Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Na+].C([O-])(=O)C.[Na+].C1(=O)OCCO1.[C:14]([O:23][CH:24]([O:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:25])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1.O=O.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[F:32][C:33]1[CH:34]=[C:35]([F:39])[CH:36]=[CH:37][C:38]=1[C:20]1[CH:21]=[C:15]([C:14]([O:23][CH:24]([O:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:25])=[O:22])[C:16]([OH:17])=[CH:18][CH:19]=1
Reactant: CCOC(=O)OC(C)OC(=O)c1ccccc1O
Reactant: Fc1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O=C1OCCO1
Solvent: CC(=O)O
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C

Procedure:
A glass-lined autoclave is charged with 1 mmole of palladium acetate, 5 mmole of sodium chloride, 1.6 mmole of sodium acetate, 2 mmole of phosphomolybdenovanadic acid, 10 g of ethylene carbonate, 5.0 ml of acetic acid, 465 mmole of 1-(ethoxycarbonyloxy)ethyl salicylate, and 510 mmole of m-difluorobenzene. The mixture is stirred for 48 hours at 90° C. and under 200 psi oxygen pressure. The solution is cooled to 25° C. and excess m-difluorobenzene is removed by distillation. Fifty ml of water and 150 ml of toluene are then added to the residue. The pH is adjusted to 7-8 with aqueous sodium hydroxide (80 mmoles). The layers are separated and the aqueous solution is extracted with 150 ml of toluene. The toluene and then the excess starting materials are removed by distillation. The resulting residue is recrystallized from methanol to obtain pure 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:26])[CH2:6]1)[C@:19]1([CH3:20])[C:14](=[C:15]([CH3:25])[C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[C:27]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>COC(OC)(C)C.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:26])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([C:15]([CH3:25])=[C:16]([O:24][CH3:27])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=C(C)C(=O)CC[C@@]43C)[C@H]12
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)OC
Product: COC1=C(C)C2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 6 h
Yield: 512.7 %

Procedure:
5.0 g of 15α-acetoxy-4-methylandrost-4-ene-3,17-dione is stirred at 80° C. in 40 ml of 2,2-dimethoxypropane with 500 mg of pyridinium 4-toluenesulfonate. After 6 hours, 1 ml of triethylamine is added thereto; the mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum. The crude product is chromatographed on silica gel containing 2% triethylamine with a hexane-ethyl acetate gradient, thus obtaining 3.8 g of 15α-acetoxy-3-methoxy-4-methylandrosta-3,5-dien-17-one as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.C(#N)C.C[Si]([CH:19]=[N+:20]=[N-:21])(C)C.C(OCC)C>O1CCCC1>[N+:20](=[CH:19][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[N-:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)Cc1ccc(I)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 4-iodophenylacetyl chloride (12) prepared above was dissolved in tetrahydrofuran (THF) (2 mL) and acetonitrile (2 mL) and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 4.00 mL, 8.00 mmol), which was stirred overnight (14 h) after warming up to room temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=1/1) to give 1-diazo-3-(4-iodophenyl)propan-2-one (13) as a pale yellow solid (635 mg, 2.22 mmol, 54.9%, 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:24](=[O:25])[C:21]1[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)cc1
Yield: 71.7 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 2.00 g (0.00869 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 2.74 g (0.01738 mol) of p-toluoyl chloride with the exception that after removing ethyl acetate the resultant solid was purified by crystallization from an ethyl acetate/hexane solution containing a small amount of methanol, followed by recrystallization from an ethyl acetate/methanol solution, to provide 2.17 g of the desired titled compound (m.p. 209°-214° C.).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:21][N:20]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:27])=[O:26])[C:19](=[O:31])[CH2:18]1)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:21][N:20]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:27])=[O:26])[C:19](=[O:31])[CH2:18]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(O)c1
Reaction time: 20 h
Yield: 85.1 %

Procedure:
3-[4-(2-Benzyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzamide (1.8 g, crude) was dissolved in 50 mL of EtOH and 20 mL of EtOAc. 10% Pd/C (200 mg) was added and the mixture was stirred under H2 for 20 h. After filtration and concentration, the residue was purified on silica gel to give 1.2 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)n1
Yield: 78.4 %

Procedure:
To a solution of tert-butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (200 mg, 0.64 mmol) and 2,4,5-trichloropyrimidine (123 mg, 0.67 mmol) in N,N-dimethylformamide (2.9 mL) was added potassium carbonate (264 mg, 1.91 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as a light brown gel (231 mg, 79%). LCMS for C17H16Cl2N5 [(M-Boc+H)+H]+: m/z=360.0, 362.0.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.Cl.[CH3:18][N:19]([C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[O:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[CH:27][CH:26]=1)[C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C(N(CC)CC)C>O1CCCC1>[F:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]([N:33]2[CH2:34][CH2:35][O:36][C@@H:31]([C:28]3[CH:27]=[CH:26][C:25]([N:19]([CH3:18])[C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)=[CH:30][CH:29]=3)[CH2:32]2)[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)[C@@H]1CCOC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1)[C@@H]1CCOC1
Yield: 39 %

