Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(Cl)[Cl:21].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:21])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a N2 purged round bottom flask was added 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (2.10 g, 7.20 mmol) and anhydrous CHCl3 (30 mL). The solution was cooled to 0° C. prior to the addition of oxalyl chloride (1.3 mL, 14 mmol) and anhydrous DMF (1 mL). The reaction solution was stirred 1 h under N2. The solution was concentrated under reduced pressure on the rotavapor to afford 2.4 g crude product. The crude acid chloride was used without further purification in the next reaction step.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccncc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 3-methyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1) in DCM (5 mL) was added TFA (1.445 g, 976.4 μL, 12.67 mmol). The reaction mixture was stirred for 48 h at RT, then the solvent was removed under reduced pressure. The crude was redissolved in MeOH and loaded into a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 2-methyl-1-(3-nitro-4-pyridyl)piperazine (334 mg, 71%). MS (ES+) 223.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Reactant: NCCCCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCCO)n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 216 mg (0.444 mmol) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea, 87.0 mg (0.976 mmol) 4-amino-butan-1-ol and 5 ml THF was stirred at r.t. for 12 h. The reaction mixture was evaporated and the residue purified by chromatography on silica (dichloromethane/ethanol 96:4). Yield 127 mg (58%) of the title compound.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:1]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1ccc(Cl)cc1Cl
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (40 ml of 70% w/v solution) was added slowly with stirring to glacial acetic acid (42 g). The temperature rose to reflux and tetrabutylammonium hydrogen sulphate (0.5 g) and 2,4-dichlorobenzyl chloride (100 g) were added and the mixture heated under reflux for eight hours. The mixture was cooled to 70°-75° C. and aqueous sodium hydroxide (35 ml of 70% w/v solution) added. The temperature was maintained in the range 70°-75° C. for 30 minutes. The product was extracted into petroleum ether (boiling range 80°-100° C. 90 ml) at 75° C. and the organic extract was diluted with petroleum ether (150 ml), washed with dilute aqueous hydrochloric acid, and filtered. The filter was washed with petroleum ether (40 ml) and the filtrate and washings combined and allowed to cool to give crystals of 2,4-dichlorobenzyl alcohol having a purity of 99.8% and in a yield of 95%.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3](OC)=[O:4].CC[O-].[Na+].[O:14]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[O:21][N:20]=2)[CH2:15]1>CO>[OH:4][C:3]1[CH2:2][CH:24]([C:22]2[O:21][N:20]=[C:19]([CH:16]3[CH2:17][CH2:18][O:14][CH2:15]3)[CH:23]=2)[CH2:25][C:26](=[O:28])[CH:27]=1
Reactant: CC(=O)C=Cc1cc(C2CCOC2)no1
Reactant: COC(=O)CC(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)CC(c2cc(C3CCOC3)no2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
10.6 g of dimethyl malonate in 300 ml of methanol were initially taken, and 14.4 g of a 30% strength sodium ethylate solution in methanol were added at room temperature. Thereafter, 16.0 g of 4-[tetrahydrofur-3-yl-isoxazol-5-yl]-3-buten-2-one were added and the mixture was stirred for 1 day at 25° C. The residue which remained after the solvent had been removed was taken up in 10% strength sodium hydroxide solution and stirred for 24 hours at 25° C. The sodium hydroxide phase was washed with methyl tert-butyl ether, acidified to pH 2 with concentrated hydrochloric acid and then heated at 85° C. for 2 hours. The solid formed was filtered off, washed with water and dried. 12.3 g of a beige solid of melting point 142°-144° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([OH:28])=[O:27].[CH3:29]N1C=CCN(C2C=CC(C)=CC=2)N1>CCOCC>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCCCCCCCCCCCCOc1ccc2c(C)c(C(=O)O)oc2c1
Reactant: Cc1ccc(N2CC=CN(C)N2)cc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc2c(C)c(C(=O)OC)oc2c1
Reaction time: 1 h

