Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[S:11]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:18])=[O:17])=[C:4]([NH:10][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:17])=[O:18])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: O=S(=O)(Nc1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Yield: 63.8 %

Procedure:
N,N′-(4,5-Dichloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (120 mg) was prepared by using 4,5-dichloro-benzene-1,2-diamine (0.06 g, 0.33 mmol) and Benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol), following procedure as in Example 32.
Reaction SMILES: [Li][C@H:2]1[CH2:6][CH:5]([C:7](O)=O)N([Li])[C:3]1=O.[Li][CH2:13][CH2:14][CH2:15][CH3:16]>CCOCC>[CH:2]1([CH:15]([C:14]2[CH:13]=[CH:5][CH:6]=[CH:2][CH:3]=2)[CH3:16])[CH:6]=[CH:5][CH:7]=[CH:3]1
Reactant: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 176.2 %

Procedure:
To a solution of 0.77 g of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (6 mmol) in 40 mL of ether was added 7.8 mL of n-BuLi (1.6 m solution in hexanes, 13 mmol) at 0° C. This solution was stirred for 30 min at room temperature. The solvent was removed under vacuum and 25 mL of ether added. 6-Methyl-6-phenylfulvene, 1.0 g, (6 mmol) in 5 mL of ether was added dropwise at -78° C. and the color of the reaction mixture turned green. The resulting solution was stirred for 7 h at -78° C. and the color of the reaction mixture turned yellow. Water, 25 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 0.9 g (89% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =2.0° (CHCL3), 5.8% ee.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1>CN(C=O)C>[Br:15][C:13]1[CH:14]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[N:11][CH:12]=1
Reactant: COCCO
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cncc(Br)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-Methoxyethanol (2.7 ml; 33.8 mmol) is added dropwise to a suspension of NaH (55% suspension; 1.62 g; 37.14 mmol) in DMF (60 ml). After stirring for 30 minutes, 3,5-dibromopyridine (4.0 g; 16.88 mmol) is introduced and the mixture heated to 50° C. for 1 hour. The reaction mixture is poured on water and extracted with ethyl acetate three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 85:15) yields the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[NH3:12]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([NH2:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(F)cn1
Reactant: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N)cn1
Temperature: 0 °C
Yield: 99 %

Procedure:
A large steel reaction vessel was charged with a solution of 5-fluoro-pyrazine-2-carboxylic acid methyl ester (17.45 g, 111.78 mmol) in tetrahydrofuran (200 mL). The reaction solution was cooled to 0° C. and was saturated with ammonia gas over 2–3 h. The vessel was then tightly sealed. The reaction was then mechanically agitated and allowed to warm to 25° C. overnight. The vessel was then cooled to −78° C. for 15–20 min, the vessel was carefully vented, and the contents of the vessel were diluted with diethyl ether (100 mL). The resulting precipitate was isolated via filtration, rinsed with petroleum ether (2×100 mL), and air-dried to afford 5-amino-pyrazine-2-carboxylic acid methyl ester (16.97 g, 99%) as an off-white solid: mp 229–231° C.; EI-HRMS m/e calcd for C6H7N3O2 (M+) 153.0538, found 153.0537.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[N:20]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:22]([CH3:24])[CH:23]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[N:20]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:22]([CH3:24])[CH:23]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cn(C)c(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cn(C)c(-c4ccc5c(cnn5C)c4)n3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 30 °C
Reaction time: 17 h