Procedure:
2-Chloro-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.26 g, 1.09 mmol) was added to a solution of (2S)-2-(4-(N-methyl-N-((3R)-tetrahydrofuran-3yl)amino)phenyl)morpholine hydrochloride obtained in Reference Example 6 (0.4 g, 1.19 mmol) and triethylamine (0.6 g, 5.93 mmol) in tetrahydrofuran (20 ml) at room temperature for 15 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoropyridin-4-yl)-2-((2S)-2-(4-(N-methyl-N-((3R)-tetrahydrofuran-3-yl)amino)-phenyl)morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.20 g, 39%) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@@H:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:12][C@@H:10]1[CH2:11][C@H:8]([NH2:7])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of (cis-3-benzyloxycyclobutyl)carbamic acid tert-butyl ester (2.40 g, 8.67 mmol) in DCM (20 mL) was added TFA (4 mL) and the mixture stirred at RT for 3 h. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and loaded onto SCX-2 (20 g). The cartridge was washed with DCM then MeOH then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow oil (1.48 g, 95%). 1H NMR (CDCl3, 400 MHz): δ 7.36-7.30 (5H, m), 4.40 (2H, s), 3.73-3.61 (1H, m), 3.06-2.93 (1H, m), 2.72-2.58 (2H, m), 1.74-1.61 (2H, m), 1.47 (2H, s, br).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[NH2:15][OH:16]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=[N:15][OH:16])=[CH:4][CH:3]=1
Reactant: C[C@](C=O)(c1ccc(Br)cc1)C1CC1
Reactant: NO
Solvent: CCO
Product: C[C@](C=NO)(c1ccc(Br)cc1)C1CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To the crude solution from the previous step (solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal) retained in the reactor is charged 6.2 kg of 200 proof ethanol. The batch was then concentrated via vacuum distillation (Tjacket NMT 50° C.) to ˜7 L. To the batch was charged 6.2 kg of 200 proof ethanol. The batch temperature is then adjusted to 0±5° C. To the cooled batch is charged hydroxylamine (50 wt % aqueous solution, 1.0 kg, 15.4 mol, 1.5 equiv) at a rate to maintain the internal temperature of the batch <30° C. The batch is then agitated at an internal temperature of 20±5° C. for 2 h. An HPLC sample is removed to determine conversion (target >97 A % conversion 220 nm, for this batch: >99 A % conversion). To the batch is charged isopropyl acetate (19 kg) and 5 wt % aqueous sodium chloride (9.2 kg). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut (mass aqueous cut 7.6 kg). To the batch is charged 5 wt % aqueous sodium chloride (9.2 kg). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut (mass aqueous cut 14.5 kg). The batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.). To the batch is charged acetonitrile (10 L). The batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.). The batch was drained and the reactor rinsed with acetonitrile (2 L). The rinse was combined with the original batch and the resulting solution massed 7.75 kg (HPLC purity: 80.4 A % (220 nm), Karl Fisher 3.2% water and the Proton NMR wt % assay (with dimethyl fumarate as an internal standard) is 28.0 wt % (2.76 kg, 78.7% yield) of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (8) for the two step process. The solution is used as is for the following step.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-].CC1CC=CCC=1>[Pd].C(O)C>[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To an ice-cooled suspension of palladium on activated carbon (4.50 g, 10% w/w) and (R)-5-(2-azido-1-(tert-butyldimethylsilyloxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one (4.50 g, 10.0 mmol) in ethanol (50 mL) was added drop-wise 1-methyl-1,4-cyclohexadiene (11.0 mL, 97.9 mmol). The coolant was removed, and the suspension stirred at ambient temperature for 10 minutes and then heated to 50° C. for one hour. The reaction mixture was allowed to cool and the suspension filtered through celite. The filter-cake was washed with further ethanol, and the combined filtrates concentrated under reduced pressure. The residue was triturated with acetonitrile to afford the title compound (3.03 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 84 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.50 (s, 3H), 2.89-3.09 (m, 4H), 3.68-3.88 (m, 4H), 4.14 (s, 3H), 6.99-7.78 (m, 7H), 7.76 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([N:12]=[N+]=[N-])[CH3:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([NH2:12])[CH3:11]
Reactant: C[C@@H](Cc1cc(F)ccc1Br)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N)Cc1cc(F)ccc1Br
Reaction time: 4 h
Yield: 14.9 %

