10.0 g, 0.035 mol) was added to 60.0 g of 99% nitric acid over 20 min at 45°-50° C. followed by heating at reflux (55° C.) for 1.5 hr. At this point 20 mL of 30% by weight oleum was added at such a rate that the temperature was kept at 75° to 80° C. After the addition was complete (approximately 30 min.), the reaction mixture was cooled to room temperature. The product was collected by filtration, and thoroughly washed with water to give after drying in vacuo, 8.6 g (85% yield) of 99.7% PCNB with 0.17% hexachlorobenzene (GC assay). Variations on this one-pot, two-step process were examined and are summarized in TABLE I.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[S:13][C:14]([Br:17])=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][N:8]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])[S:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:10])=[O:11]
Reactant: COCCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2ccc(Br)s2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) in dry THF (2 ml) was added to sodium hydride (121 mg of a 60% oil dispersion, 3 mmol) in dry THF (1 ml). The resulting suspension was cooled to 0° C. and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) was added dropwise via syringe. The solution was warmed to room temperature, and stirring continued overnight. Evaporation of solvent left an oil that was extracted into ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. Flash chromatography of the residue on silica gel using 10-15% ethylacetate/hexanes yielded 480 mg (56%) of a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:33])([C:30](O)=[O:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C1(N=C=NC2CCCCC2)CCCCC1.[CH:61]1[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][NH2:69])=[CH:63][CH:62]=1>C(OCC)(=O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:33])[C:30](=[O:31])[NH:69][CH2:68][CH2:67][C:64]2[CH:65]=[CH:66][CH:61]=[CH:62][CH:63]=2)=[CH:22]1
Reactant: NCCc1ccccc1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of N-[(9H-fluoren-9-ylmethyloxy)carbonyl]-α-methyl-DL-tryptophan (8.80 g, 20 mmol) in dry ethyl acetate (350 mL) was added pentafluorophenol (3.68 g, 20 mmol) and stirred for 10 minutes. The reaction mixture was cooled to 0° C. and a solution of dicyclohexylcarbodiimide (20 mmol) in ethyl acetate (25 mL) was added dropwise. This solution was stirred for one hour at 0° C. then at room temperature for four hours before leaving it at 4° C. overnight. The mixture was filtered and the precipitate washed with cold ethyl acetate (30 mL) and a solution of 2-phenethylamine (2.66 g, 22 mmol) in ethyl acetate (30 mL) was added dropwise to the combined filtrates. The mixture was left to stir for 48 hours at room temperature. The reaction mixture was filtered and the residue washed with cold ethyl acetate (2×30 mL) to give the title compound (3.73 g, 75%). The filtrates were combined and the solvent removed in vacuo and taken up again in ethyl acetate (5 mL) to give a second crop of 1.67 g (15%), a total of 90% yield as a white solid, mp 179°-181° C. (EtOAc); IR (film) 1708, 1652 cm-1 ; NMR (DMSO d6) δ1.30 (3H, s), 2.64 (2H, t, J 7.2Hz), 3.2-3.3 (4H, m), 4.19 (1H, t, J 6.7Hz), 4.25-4.40 (2H, m), 6.9-7.9 (20 H, m), 10.8 (1H, s).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.O1CCCC1.CS([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: CS(=O)(=O)c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-n2cnc(Br)c2)nc1
Temperature: 105 °C
Yield: 85.7 %

Procedure:
A dried pressure tube was charged with 4-bromo-1H-imidazole (100 mg, 667 μmol), tetrahydrofuran (3 ml), N,N-dimethylformamide (2 ml), 2-(methylsulfonyl)-5-(trifluoromethyl)pyridine (150 mg, 667 μmol), and cesium carbonate (261 mg, 800 μmol). The tube was sealed and heated at 105° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The 2-(4-bromo-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine (167 mg, 86% yield) was obtained as a crystalline white solid. MS (ISP): m/z=292.0 [M+H]+ and 294.2 [M+2+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=1[C:4]([O:6]C)=O.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:6][C:4]1[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])[N:1]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(N)cccc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(OC)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of methyl 2-amino-6-methoxybenzoate ((1.30 g, 7.17 mM) and dimethyl acetylenedicarboxylate (1.17 g, 8.23 mM) in t-butanol (11 mL) was refluxed under a nitrogen atmosphere for 4 hr. The reaction mixture was cooled to room temperature, potassium t-butoxide (0.92 g, 8.23 mM) was added, and the resulting mixture was heated to 90° C. for 1.5 hr during which solids precipitated out of solution. The mixture was cooled to room temperature, filtered and the collected solids were dissolved in water. The resulting solution was acidified with 1N H2SO4 to form a light tan precipitate. The solids were collected, filtered, washed with water and air dried to provide the desired compound (1.35 g, 65%) as a tan solid. A 0.28 g portion of this material was recrystallized from ethyl acetate to provide an analytical sample (0.24 g) of the title compound as a white solid, mp 184°-186° C.; MS(CI): 292 (M+H). Analysis for C14H13NO6 ·0.2 H2O: Calculated: C, 57.03; H, 4.58; N, 4.75 Found: C, 56.99; H, 4.40; N, 4.70
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:33])=[C:18]([CH3:32])[C:19]4[N:20]([CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:34]Cl.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:33])=[C:18]([CH3:32])[C:19]4[N:20]([C:22]([I:34])=[C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClI
Reactant: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2cc(-c3ccc(F)cc3)nc2c1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution, cooled to 0° C., of 3.2 g (7.3 mmol) of 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine in 20 mL of chloroform is added dropwise a solution of 1.8 g (11 mmol) of iodine monochloride in 3 mL of methanol and the medium is stirred for one hour at room temperature. The medium is then basified by addition of aqueous sodium hydrogen carbonate solution and 5% sodium thiosulfate solution is then added until the medium has decolorized.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.[C:21](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:14]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=1[O:19][CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(Br)cc1CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.306 mL, 0.612 mmol) was added to a solution of (5-bromo-2-methoxy-phenyl)-acetic acid (100 mg, 0408 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (103.7 mg, 98%).