Procedure:
In a 25 mL round bottom flask, (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-(1-methyl-1H-indazol-5-yl)-1H-imidazol-4-yl)benzo[d]thiazol-6-yl)acetate 15 mg, 0.024 mmol) was dissolved in THF (1.5 mL) EtOH (0.7 mL) and water (0.5 mL). Then aqueous NaOH (2 N) (0.4 mL) was added. The reaction mixture was stirred at 30° C. in oil bath for 17 h. The resulting reaction mixture was concentrated. The residue was purified on Gilson reverse phase HPLC with CH3CN and water (10 mL) to afford the product. LCMS-ESI+: calc'd for: C32H30ClN5O3S: 600.2, 602.2, 601.2 (M+H+); Found: 600.3, 602.3, 601.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.03 (d, J=0.8 Hz, 1H), 7.99 (dd, J=1.6, 0.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.83 (s, 1H), 7.67-7.58 (m, 3H), 7.50 (dd, J=8.6, 2.3 Hz, 1H), 7.42 (ddd, J=8.3, 5.5, 2.2 Hz, 2H), 5.01 (s, 1H), 4.03 (d, J=0.7 Hz, 3H), 3.75 (s, 3H), 2.55 (s, 3H), 0.82 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C=O)C>[CH2:16]1[C:17](=[O:18])[N:13]([O:10][C:9](/[CH:8]=[CH:7]/[C:3]2[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=2)=[O:11])[C:14](=[O:19])[CH2:15]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/c1cccnc1)ON1C(=O)CCC1=O

Procedure:
A solution of 3-(3-pyridyl)acrylic acid (500 mg: commercially available from Aldrich Chemical Company), N-hydroxysuccinimide (463 mg), and EDCl (707 mg) in methylene chloride (20 mL) and DMF (10 mL) was stirred at ambient temperature for 18 hours. The product was isolated as described in Example 3a to yield 740 mg of the title compound as a white solid. MS (Cl/NH3) m/e 247 (M+H)+. 1H NMR(CDCl3, 300 MHz) δ2.87 (br s,4H), 7.15 (d,J=16 Hz,1H), 7.48-7.53 (m,1H), 8.02 (d,1H), 8.31 (dt,J=9 Hz,1H), 8.66 (dd,J=6 Hz,1H), 8.99 (d,J=2 Hz,1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([NH:19][NH2:20])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1OCc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(NN)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of 2-(benzyloxy)-4-fluorobenzonitrile (4.8 g, 21 mmol), in ethanol (80 mL) was treated with hydrazine monohydrate (2.6 g, 2.5 mL, 53 mmol) and heated to reflux for 3 days. The mixture was cooled to room temperature and concentrated. Water was added and the residue was extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and condensed to give 2-(benzyloxy)-4-hydrazinylbenzonitrile (3.8 g, 15.8 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 2H), 5.16 (s, 2H), 6.36 (dd, J=8.73, 1.75 Hz, 1H), 6.61 (d, J=1.61 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 7.32-7.51 (m, 5H), 7.78 (s, 1H). ES-MS m/z 240 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[N:17]=[CH:18][C:11]=3[N:10]=[C:9]2[CH3:21])=[CH:4][CH:3]=1.Br.Br[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:11]2[N:10]=[C:9]([CH3:21])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:7][CH:6]=3)[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: BrCCCN1CCCC1
Reactant: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Agent: Br
Product: COc1cc2c(=O)n(-c3ccc(OCCCN4CCCC4)cc3)c(C)nc2cn1

Procedure:
The title compound was synthesized as a white solid (m.p.:123-126° C.) by the method according to Example 63, using 3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 197 and 1-(3-bromopropyl)pyrrolidine hydrobromide as starting materials, followed by recrystallization (ethyl acetate/diethyl ether).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([O-:3])[NH2:2].[NH4+:6].[S:7](=[O:11])(=[O:10])([OH:9])[NH2:8].O.[OH-].[K+:14]>>[S:1]([NH:2][S:7]([O-:11])(=[O:10])=[O:9])([O-:3])(=[O:5])=[O:4].[NH4+:8].[NH4+:6].[S:1]([NH:2][S:7]([O-:11])(=[O:10])=[O:9])([O-:3])(=[O:5])=[O:4].[K+:14].[K+:14]
Reactant: NS(=O)(=O)O
Reactant: NS(=O)(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])NS(=O)(=O)[O-]

