Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=2[NH:3]1>C1COCC1>[NH:3]1[CH2:2][CH2:7][O:6][C:5]2[N:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]1=2
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CO2
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a suspension of methyl 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (1.24 g, 5.96 mmol) in THF (30 mL) at 0° C. was added borane-tetrahydro-furan complex (23.83 mL, 23.83 mmol). The reaction was warmed to room temperature and allowed to stir for 2 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction was chilled to 0° C. and quenched slowly with MeOH (20 mL). The reaction mixture was concentrated in vacuo and the treated with 5% sulfuric acid in MeOH (50 mL). The solution was heated to reflux for 1 hour. The solvent was removed under reduced pressure and the resulting oil was dissolved in EtOAc (100 mL) and washed successively with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to provide methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (1 g, 5.15 mmol, 86% yield) as a white solid. The product was used without purification. LCMS (+ESI) m/z=195.0 [M+H]+.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].Cl.[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH2:11])[CH3:7].C(OC(=O)C)(=O)C>C(O)=O>[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH:11][CH:1]=[O:2])[CH3:7]
Reactant: CCOC(=O)CN
Reactant: O=C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CNC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A hot solution of sodium formate (150 g) in formic acid (200 mL) was added to a hot solution of glycine ethyl ester hydrochloride (228.7 g; 1.64 mol) in hot formic acid (250 mL). This was allowed to stir at room temperature for 1 hour. Small portions of acetic anhydride (450 g) were added to the well-stirred suspension as an exothermic reaction ensued. The suspension was stirred overnight, the solid was filtered and the filtrate was distilled in vacuo to remove excess reagents. The residue was filtered and then distilled to give N-formylglycine ethyl ester (182 g; 85%) having a boiling point of 105°-110° C. under vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[NH:6][C:5]=2[N:4]([CH3:16])[N:3]=1.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl>CS(C)=O>[CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]([O:15][CH2:19][O:20][CH3:21])=[N:6][C:5]=2[N:4]([CH3:16])[N:3]=1
Reactant: COCCl
Reactant: Cc1nn(C)c2[nH]c(=O)c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCOc1nc2c(c(C)nn2C)c2ccccc12
Temperature: 70 °C

Procedure:
1,3-Dimethyl-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one (10 g) was suspended in dimethylsulfoxide (100 mL), and sodium hydride (60%, 2.1 g) was added at room temperature. The mixture was stirred with heating at 70° C. for 2 hrs, and cooled to room temperature. Chloromethyl methyl ether (4.6 mL) was added, and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, the reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to give 1,3-dimethyl-5-methoxymethoxy-3H-pyrazolo[3,4-c]isoquinoline (10.6 g).
Reaction SMILES: [C:1]1([OH:8])[C:5](=O)[C:3](=[O:4])[C:2]=1[OH:7].[CH3:9][C:10]([C:13]1[S:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19]C2C(Cl)(Cl)C(=O)C=2Cl)[CH:18]=1)([CH3:12])[CH3:11].FC(F)(F)S(O)(=O)=O>O>[CH3:12][C:10]([C:13]1[S:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19][C:5]2[C:3](=[O:4])[C:2](=[O:7])[C:1]=2[OH:8])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)S1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)C1=CC(=Cc2c(O)c(=O)c2=O)C=C(C(C)(C)C)S1
Temperature: 90 °C

