Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=2)/[CH:9]=[CH:10]/[C:11](OCC)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].P(Br)(Br)[Br:26]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8](/[CH:9]=[CH:10]/[CH2:11][Br:26])[CH:16]=[CH:17][CH:18]=2)=[CH:2]1
Reactant: CCOC(=O)/C=C/c1cccc(-c2ccsc2)c1
Reactant: BrP(Br)Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: BrC/C=C/c1cccc(-c2ccsc2)c1

Procedure:
1.0 g of the resulting ester compound was reduced in a customary manner with lithium aluminum hydride, and then brominated by phosphorus tribromide. 0.7 g of (E)-3-[3-(3-thienyl)phenyl]-2-propenyl bromide obtained thus was dissolved in 10 ml of dimethylformamide, and 0.6 g of potassium phthalimide was added. The mixture was stirred overnight at room temperature, and the solution was worked up in a customary manner to give (E)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl] phthalimide. 0.7 g of the resulting phthalimide compound was dissolved in a mixture (3 ml) of tetrahydrofuran and ethanol (1:1), and 0.5 ml of hydrazine hydrate was added. The mixture was stirred at room temperature for 1 hour, and then worked up in a customary manner to give 0.42 g of the captioned compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1.[OH-].[Na+]>C(O)(=O)C.[Zn]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNCCC(O)c1ccccc1

Procedure:
2-Methyl-5-phenylisoxazolidine (2.0 g, 12.3 mmol) and Zn powder (1.2 g, 18.3 mmol) in 10 molar aqueous acetic acid are heated to 65°-70° C. for 4 hours. Additional Zn powder (0.4 g, 6.1 mmol) is added and heating is continued for one more hour. The reaction mixture is neutralized with sodium hydroxide and extracted with chloroform. The extract is dried K2CO3) and concentrated to give N-methyl-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:16])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(C3CCCCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(C3CCCCC3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 129.6 mg of (2S,4R)-1-acetyl-4-[(4-cyclohexylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 94.4 mg (72.9%, cis:trans=10:1) of the title compound was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:30]([NH:32][CH2:33][CH2:34][OH:35])[CH3:31]>>[CH2:30]([N:32]([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:1])[F:28])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:33][CH2:34][OH:35])[CH3:31]
Reactant: CCNCCO
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CCN(CCO)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and 2-Ethylaminoethanol were converted to yield 2-(Ethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanol as light yellow oil, MS: 433 (MH+).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][CH:22]=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:22]=[N:21][CH:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC=O)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cncn23)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (3.66 g, 11.1 mmol, prepared using J.3 from Example #2, Step C with ethyl formate) was suspended in DCE (80 mL) then POCl3 (1.08 mL, 11.6 mmol) was added. The mixture was heated to about 80° C. for about 90 min and then cooled to rt. The mixture was treated with about 50 mL saturated aqueous NaHCO3 and then stirred for about 15 min. The layers were separated and aqueous layer was extracted with DCM (40 mL). The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure to give 6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (3.46 g, 100%): LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z 313 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[C:6]([O:17][CH3:18])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([O-:13])=O)=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>ClCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[O:27][CH3:28])[C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([O:17][CH3:18])=[O:16])=[CH:15][CH:14]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 8 h

Procedure:
2.1 g (15.72 mmol) of aluminum chloride, a solution of 2.39 g (12.02 mmol) of monomethyl terephthalate chloride dissolved in 2 ml of dichloromethane and 1.2 ml (9.25 mmol) of 1,2-dimethoxybenzene dissolved in 2 ml of dichloromethane were added to 10 ml of dichloromethane, and they were stirred overnight. The reaction solution was poured into 5 g of 1 N hydrochloric acid/ice. After the treatment with chloromethane as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was washed with ethyl acetate and dichloromethane to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:22][O:21][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1Cl
Temperature: 150 °C