Procedure:
0.4 g (1.03 mmoles) of 3-methyl-6-tetradecyloxy-benzofuran-2-carboxylic acid and 0.3 g (2.00 mmoles) of 1-methyl-3-p-tolyltriazine are stirred in ether and refluxed for 15 minutes. The mixture is then allowed to stand at room temperature for 1 hour. It is then refluxed for 15 minutes. The reaction mixture is worked-up by extraction with diethyl ether and HCl. The ether is distilled off and is replaced by dioxane. The resultant mixture is heated on a steam bath for 1 hour. It is then extracted with diethyl ether/HCl, H2O and NaHCO3 (aq.). The extract is evaporated and the ether replaced with methanol. The methyl ester of 3-methyl-6-tetradecyloxy-benzofuran-2-carboxylic acid is allowed to crystallize from the mixture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[C@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C@@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1
Product: CC(=O)c1cccc(O[C@H](CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[(2R)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 485.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2](C)=[CH:3][C:4]1[CH:13]=[C:12]2C(C(C)=CC(=O)[O:11]2)=CC=1.[C:17]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])(=O)[CH2:18][CH2:19][CH3:20]>>[Cl:1][CH2:2][CH:3]=[CH:4][C:13]1[C:12]([OH:11])=[CH:20][CH:19]=[C:18]2[C:17]=1[O:22][C:23](=[O:27])[CH:24]=[C:25]2[CH3:26]
Reactant: CC(Cl)=Cc1ccc2c(C)cc(=O)oc2c1
Reactant: CCCC(=O)OC(=O)CCC
Product: Cc1cc(=O)oc2c(C=CCCl)c(O)ccc12
Temperature: 180 °C

Procedure:
A solution of 7-(2-chloro propenyl)-4-methyl coumarin (120 g, 0.48 mol) in a mixture of p-disopropyl-benzene (1 L) and n-butyric anhydride 160 mL was heated to 180° C. for 24 hours. The organic layer was evaporated under reduced pressure and residue recrystallizated from ethanol to afford 75 g of the desired compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][N:28]1[C:29](=[O:38])[C:30]2=[CH:37][CH:36]=[CH:35][CH:34]=[C:31]2[C:32]1=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1cccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reaction time: 15 h
Yield: 13.3 %

Procedure:
To a suspension of 2-thiophenemethanol (4.15 mL, 43.64 mmol), triphenylphosphine (12.59 g, 48.01 mmol) and N-hydroxyphthalimide (7.83 g, 48.01 mmol) in THF (120 mL) at 0° C. was added dropwise diethylazodicarboxylate (7.56 mL, 48.01 mmol) in THF (20 mL). The reaction mixture was allowed to stir for 15 h after which the solvent was removed under vacuum to dryness. Et2O (50 mL) was added to triturate the triphenylphosphine oxide and diethylhydrazinedicarboxylate, which was filtered off and washed with a little Et2O. The ethereal solution was concentrated under vacuum to give a residue which was filtered through a pad of silica (eluting with EtOAc/PE, 3:7). Removal of the solvent under reduced pressure afforded N-(thiophen-2-ylmethoxy)phthalimide (1.50 g, 13%), as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:7]=2[CH:34]=1.O.NN>C(O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH2:17])=[CH:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:7]=2[CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 28, 8-trifluoromethyl-1-(phthalimidomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol, to give 8-trifluoromethyl-1-(aminomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.CN([CH:36]=[O:37])C>C1COCC1>[CH2:16]([C:3]1[C:2]([CH:36]=[O:37])=[CH:11][C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5.43 g of 3-bromo-2-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 110 ml of THF was cooled to −78° C. with an acetone/dry ice bath and treated dropwise with 14.5 ml of butyllithium 1.6M in hexane (1.5 eq.). The mixture was kept at −78° C. for 1 hour. DMF (2.4 ml) was added at −78° C. The reaction mixture was stirred at −78° C. for 15 min. then was allowed to warm to room temperature for 2 hours. The mixture was quenched with water (100 ml) and the pH was adjusted to 2 with hydrochloric acid 25%. The mixture was extracted with 3 portions of 100 ml of ether. The combined organic extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (SiO2, hexane then 5% ethyl acetate/hexane) yielding 4.41 g of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[C:24]#[CH:25].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:25][C:24]#[CH:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: C#CCBr
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and propargyl bromide with sodium hydride in dimethylformamide there is obtained 1-[4-bromo-2-fluoro-5-(2-propynyloxy)-phenyl]-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 136°-138° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCCC1
Yield: 60.5 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with pyrrolidine (0.36 ml, 4.3 mmol) to give the title compound as a solid (130 mg, 60%), except that the mixture was heated at 45° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM). NMR Spectrum 1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.38 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.79 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.51 (s, 1H), 7.77-7.71 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 11.07 (br s, 1H); Mass spectrum MH+ 500.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].CS[C:7]1[N:8]=[N:9][CH:10]=[CH:11][N:12]=1.C(=O)=O>C1C=CC=CC=1.O>[CH2:2]([O:4][C:7]1[N:8]=[N:9][CH:10]=[CH:11][N:12]=1)[CH3:3]
Reactant: CSc1nccnn1
Reactant: CCO
Agent: O=C=O
Agent: [Na]
Solvent: O
Solvent: c1ccccc1
Product: CCOc1nccnn1
Temperature: 0 °C
Reaction time: 0.57 h