Procedure:
This Example illustrates the preparation, by a reaction analogous to D→E shown in FIG. 1, of the squaric acid derivative of Formula II in which Q1 is a 2,6-bis(1,1-dimethylethyl)-4-thiopyrylidene grouping and R1 is ahydrogen atom. 3-[2,6-Bis(1,1-dimethylethyl)-(4H-thiopyran-4-ylidene)methyl]-2,4,4-trichlorocyclobut-2-en-1-one (279 mg, 0.59 mmole, prepared in Example 51 above) was added to a solution of trifluoromethane sulfonic acid (1.0 mL) in water (35 mg). The colorless reaction mixture was stirred under nitrogen with heating to 90° C. for 5 hours, after which it was cooled to 20° C. and stirred for 12 hours at that temperature. The reaction mixture was quenched into ice/water (15 mL) dropwise, with efficient agitation. A brown precipitate formed which was initially crystalline, but become gummy after standing for several minutes. This was separated by filtration, washed with dilute aqueous sodium sulfate, and separated into two portions. One portion was dried, to give a red-brown amorphous solid (110 mg). The second portion was partly purified by flash chromatography on silica gel with 10-16-20 % methanol/dichloromethane as eluent to yield a still impure product (55 mg, exhibiting, inter alia, mle 363 in the mass spectrum), which was used directly in Example 70 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:43][CH2:37][C:38]1[O:42][CH:41]=[CH:40][CH:39]=1)=[O:25]
Reactant: NCc1ccco1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccco2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with furfurylamine.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H](CO)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
D-xylose and D-lyxose: 1.8%
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([N:12]([CH2:15][CH3:16])[CH2:13]C)C.N1CCC1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[CH2:13][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: BrCc1ccc(Br)cc1
Agent: C1CNC1
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A solution of 4-bromobenzyl bromide (1.00 g, 4.0 mmol) and triethylamine (0.84 ml, 6.0 mmol) in THF (20 mL) was stirred at ambient temperature for 10 minutes. Azetidine (0.54 ml, 8.0 mmol) was then added and a white precipitate resulted. The slurry was stirred at ambient temperature for 18 h then evaporated in vacuo. The resultant residue was partitioned between DCM and saturated aqueous sodium hydrogen carbonate, the organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (0.76 g, 3.40 mmol) as a colourless oil. 1H NMR (CDCl3, 400 MHz): 7.42 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 3.50 (s, 2H), 3.19 (t, J=7.0 Hz, 4H), 2.08 (p, J=7.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C[C:13]([N:15](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:15])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1n[nH]c2cc(Cl)ccc12
Temperature: 120 °C

Procedure:
A DMA (48 mL) solution containing the intermediate from Step B (4.0 g, 14.36 mmol), zinc powder (113 mg, 1.72 mmol), zinc cyanide (1.01 g, 8.86 mmol), 1,1′-bis(diphenylphosphino)ferrocene (318 mg, 0.58 mmol) and tris(dibenzylideneacetone)dipalladium (263 mg, 0.29 mmol) was heated at 120° C. for 45 minutes. The solution was cooled to room temperature and partitioned between EtOAc and 0.5M HCl aq. The organic phase was washed twice with 0.5M HCl aq and brine. The organic phase was then dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CH3 CN-d3): δ 7.83 (d, J=8.7 Hz, 1H); 7.77 (d, J=1.7 Hz, 1H); 7.36 (dd, J=8.7, 1.7 Hz, 1H). m/z=178.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11](=O)[CH2:12][CH:7]2[CH2:6]1)=[O:4].C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.O.[Cl-].[Na+].O>[CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:24]#[N:25])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(=O)CC2C1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
N,N-dimethyl-5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxamide 1g (12.9 g, 0.066 mol) and 4-toluenesulfonylmethyl isocyanide (14.2 g, 0.0727 mol) were dissolved in 240 mL of 1,2-dimethoxyethane with stirring upon cooling by an ice-water bath, followed by dropwise addition of a solution of potassium tert-butoxide (14.8 g, 0.132 mol) in tert-butanol. Upon completion of the addition, the ice-water bath was removed. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 100 mL of water and 50 mL of saturated brine and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (7.0 g, yield 51%) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH:46]=[C:45](B(O)O)[CH:44]=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:35]([O:39][C:40]([N:42]1[CH:46]=[C:45]([C:24]2[CH:23]=[CH:22][N:21]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)[N:19]=[C:20]3[CH:25]=2)[CH:44]=[N:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5cnn(C(=O)OC(C)(C)C)c5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 105 °C
Yield: 104.4 %

