Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: FC(F)(F)c1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-(Trifluoromethyl)[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C@@H:4]([CH3:8])[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:30][NH:31][CH3:32].C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C@@H:4]([CH3:8])[C:5]([N:31]([CH3:32])[CH3:30])=[O:6])[CH3:2]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)O
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)N(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
The product of Example 4 (3 g, 10 mmol) was dissolved in dichloromethane (10 ml), oxalyl chloride (2.6 ml, 30 mmol) was added dropwise, and it was reacted at room temperature for 1 hr, then the reaction solution was concentrated to give a pale yellow oil which was further dissolved in dichloromethane. And then the resulted solution was added dropwise to an ice-water bath cooled solution of dimethylamine hydrochloride (1.6 g, 20 mmol) and triethylamine (4.3 ml, 30 mmol) in dichloromethane, then the mixture was slowly warmed to room temperature to react for 1 hour. The pH thereof was adjusted to about 7 with 1N hydrochloric acid, then it was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized with petroleum ether and ethyl acetate to give a white solid 3.1 g, yield: 95%. 1HNMR (300 MHz, CDCl3): δ 7.3-7.5 (5H, m), 7.2 (1H, m), 6.7-6.8 (3H, m), 5.0 (2H, s), 2.8-2.9 (1H, m), 2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.8-1.9 (1H, m), 1.4-1.6 (1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8, 14.1). ESI-MS: 326.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[O:4][C:5]([CH3:14])([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:14][C:5]1([CH3:13])[O:4][C:3](=[O:15])[C:2]([NH:1][CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: CC1(C)OC(=O)C(N)=C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)NC1=C(c2ccccc2)C(C)(C)OC1=O
Temperature: 130 °C

Procedure:
A mixture of 3-amino-5,5-dimethyl-4-phenyl-2(5H)-furanone (175 mg, 0.86 mmol), methyl 2-bromo-4-methylpentanoate (360 mg, 1.73 mmol) and cesium carbonate (310 mg, 0.95 mmol) in DMF (4 mL) was heated to 130° C. for 18 h. The mixture was cooled, diluted with EtOAc and washed with water (2×) and brine, then dried over MgSO4 and concentrated. Purification by flash chromatography (20% EtOAc/hexanes) provided methyl 2-[(5,5-dimethyl-2-oxo-4-phenyl-2,5-dihydro-3-furanyl)amino]-4-methylpentanoate.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[CH:3][C:4]([F:13])=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2cc(F)cc(F)c2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)cc(F)c2N1CCCCl
Yield: 50 %

Procedure:
5,7-Difluoro-4H-benzo[1,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs2CO3 (1.08 g, 3.3 mmol), and 1-chloro-3-iodopropane (0.296 g, 1.45 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.17 g, 49%). Rf=0.66 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.67-6.58 (m, 2H), 4.55 (s, 2H), 4.16-4.10 (m, 2H), 3.59-3.52 (m, 2H), 2.21-2.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]=[C:23]=[O:24])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:23]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=[C:2]3[CH3:1])=[O:24])=[CH:19][CH:20]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2c(C)n1
Temperature: 87.5 °C
Reaction time: 3 h