Procedure:
To ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate (3.9 g) are added triethoxymethane (3.1 g) and acetic anhydride (3.4 g), and the mixture is heated at 150° C. for one hour. The mixture is concentrated to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate. To the product is added ethanol (50 ml) and thereto is added cyclopropylamine (1.1 ml) at room temperature, and the mixture is stirred for 30 minutes. Ethanol is distilled off to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-cyclopropylaminoacrylate. To the product is added anhydrous dioxane (30 ml) and thereto is added portionwise 60% sodium hydride (0.6 g). The mixture is stirred at room temperature for 30 minutes and then refluxed for one hour. The reaction mixture is poured into aquoeus saturated ammonium chloride and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated to give ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylate (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
30 g of 3-[5-(4-Fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 50 ml of DMF. 14.3 g of imidazole and 19 g of tert-butyldimethylsilyl chloride in 25 ml of DMF are added, and the mixture is then stirred at room temperature until the reaction has gone to completion (2-4 h). The reaction solution is concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, giving 10:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19][S:20](O)(=[O:22])=[O:21].[OH-].[K+:25]>>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:20]([O-:22])(=[O:21])=[O:19])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+:25]
Reactant: CCCCCCCCCCCCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)[O-])cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 1-phenyldodecane (7.5 g, 30.5 mmol) and concentrated H2SO4 (8.4 mL) was stirred vigorously at 90° C. for 1 h, cooled to room temperature, and then gradually poured with stirring into 10% aqueous KOH solution (175 mL). The resulting white precipitate was collected by filtration, washed with cold water (40 mL) and dried to give potassium 4-dodecylbenzene sulfonate (10.6 g, 29.1 mmol, 84%). This salt (10.0 g, 27.5 mmol) and POCl3 (4.2 g, 27.4 mmol) were stirred at room temperature and gradually heated to 170° C. The hot reaction mixture was poured into cold water and extracted with CHCl2. The organic layer was washed with water, dried over anhydrous Na2SO4, and filtered. Evaporation of the volatiles yielded p-dodecylbenzenesulfonyl chloride as a pale yellow liquid (9.2 g, 97%) which eventually became crystalline, mp 33° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.5), 1.20-1.38 (m, 18H), 1.60-1.68 (m, 2H), 2.72 (t, 2H, J=7.5 Hz), 7.40 (d, 2H, J=8.4 Hz), 7.79 (d, 2H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 29.1, 29.3, 29.3, 29.5, 29.6, 30.9, 31.9, 36.0, 127.0, 129.6, 141.7, 151.6.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15](Cl)=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].N.O>C1COCC1>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:15]2[C:9]3[CH:8]=[N:7][C:6]([NH:5][CH2:4][C:3]4[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=4[Cl:1])=[N:11][C:10]=3[CH:12]=[CH:13][N:14]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: Clc1ccccc1CNc1ncc2c(Cl)nccc2n1
Reactant: CCOC(=O)C1CCNCC1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
(2-Chloro-benzyl)-(5-chloro-pyrido[4,3-d]pyrimidin-2-yl)-amine 9 (500 mg, 1.64 mmol), Piperidine-4-carboxylic acid ethyl ester 12 (0.51 mL, 3.28 mmol) and NH3 (25% solution in water, 0.22 mL, 3.28 mmol) were dissolved in THF (5 mL) and stirred at 100° C. in a high pressure flask for 15 hours. To the mixture water (5 mL) was added and the precipitate formed was filtered off and dried in vacuo. The obtained colorless solid (583 mg, 1.37 mmol, 84%) was used without further purification.
Reaction SMILES: [C:1]([N:8]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][O:10][CH:9]1[C@H:17]([NH2:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].O>CO.O>[C:1]([N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][CH:9]1[C@H:17]([NH2:26])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)C1=COC([C@H](N)CCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C(=O)O)=COC1[C@H](N)CCc1ccccc1