Procedure:
A mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (150 mg), [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid (123 mg), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (24 mg) and sodium carbonate (92 mg) in dioxane (3.1 mL) and water (0.4 mL) was degassed, placed under an argon atmosphere and heated at 105° C. under microwave irradiation for 30 minutes. On cooling, a further portion of catalyst was added (24 mg) and the mixture heated for a further 30 minutes under microwave irradiation. On cooling, the reaction was partitioned between aqueous ammonium chloride solution and DCM and the organic phase washed with brine, dried and concentrated in vacuo to give the crude title compound (183 mg) which was used in the next step (deprotection of both Boc groups under the standard conditions given in Example 1.0) without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.C(NC(C)C)(C)C.[Li].C([Li])CCC.C(NC(C)C)(C)C.[Cl:38][CH2:39][CH2:40][CH2:41][CH:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53])[C:43](Cl)=[O:44]>O1CCCC1>[Cl:38][CH2:39][CH2:40][CH2:41][CH:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:53])([F:54])[F:55])[C:43](=[O:44])[CH2:10][C:9]([C:7]1[CH:6]=[CH:5][C:4]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]2)=[C:3]([O:2][CH3:1])[N:8]=1)=[O:11]
Reactant: COc1nc(C(C)=O)ccc1-n1cnc(C)c1
Reactant: O=C(Cl)C(CCCCl)c1ccccc1C(F)(F)F
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1nc(C(=O)CC(=O)C(CCCCl)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 0.5 h

Procedure:
A solution of 1-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]ethanone obtained in Preparation Example 1-8 (412 mg) in tetrahydrofuran (10 ml) was added at −30° C. to a lithium diisopropylamine solution prepared from n-butyllithium (1.4 mL) and diisopropylamine (528 μL) in tetrahydrofuran (30 mL). After stirring at the same temperature for 30 minutes, 5-chloro-2-(2-trifluoromethylphenyl)valeric acid chloride (532 mg) was added and the mixture was stirred for 1.5 hours. After further stirring at room temperature for 30 minutes, the reaction was terminated with water, followed by dilution with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The oil after concentration under reduced pressure was purified by silica gel chromatography (mobile phase:ethyl acetate/heptane=0 to 100%) to obtain the title compound (90 mg).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][CH:12](OCC)OCC.[OH-].[Na+]>C1COCC1.O>[C:2]1([C:1]2[S:8][CH:11]=[CH:12][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of thiobenzamide (1 g, 7.3 mmol) in THF (10 ml) was added a solution of 2-bromo-1,1-diethoxy-ethane (1.4 g, 7.3 mmol) in THF (5 ml) and the reaction was heated at reflux overnight. The reaction mixture was cooled to room temperature and diluted with water (50 ml). The solution was basified with dilute sodium hydroxide and extracted with ethyl acetate: pet ether (1:4). The organic layer was then washed with water, brine and dried. Evaporation gave a residue which was purified by column chromatography over silica gel using EtOAc/pet ether as eluent to give 2-phenyl thiazole (400 mg, 34%) as solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C(OCC)C>[CH3:6][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CCCCCCCCNC
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Product: CCCCCCCCN(C)C(=O)CCl
Reaction time: 3 h
Yield: 66.4 %

Procedure:
Chloroacetyl chloride in diethylether was added dropwise to N-methyloctylamine in diethylether at −2° C. The organic solution was returned to room temperature, followed by stirring for 3 hours. The resulting solution was successively washed with an aqueous 1 mol/L hydrochloric acid solution and water, and then dried over anhydrous sodium sulfate. After removal the solvent under vacuum, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=23:2) to give N-methyl-N-octyl-chloroacetamide (yield: 66.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]([N:25]([CH3:36])[C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([CH3:33])[O:32][C:28]=2[CH:27]=1)=[O:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:22][C:23]([N:25]([CH3:36])[C:26]3[CH:35]=[CH:34][C:29]4[N:30]=[C:31]([CH3:33])[O:32][C:28]=4[CH:27]=3)=[O:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(Cl)c4)c4ccccc4c3=O)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a solution of 4-(3-chlorophenyl)phthalazin-1(2H)-one (0.5 g, 1.94 mmol) in DMF (20 mL) was added NaH (60%) (0.116 g, 2.91 mmol) portionwise at 0° C. After stirring for 30 min, 2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl) acetamide (0.55 g, 1.94 mmol) in DMF (2 mL) was added dropwise and the reaction mixture warmed to rt overnight. The reaction was quenched with water and the solid collected by filtration. The crude was purified by column chromatography (60-70% EtOAc/hexane) to give 2-(4-(3-chlorophenyl)-1-oxophthalazin-2(1H)-yl-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (0.22 g), (MS: ESI +ve, 459.17 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 2.63 (s, 3H), 3.24 (s, 3H), 4.73 (s, 2H), 7.44-7.46 (d, J=8.0, 1H), 7.55-7.66 (m, 4H), 7.69-7.74 (q, 2H), 7.93 (s, 3H), 8.29-8.31 (d, J=7.2, 1H). Representative compounds of the invention were prepared in a similar manner to examples 1 from 4-chlorophthalazin-1(2H)-one, the corresponding boronic acid or ester, and the appropriate alkylating agent (scheme 1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(OC)(C)(C)C>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: Cc1cnc2nc(CO)nn2c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1cnc2nc(C=O)nn2c1
Yield: 77.4 %