Procedure:
Sodium (30.8g - 1.34g.atm) is reacted with 6 pints of absolute ethyl alcohol below 43° C. 3- Methylthio-1,2,4-triazine (159 g. - 1.25 m) is added, and the black mixture stirred under nitrogen at 40° to 44° C. for 34 minutes. The heating bath is replaced by ice water and carbon dioxide gas bubbled in, giving a red-orange mixture at pH 9 within 23/4 hours. Water (1.25 m) is added and carbon dioxide addition continued for 35 minutes without visible or pH change. Air is introduced for another half hour, giving a brown mixture. One liter of benzene is added and the contents filtered with suction at 19° C. The solids are slurried in a liter of water and extracted with CHCl3 several times. The combined filtrate and extracts are vacuum distilled, giving 3-ethoxy-1,2,4-triazine, b.p. 113°-115° C. at 16 mm. The pot residue is recrystallized from methanol to give 16 g. of golden brown platelets, m.p. 95°-99° C. Recrystallizing again from methanol, and finally from ethyl alcohol, yields 7.7 g. of 3,3'-diethoxy-5,5'-bis-1,2,4-triazinyl.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:21]([C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1ccccc1
Product: Nc1nnc(Oc2ccccc2)c(-c2ccccc2)n1
Yield: 14.8 %

Procedure:
6-Phenoxy-5-phenyl-1,2,4-triazin-3-amine (78 mg, 14%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.5 g, 1.99 mmol) and phenol (0.74 g, 7.90 mmol) according to the general procedure of Example 3.
Reaction SMILES: CS[C:3](=[N:12][CH3:13])[N:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[NH2:14][OH:15].Cl.NO>>[C:6]1([N:4]([CH3:5])[C:3]([NH:12][CH3:13])=[N:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: CN=C(SC)N(C)c1ccccc1
Agent: Cl
Product: CNC(=NO)N(C)c1ccccc1

Procedure:
The above compound is also made by the reaction of S-methyl-N-phenyl-N,N'-dimethylisothiourea (3.3g, 0.017 mol) with hydroxylamine (0.088 mol) generated from hydroxylamine hydrochloride (5.86g, 0.088 mol) as in Example 1. The compound was confirmed by comparison of its NMR and thin layer chromatographic Rf values with a previously prepared compound. The yield was calculated to be about 1%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21]C(=O)C)[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([OH:21])[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)c(OC(C)=O)c2)CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(Cl)c(O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
The compound of step 2 (400 mg, 1.088 mmol) was dissolved in methanol (3.5 ml), potassium carbonate (3 mg, 0.02 mmol) was added, and the mixture was stirred at room temperature for 6 h and evaporated to dryness to yield the title compound (300 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH:16]1[CH:21]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:17]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CC(O)C>C1COCC1>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[CH3:17])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of phenol 4 (1 g, 3.29 mmol) and PPh3 (1.8 g, 6.58 mmol) in THF (25 mL) was added DIAD (1.3 mL, 6.58 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. 2-Propanol (0.4 mL, 4.94 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 20 hours. The mixture was extracted with EtOAc/H2O (50 mL/50 mL) and was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the desired product 6 (913 mg, 80%).
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:35](=O)([O-])[O-].[K+].[K+].IC.Cl>C(#N)C>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH3:35])[C:21](=[O:25])[CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), and Iodomethane (404, 10 equiv) were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After being cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4 mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]([CH:32]([CH:39]2[CH2:41][CH2:40]2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=1.[H-].[Na+].Cl>C1COCC1>[CH:39]1([CH:32]([C:28]2[CH:27]=[C:26]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH:12]=3)[N:31]=[CH:30][N:29]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:41][CH2:40]1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OC2CCCCO2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OC3CCCCO3)c2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanol (189 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (174 mg) in THF (2.8 mL) was added 60% sodium hydride (25 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was cooled to 0° C., and neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane and then methanol/ethyl acetate) to give the title compound (164 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:9])[CH2:3]1>CC(C)=O>[C:4]1(=[O:9])[CH2:5][CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3]1
Reactant: O=C1CCCCC(O)C1
Solvent: CC(C)=O
Product: O=C1CCCCC(=O)C1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a 10°-20° C. solution of 20 g. (0.156 mole) of 3-hydroxycycloheptanone in 700 ml. of acetone was slowly added 54.9 ml. of 2.67M Jone's reagent (0.146 mole). The mixture was stirred 15 minutes and then quenched by addition of 12 ml. of isopropanol. The reactlon was filtered through diatomaceous earth and the filtrate concentrated on a rotovapor to about 100 ml. The residue was diluted with 300 ml. of saturated sodium chloride and then extracted with six 250 ml. portions of ether. The combined organic extract was washed with two 100 ml. portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure (aspirator) to yield an oil. Distillation of the crude oil gave 11.5 g. (58%) of the title compound as an oil.