Procedure:
Diammonium imidodisulfate was prepared by adding 114 grams (1.0 mole) of ammonium sulfamate to 97 grams (1.0 mole) of sulfamic acid in a 1-liter beaker. The mixture was heated on a hot plate with constant stirring. At about 130° C. a stirrable slurry was obtained and at about 155° C. an exothermic reaction began, forming a solid. When the solid cooled, it was dissolved in about 375 grams of 45 percent potassium hydroxide. Water was added to bring the total volume to 800 milliliters. The solution was filtered and then heated under vacuum to expel ammonia. Upon cooling, concentrated hydrochloric acid was carefully added to the solution to adjust the mixture to pH 7.5. A precipitate was obtained and upon filtering, about 150 grams of potassium imidodisulfate was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.Cl.[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1.C(N(CC)CC)C>CN(C=O)C>[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][N:29]([C:5]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=4)=[O:6])[CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-Methylbenzoyl chloride (14 mg, 0.09 mmol) was added to a mixture of 1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (30 mg, 0.09 mmol), triethylamine (64 μL, 0.46 mmol), and DMF (0.7 mL) at 25° C. The mixture was allowed to stir at 50° C. overnight before it was cooled to 25° C. The mixture was filtered and then purified by reverse phase-HPLC to give (1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(m-tolyl)methanone. ESI-MS m/z calc. 373.2. found 374.2 (M+1)+. Retention time: 2.04 minutes (4 min run).
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH2:24])[CH3:23].C(OCC)(=O)C>CCCCCC>[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH:24][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])[CH3:23]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](Nc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and (R)-2,2,1-trimethylpropylamine (0.2M in ethanol, 23 ml, 0.0046 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The ethanol is evaporated on a rotary evaporator. The reaction is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-[(R)-2,2,1-trimethylpropylamino]-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.345 g (0.00095 mol, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=2)[N:31]=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([C:35]([F:36])([F:38])[F:37])=[N:33][N:34]=4)[N:31]=3)[CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(C(CCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: Fc1ccc(C(CCCN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 1-[4,4-bis(4-fluorophenyl)butyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[4,4-bis(4-fluorophenyl)butyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[N:26]=[N:25][C:24]([CH2:27][C:28]#[N:29])=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:30]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[C:30]1(=[C:27]([C:24]2[N:25]=[N:26][N:22]([C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:23]=2)[C:28]#[N:29])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCCC1
Reactant: N#CCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(=C1CCCC1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
To a flask charged with dry sodium hydride (0.32 g, 13.3 mmol) was added (2-trityl-2H-tetrazol-5-yl)-acetonitrile (2.34 g, 6.67 mmol). The solids were swirled to mix, cooled to 0° C., and 25 mL THF was added quickly, resulting in vigorous H2 evolution and a bright yellow foam. The mixture was stirred at 0° C. for 5 min, at which time the ice bath was removed and stirring continued for 10 min. Cyclopentanone (0.65 mL, 7.33 mmol) in 10 mL THF was added quickly resulting in a clear orange solution. The mixture was stirred for 2 h, partitioned between EtOAc and sat. NH4Cl (aq), and the organic phase dried (MgSO4) and concentrated. Flash chromatography of the residue (CH2Cl2) furnished 2.05 g (74%) of cyclopentylidene-(2-trityl-2H-tetrazol-5-yl)-acetonitrile as a white solid. 1H NMR (CDCl3) δ 7.32 (m, 9H), 7.10 (m, 6H), 2.86 (m, 4H, —CH2CCH2—), 1.84 (m, 4H, —CH2CH2CH2CH2—).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7]2)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7]2
Reactant: CC(C)(C)OC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Yield: 96.8 %