Procedure:
To a solution of (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethyl azide (1.00 g, 3.87 mmol) in 20 mL of THF and 4 mL of water was added PPh3 (2.03 g, 7.74 mmol) and the mixture was stirred for 4 h. The solvent was evaporated and the residue was purified by silicagel column eluting first with DCM, then DCM:MeOH:NH4OH (94:5:1). The fraction with product was evaporated to give (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamine (134 mg, 15%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 1H), 6.97 (m, 1H), 6.83 (m, 1H), 3.28 (m, 1H), 2.66-2.87 (m, 2H), 1.68 (s, 2H), 1.17 (d, J=6.21 Hz, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[OH:17][CH2:18][CH2:19][O:20][CH2:21]C1C=C(C=CC=1)C#N>>[OH:16][N:15]=[C:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:21][O:20][CH2:19][CH2:18][OH:17])[CH:12]=1)[NH2:1]
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Reactant: N#Cc1cccc(COCCO)c1
Product: NC(=NO)c1cccc(COCCO)c1

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-[(2-hydroxyethoxy)methyl]benzonitrile obtained in step 1 (0.90 g; 5.08 mmol) to give the title compound as a yellowish oil (1.26 g, quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (s, 1H), 7.64 (bs, 1H), 7.60-7.55 (m, 1H), 7.37-7.31 (m, 2H), 5.75 (bs, 2H), 4.66-4.62 (m, 1H), 4.50 (s, 2H), 3.56-3.51 (m, 2H), 3.48-3.44 (m, 2H). LC/MS (Method B): 211.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15](C5C=CC=CN=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:44](O)([C:46](F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:12]5[CH:13]=[N:14][CH:9]=[CH:44][CH:46]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccn3)CO4)cc2)CCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3cccnc3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 56 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-(pyridin-2-yl)-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (8 mg, 56% yield). LCMS (Method A) RT=3.73 min, M+1=474. 1H NMR (500 MHz, CDCl3): 8.99 (1H, d), 8.86 (1H, dd), 8.30 (1H, dt), 7.75 (1H, dd), 7.48 (2H, d), 7.42 (2H, d), 7.37 (1H, s), 7.31-7.20 (3H, m), 7.01 (2H, d), 5.78 (2H, s), 2.83-2.72 (2H, m), 2.63-2.54 (2H, m), 2.30-2.17 (1H, m), 2.05-1.90 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])=[CH:4][CH:3]=1.[C:17](O)(=[O:19])[CH3:18].C(OC(=O)C)(=O)C>CCOCC>[C:17]([N:8]([CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:19])[CH3:18]
Reactant: CCCCCCC(C)Nc1ccc(I)cc1
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCC(C)N(C(C)=O)c1ccc(I)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 70 %

Procedure:
A flask containing N-(4'-iodophenyl)-2-amino octane (1.50 g, 4.5 mmol) was charged with acetic acid (15 ml) and acetic anhydride (15 ml). The reaction flask was immersed in an oil bath which was warmed to 70° C. over a period of 0.5 hr. After stirring for 19 hrs, the reaction was allowed to cool, diluted with ether (200 ml), washed with water (2×50 ml), saturated aqueous sodium bicarbonate (4×50 ml), water (2×50 ml) and brine (50 ml), dried (Na2SO4), filtered, and evaporated in vacuo. Flash column chromatography (silica, 1:4; EtOAc:hexanes) provided N-acetyl-N-2-octyl-4-iodoaniline (1.48 g, 70%) as a white solid. Mp 60°-62° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH2:13])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (0.5 g) and DMF (0.1 ml) in DCM (10 ml) was added dropwise oxalyl chloride (0.6 ml). After stirring for 2 h, ammonia gas was purged through. After completion of reaction by tlc, the solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated in vacuo to yield the title compound, 0.18 g
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3].C(O)[CH2:17][CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH2:17][CH2:18][OH:19])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1CC(=O)OC
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCNc1ccccc1CC(=O)OCCCO

Procedure:
A mixture of 2.25 g. of methyl 2-(allylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 2-(allylamino)phenylacetate.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:18](OC(OCC)OCC)C>>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[N:1]=[CH:18][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: COc1cccc(C(=O)Nc2nnn[nH]2)c1N
Product: COc1cccc2c(=O)n(-c3nnn[nH]3)cnc12

Procedure:
A suspension of 5.3 g of 2-amino-3-methoxy-N-(1H-tetrazol-5-yl)benzamide in 30 ml of triethoxymethane was refluxed for 14 hours to give 8-methoxy-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 260°-261° C. (dec) after recrystallization from dimethylformamide.
Reaction SMILES: [N:1]([CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([Br:25])[CH:24]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([CH:4]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH2:1])[CH:24]=[C:23]([Br:25])[CH:22]=1
Reactant: [N-]=[N+]=NC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Temperature: 60 °C
Yield: 68 %

Procedure:
To a stirred reaction of 2-(8-(3-(azido(phenyl)methyl)-5-bromophenoxy)octyl)-1,3-dioxolane (1.19 g, 2.45 mmol) in tetrahydrofuran (15 mL) and water (0.3 mL), was added triphenylphosphine (0.71 g, 2.69 mmol). The reaction mixture was heated to 60° C. for 16 hours. The reaction mixture was cooled, concentrated and purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford impure title compound as a colourless oil (0.77 g, 68%).