Procedure:
The product from Example 178A (375 mg, 2.2 mmol) in toluene (7 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.31 mL, 2.2 mmol). After stirring at 85-90° C. for 3 hours, the mixture was cooled to room temperature and filtered. The filter cake was treated with methanolic HCl to provide the title compound as the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.17 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.45-7.60 (m, 4H), 7.32 (d, 2H, J=8.1 Hz), 7.06 (t, 1H, 5.7 Hz), 4.34 (d, 2H, 5.8 Hz), 2.84 (s, 3H), 2.75 (s, 3H); MS (ESI+) m/z 383/385 (M+H, 79Br/81Br).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:15]([NH:17][CH3:18])=[O:16])=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:12]=[C:11]1[CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH3:32]C1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[C:15](=[O:16])[N:17]([CH3:32])[CH2:18][N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:13]=2[N:12]=[C:11]1[CH2:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1nc(Nc2ccc(Cl)cc2Cl)c(C(=O)NC)n1COCc1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nc2c(n1COCc1ccccc1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A solution of 1-benzyloxymethyl-4-[(2,4-dichlorophenyl)amino]-2-ethyl-N-methyl-1H-imidazole-5-carboxamide (2.70 g, 6.23 mmol) dissolved in toluene (100 mL) was treated with paraformaldehyde (8.0 g) and p-TsOH.H2O (0.67 g, 3.52 mmol). The reaction mixture was heated at reflux for 15 min. The mixture was cooled to rt, and transferred to a separatory funnel containing saturated aqueous NaHCO3 (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in hexanes) to afford 7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (1.6 g, 58% yield) as a colorless amorphous solid: 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=2.2 Hz, 1H), 7.34-7.29 (m, 5H), 7.19 (dd, J=8.4, 2.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 5.84 (s, 2H), 4.85 (s, 2H), 4.71 (s, 2H), 2.97 (s, 3H), 2.77 (q, J=7.7 Hz, 2H), 1.28 (t, J=7.7 Hz, 3H); HRMS (ESI) m/e 445.1212 [(M+H)+, calcd for C22H23N4O2Cl2 445.1198].
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC(CO)CC3)cc1OCC2
Yield: 48 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4-piperidine methanol, were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from methanol to give 372 as a white solid (69 mg, 48%). LCMS: RT=2.57 min, [M+H]+=410. 1H NMR 400 MHz (DMSO-d6) δ: 9.10 (1H, s), 7.90 (1H, s), 7.84 (1H, s), 6.32 (1H, s), 5.99-5.90 (1H, m), 4.54-4.44 (5H, m), 4.34 (2H, d, J=13.11 Hz), 3.28 (2H, t, J=5.64 Hz), 2.84 (2H, t, J=12.55 Hz), 1.71 (2H, d, J=13.74 Hz), 1.65 (1H, m), 1.49 (6H, d, J=6.60 Hz), 1.13 (2H, t, J=12.33 Hz)
Reaction SMILES: [NH3:1].[O:2]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[O:2]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:1])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
Saturated with anhydrous ammonia a solution containing 23 g (0.1 mole) of 3-phenoxybenzoyl chloride and 250 ml of AR chloroform. Continued stirring for 30 min., chilled to 0° and filtered. The product was pulverised, triturated in cold water and oven-dried to give 21.3 g, m.p. 127°-128°.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24]([OH:32])(=[O:31])[C:25]([CH2:27][C:28]([OH:30])=O)=[CH2:26]>C1(C)C(C)=CC=CC=1>[C:24]([O:32][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:31])[C:25]([CH2:27][C:28]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:30])=[CH2:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Product: C=C(CC(=O)OCCCCCCCCCCCCCCCCCCCCCC)C(=O)OCCCCCCCCCCCCCCCCCCCCCC

Procedure:
In 800 g of xylene, 1641 g (2.2 moles) of dibehenyl itaconate of the formula, C22H45OCOCH2C(═CH2)COOC22H45, obtained by a reaction between behenyl alcohol and itaconic acid, and 875 g (1.0 mole) of the organopolysiloxane having mercapto groups at both terminals represented by the following formula were reacted in the presence of 1 g of triphenylphosphine as a catalyst at 130° C. for 5 hours. 2440 g, corresponding to a yield of 97%, of Silicone wax (H) was obtained by stripping the solvent.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[C:8]([F:26])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:9]3[CH:24]=[CH:25][C:6]([Cl:5])=[CH:7][C:8]=3[F:26])=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
1,2-Dibromoethane (5.4 ml, 62 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5 g, 15.6 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (8.6 g, 62 mmol) in DMF (50 ml) and the mixture stirred for 18 hours at ambient temperature. Water was added and the resulting precipitate was collected by filtration. The solid was purified by chromatography on neutral alumina eluting with methylene chloride/methanol (95/5). The semi-purified product was repurified by chromatography on silica eluting with methylene chloride/methanol (97/3). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (3.58 g, 54%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CC[C@H]1CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CC[C@H]1COS(C)(=O)=O
Yield: 92.7 %

Procedure:
To a solution of the compound (18) (8.50 g; 0.0733 mol) and triethylamine (22.20 g; 0.22 mol) in chloroform (100 ml), methanesulfonyl chloride (16.79 g; 0.147 tool) is dropwise added under ice-cooling, and the resultant mixture is stirred for 7 hours at room temperature. The reaction mixture is washed with water, dried and concentrated under reduced pressure to give trans-1,2-bis (methanesulfonyloxymethyl)cyclobutane (19) (18.50 g). m.p., 60° to 62° C. (crystallized from ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([O:15]C2CCCCO2)[CH3:14])[CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:15])[CH3:14])[CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(OC1CCCCO1)C1CCN(C(=O)OC(C)(C)C)C1C
Agent: Cl
Solvent: CC(=O)O
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)C1C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
To a solution of 1-t-butyloxycarbonyl-2-methyl-3-(1-tetrahydropyranyloxyethyl)pyrrolidine (10.2 g) in acetic acid (100 ml) was added 6N-hydrochloric acid solution (100 ml) at ambient temperature. After stirring for 12 hours, the solvent was evaporated. The residue was dissolved into a mixture of tetrahydrofuran (50 ml) and water (50 ml). To the solution was dropwise added allyl chloroformate (4.1 ml) at 0° C., while adjusting pH to 9~10 with 30% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and then the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated to give 1-t-butyloxycarbonyl-3-(1-hydroxyethyl)-2-methylpyrrolidine 7.45 g).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([OH:7])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3]
Reactant: CSCCl
Reactant: C/C=C(\C)C(=O)O
Solvent: CCN(CC)CC
Product: C/C=C(\C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting tiglic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 95° C./12 mm Hg, nD20 1.4890.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: O=C(O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A mixture of 2-hydroxyphenylacetic acid (1.52 g, 0.01 mol), 4-fluoro-3-nitrobenzotrifluoride (2.09 g, 0.01 mol), potassium carbonate (2.76 g, 0.02 mol) in dimethylformamide (10 mL) was heated at 95° C. 16 h. The solvent was evaporated, the residue was acidified with dilute HCl, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid). Recrystallization from EtOAc/hexane gave the title compound; mp 165°-167° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:21][CH:20]2[CH2:22][CH:16]([CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)[CH2:15]1>CC#N>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][CH2:13][N:14]2[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]3)[CH2:21]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCN)C2)C1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCNCc3ccc(C#N)cc3)C2)C1
Temperature: 40 °C
Reaction time: 32 h
Yield: 74 %