Procedure:
A slurry of (6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol (15.7 g, 95.6 mmol) from step 1 above, TEMPO (112 mg, 7.2 mmol), iodobenzene diacetate (33.9 g, 105.2 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 2 hours. Once the reaction was deemed complete, methyl tert-butyl ether (50 mL) was added slowly to precipitate the product. The concentrated mother liquor was introduced into a silica gel column and eluted with 2% MeOH/CH2Cl2 to give an additional amount of the aldehyde product as a white solid (12 g, 80%). 1H NMR (CDCl3) □: 2.54 (s, 3H), 8.73 (s, 1H), 8.85 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCCBr
Reactant: CC1=COc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccccc2C(=O)N1CCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of 4,5-dihydro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 20 ml of dimethylformamide, then 68 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated at room temperature for 1 hour, then 0.78 ml (4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated for 6 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]=[C:13]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]1)[CH2:14][C:15](O)=[O:16].CC(C)N=C=NC(C)C>C1COCC1>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:16])[CH2:14][C:13](=[O:12])[N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:32])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: CNC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(NC(=O)CC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Reaction time: 8 h
Yield: 39.2 %

Procedure:
4-Amino-N-methyl-benzamide (40 g, 0.3 mol) was added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.3 mmol) and DIC (50 mg, 0.4 mmol) in THF (2 mL) and the mixture was stirred overnight. The resulting precipitate was filtered and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (methanol in chloroform) to afford 56 mg (40%) of N-methyl-4-{3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionylamino}-benzamide. LCMS: 477.17 (M+1)+, 94.5%, 1H NMR: (DMSO-d6): δ 7.8 (m, 2H), 7.6 (m, 4H), 7.4 (m, 1H), 4.0 (m, 2H), 3.8 (m, 4H), 3.6 (m, 3H), 3.2 (m, 2H), 3.0 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]#[N:22])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.[OH-].[K+].[CH3:25]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]([CH3:25])[C:21]#[N:22])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)C#N)c3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of acetonitrile 18 (0.200 g, 0.682 mmole) in 10 mL dimethylformamide was added pulverized potassium hydroxide (0.046 g, 0.818 mmole) and methyl iodide (0.161 g, 0.818 mmole). After stirring at rt for 2 hours, the orange reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 95:5) to afford 0.087 g (42%) of propionitrile 19 as a white solid. Used as is for conversion to 21, infra.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Brc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 188.6 %

Procedure:
To a benzene solution of 5.05 g (0.051 mole) of phosgene in 50 ml of benzene at 10° C. under nitrogen gas was added dropwise 15.5 g (0.047 mole) of 1-benzyl-3-(3-bromophenoxy)pyrrolidine in 50 ml of dry benzene. The reaction mixture was stirred for 6 hr, diluted with ice-water mixture. The benzene layer which developed was separated and dried over magnesium sulfate and concentrated in vacuo to give 27 g of oil. The oil was triturated with hot 30/60 petroleum ether and the mixture stirred overnight. The petroleum layer was decanted and the oil again treated with fresh petroleum ether. The oil was again separated to give 20 g of oil crude product.