Procedure:
A solution of methyl N-Boc-2-[(1R)-1-amino-3-phenylpropyl]-4-oxazolecarboxylate (388 mg) and potassium carbonate (1.5 g) in 90% methanol/water (10 mL) is brought to gentle reflux for 40 min. The reaction mixture is cooled, water is added and extracted thrice with ethyl acetate. The aqueous layer is acidified to pH 3 and extracted three times with ethyl acetate. The combined organic layer is washed twice with brine, dried (Na2SO4) and concentrated. The crude title product (372 mg) was >95% pure by NMR: 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 2.18 (m, 1H), 2.22 (m, 1H), 2.69 (m, 2H), 5.01 (m, 1H), 5.88 (bs, 1H, NH), 7.16 (m, 3H), 7.23 (m, 2H), and 8.01 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc2c1CCC2
Yield: 86.7 %

Procedure:
In a 500 mL Parr shaker vessel, 4-nitroindane (10 g, 61 mmol) was dissolved in 50 mL ethanol. A slurry of 10% Pd/C (1 g) in ethanol was added. The mixture was then placed on a Parr shaker under a hydrogen atmosphere (50 psi) for 1 hour, at which point t.l.c. (20% ethyl acetate in hexanes) showed that all the starting material had disappeared. To work up the reaction, the mixture was filtered twice through Celite, washing with a large amount of ethanol, and once through filter paper. The ethanol was evaporated under reduced pressure, and the crude product purified by flash chromatography over silica gel (10% ethyl acetate in hexanes) to give 8 as a viscous, faintly colored oil (7.04 g, 86% yield): 1H NMR (400 MHz, DMSO-D6) δ 1.95 (m, 2H) 2.61 (t, J=7.3 Hz, 2H) 2.76 (t, J=7.5 Hz, 2H) 4.77 (s, 2H) 6.36 (d, J=7.8 Hz, 1H) 6.42 (d, J=6.8 Hz, 1H) 6.80 (t, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.Cl[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]>C1COCC1.CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)C(C)(C)CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 20 h
Yield: 86.7 %

Procedure:
To a solution of 6.76 mL (53 mmol) of methyl 2,2-dimethyl-3-hydroxypropionate in anhydrous THF/DMF (110 mL, 10/1) are added 4.33 g (63.6 mmol) of imidazole and 11.3 mL (53 mmol) of chlorotriisopropylsilane under nitrogen atmosphere. After stifling at room temperature for 20 h, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in TBME (175 mL). The organic layer is washed with water (30 mL), brine (30 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 13.25 g of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid methyl ester as a yellow oil, which is used in the next step without further purification. Yield: 79%; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.01-1.07 (21H, m), 1.18 (6H, s), 3.66 (3H, s), 3.69 (2H, s)
Reaction SMILES: Br[C:2]([CH3:30])([CH3:29])[C:3]([NH:5][C:6]1[C:11]2[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=[C:8]([F:17])[C:7]=1[C:18]1[C:22]([Cl:23])=[C:21]([C:24]([F:27])([F:26])[F:25])[N:20]([CH3:28])[N:19]=1)=[O:4].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:23][C:22]1[C:18]([C:7]2[C:6]3[NH:5][C:3](=[O:4])[C:2]([CH3:30])([CH3:29])[N:12]4[C:13](=[O:16])[CH2:14][O:15][C:10]([C:11]=34)=[CH:9][C:8]=2[F:17])=[N:19][N:20]([CH3:28])[C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: Cn1nc(-c2c(F)cc3c(c2NC(=O)C(C)(C)Br)NC(=O)CO3)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1nc(-c2c(F)cc3c4c2NC(=O)C(C)(C)N4C(=O)CO3)c(Cl)c1C(F)(F)F
Yield: 8.5 %