Procedure:
p-Cyanobenzylbromide (0.765 g; 3.9 mmol) was added to a stirred solution of tert-butyl 7-[2-aminoethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.04 g; 3.9 mmol; from step (a) above) in MeCN (15 mL) and the reaction mixture was stirred at 40° C. for 32 h. The solvent was evaporated and the residue subjected to column chromatography (EtOAc) to give the title compound in a 74% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](Cl)([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1>ClCCl>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:17][C:10]2[CH2:11][O:12][CH2:13][C:14]([F:16])([F:15])[C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=2)=[CH:47][CH:46]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@]1(c2cc(Br)ccc2F)N=C(N)COCC1(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A7.1) (9.0 mmol) in dichloromethane (150 ml) was subsequently added at 0° C. triethylamine (18.0 mmol) and 4,4′-dimethoxytriphenylmethyl chloride (9.9 mmol) and stirring was continued at 22° C. for 2 hours. For the workup, the mixture was washed with saturated an aqueous solution of ammonium chloride. The organic layer was dried, evaporated at reduced pressure, and the residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give pure (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (A8.1) as a colorless foam. MS (ISP): m/z=639.3 [M+H]+ and 641.4 [M+2+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.O>[Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:24]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:9]=1)=[S:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline (80 mg, 0.308 mmol) and NaHCO3 in CHCl3:H2O (2.5:1, 7 mL) with thiophosgene at 0° C. The solution was allowed to warm to 23° C. and the reaction was continued overnight. The CHCl3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10(m, 1H).
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[CH:2]=[CH2:3].[C:7]([O:16]CC)(=[O:15])/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11]>>[CH2:8]([C:7]([OH:16])=[O:15])[CH:9]([C:10]([OH:12])=[O:11])[C:2]([C:1]([OH:5])=[O:4])=[CH2:3]
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)/C=C/C(=O)OCC
Product: C=C(C(=O)O)C(CC(=O)O)C(=O)O

Procedure:
A mixture of 4.3 parts by weight of methyl acrylate, 7.7 parts by weight of diethyl fumarate and 0.5 parts by weight of diphenyl(4-oxy-butyl)phosphine is boiled and refluxed for 10 hours in a nitrogen stream. Distillation of the reaction product mixture gave a 3-butene-1,2,3-tricarboxylic acid (1,2-diethyl, 3-methyl) ester. The ester of the tricarboxylic acid is converted to a high molecular weight carboxylic acid-producing composition by reacting same with a chlorinated polyisobutene having a molecular weight of about 1000 and a chlorine content of about 4.5% at a temperature ranging from about 80°-120° C. A mixture of approximately 2000 parts by weight of mineral oil, 3.0 equivalents of a polyoxyethylene triamine having an average molecular weight of about 1000 and approximately 3.0 equivalents of the above-mentioned high molecular weight tricarboxylic acid-producing composition is heated to temperatures of 150°-200° C. over a period of 15 to 20 hours. The resulting product is filtered to give a homogeneous mineral oil solution of the acylated polyamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1O.P(Br)(Br)([Br:15])=O.O.C(=O)([O-])O.[Na+]>ClCCl>[Br:15][C:3]1[N:4]=[N:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Br:1]
Reactant: Oc1nnc(C(F)(F)F)cc1Br
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)c(Br)nn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-pyridazin-3-ol (D3) (4.0 g, 16.4 mmol) and phosphorus oxybromide (28.2 g, 98.4 mmol) was stirred at 60° C. for 4 h. After this period, the reaction mixture was poured into a mixture of ice and water, diluted with dichloromethane and neutralized with a saturated solution of sodium hydrogen carbonate. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D5 (2.28 g, 46%) as a solid. C5HBr2F3N2 requires 305; Found 306 (MH+).