Procedure:
5-(2-Bromoisobutyrylamino)-6-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-7-fluoro-2H-1,4-benzoxazine-3(4H)-one (1.15 g, 2.24 mmol) was dissolved in anhydrous acetonitrile (50 ml) and potassium iodide (0.45 g, 2.70 mmol) and potassium carbonate (0.37 g, 2.70 mmol) were added. Solution was refluxed for 2 hr and water was added. Product was extracted with ethyl acetate and solvent evaporated. Column chromatography on silica gel using hexane-ethyl acetate (7:3) as eluent afforded the title compound (84.0 mg, 0.19 mmol).
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:10]#[N:11])[CH:6]=[CH:7][C:8]#[N:9])C.[CH3:12]N>CN(C=O)C>[CH3:12][NH:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:2]=1
Reactant: CN(C)C=C(C#N)C=CC#N
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc(C#N)cn1

Procedure:
7.4 g of dimethylaminomethylene-glutacononitrile, 100 ml of DMF and 4.4 g of 35.6% strength aqueous methylamine solution were held for 2 hours at 80° C. in an 0.3 l V4A autoclave. After the mixture had been removed and concentrated, 6.4 g of 2-methylamino-5-cyanopyridine (purity 93%) were obtained, which corresponds to 90.2% of theory.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:31][C:30]=1[CH3:50]>CN(C=O)C>[Br:5][CH2:2][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:31][C:30]=1[CH3:50]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(C)c3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tetrabromomethane (3.26 g, 9.82 mmol) was added to a solution of triphenylphosphine (2.58 g, 9.82 mmol) in anhydrous DMF (20 mL) at 0° C. A solution of 2-[4-(2-hydroxy-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (1.75 g, 4.91 mmol) in DMF (7 mL) was then added dropwise and stirred the reaction mixture at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with dichloromethane (4×25 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed and the solid was triturated with ether. The resulting slurry was filtered and washed with ether several times (to remove the triphenylphosphine oxide) and finally with a solution of dichloromethane-ether (1:1) to obtain 2-[4-(2-bromo-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 0.70 g (34%).
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:14]>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(F)c(F)cc(C#N)c1F
Product: Cc1c(F)c(F)cc(C(N)=O)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4,5-trifluoro-3-methylbenzonitrile (0.50 g) in concentrated sulfuric acid (0.3 ml) was stirred on an oil bath (90° to 100° C.) for 1 hour. After cooling, to the reacting mixture was added ice-water (5 ml), the resulting precipitate was collected by filtration, washed with water sufficiently and dried to give the title compound (0.52 g), mp 105°-108° C. This crystals were recrystallized from hexane to give colorless crystals, mp 112°-113° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH2:11])([CH3:10])[CH3:9].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[N:14]=1>CC(CC)=O>[CH:8]([NH:11][C:17]1[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[N:14]=[C:13]([Cl:12])[N:18]=1)([CH3:10])[CH3:9]
Reactant: CC(C)N
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: COc1c(Cl)nc(Cl)nc1NC(C)C

Procedure:
42 ml of triethylamine, 25 ml of isopropylamine, 250 ml of methylethylketone and 32 g of 2,4,6-trichloro-5-methoxypyrimidine (prepared as indicated by Budesinsky et Coll., Ceskoslov. Farm. 10, 241-247, 1961) were stirred together at 20° C. for 6 hours. The reaction mixture was then evaporated under reduced pressure and the residue fixed on a silica gel column. This was followed by elution with a 95/5 toluene-diethylamine mixture. In this way were isolated 20.2 g of 4-isopropylamino-2,6-dichloro-5-methoxypyrimidine.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH2:16][C:5]1=2)#[N:2].[ClH:19].C(OCC)(=O)C>[Pd].C(O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH2:14][C:15]([CH3:17])([CH3:18])[CH2:16][C:5]1=2
Reactant: CCOC(=O)c1cc2c(n1CC#N)CC(C)(C)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(n1CCN)CC(C)(C)C2
Reaction time: 6 h

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 2.0 g dry weight), 167c (4.5 g, 18 mmol), 12% hydrochloric acid (9.2 mL, 37 mmol), ethyl acetate (80 mL) and ethanol (52 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The crude residue 167d was carried onto the next step without further purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCCc1ccc(O)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(O)cc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and tyramine, m.p. 129-131° C. MS [(+)ESI, m/z]: 554 [M+H]+