Procedure:
A 500 mL Par hydrogenation bottle was charged with compound 10 (5.80 g, 22.14 mmol), 10% Pd/C (0.6 g) and methanol/THF (150 mL, 1:4 v/v), and purged with hydrogen. The reaction mixture was shaken with 50 psi H2 over night. The catalyst was removed by filtration and the solvent was evaporated to give 4.98 g (97% yield) of the title compound 11 as brown solid. 1H NMR (DMSO), 11.42 (s, 1H), 7.18 (d, 1H, J=8.3 Hz), 6.83 (s, 1H), 6.71 (s, 1H), 6.67 (d, 1H, J=8.4 Hz), 1.62 (s, 9H). This product is unstable and therefore it was immediately used in the following step.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13]O)[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:40]I>C(#N)C.CCOCC>[CH2:1]([N:8]1[C@H:12]([CH2:13][I:40])[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@@H](CO)N1Cc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C1CC[C@@H](CI)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13-1 (18.5 g, 90.1 mmol), triphenylphosphine (40.1 g, 153 mmol), and imidazole (11.03 g, 162 mmol) in 225 mL of acetonitrile and 150 mL of ether at 0° C. was added iodine (34.3 g, 135 mmol) in 5 portions over 5 minutes. After 10 minutes, the reaction was heated to 50° C., and a stream of argon passed over the reaction to purge the evaporating ether. After an additional 30 minutes, the mixture was diluted with ether, the organic layer washed with NaHCO3 (sat.) and brine, dried over K2CO3, and the solvent evaporated. Flash chromatography of the residue (silica, 7-15% EtOAc/CHCl3) gave 13-2 as a yellow oil.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:4][O:3]1.O>C(Cl)Cl>[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OCC(COc2ccc(OCc3ccccc3)cc2)O1
Solvent: O
Solvent: ClCCl
Product: OCC(O)COc1ccc(OCc2ccccc2)cc1
Yield: 38.3 %

Procedure:
A mixture of 8.98 g of 2,2-dimethyl-4-[[4-(phenylmethoxy)phenoxy]methyl]-1,3-dioxolane, 15 g of a strongly acidic ion exchange resin and 200 ml of water was refluxed for 24 hours, then allowed to cool and methylene chloride was added. The mixture was filtered and the organic layer separated and saved. The aqueous layer was extracted several times with methylene chloride. All organic solutions were combined, dried and evaporated, giving 3.0 g of the desired compound, mp 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])CBr)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To 2.70 mmol of 4-chloro-5-methyl-3-trifluoromethylpyrazole and 3.9 mmol of potassium carbonate in 0.5M solution of acetonitrile add 3.25 mmol of t-butylbromoacetate. The reaction was allowed to stir at room temperature for an hour and then heated at 70° C. for 12 hours. The reaction was filtered, the filtrate concentrated to a crude oil. Fresh ether was added and the mixture was allowed to cool. The white crystals obtained were filtered and vaccum dried to give the desired intermediate 4-chloro-5-methyl-3-trifluoromethylpyrazole-1-carboxylic acid tertbutyl ester in 95% yield. LC-MS in FP m/z=300 (M++1)
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(C)CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 42.4 %

Procedure:
To a solution of 3-methoxybutane-1-ol (12) (0.58 g, 4.9 mmol) in pyridine (5 mL) was added p-(trifluoromethyl)-benzenesulfonyl chloride (0.98 g, 4 mmol). The solution was stirred at rt for 3.5 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 1 M HCl (6×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give an oil (13) (0.53 g, 40%). 1H NMR (400 MHz CDCl3) δ 8.03 (d, 2H, J=8.1 Hz), 7.81 (d, 2H, J=8.3 Hz), 4.19 (m, 2H), 3.35 (m, 1H), 3.18 (s, 3H), 1.78 (m, 2H), 1.09 (d, 3H, J=6.0 Hz); 19F δ (s). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 45.99; H, 4.64.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].O=P(Cl)(Cl)[Cl:18].CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:18])[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c(Cl)nc2c(Br)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A mixture of 8-bromo-3-ethylquinazoline-2,4(1H,3H)-dione (736 mg, 2.74 mmol, 481b), POCl3 (1.5 mL, 16.42 mmol, Sigma Aldrich), and DIPEA (0.9 mL, 5.47 mmol) was heated to reflux. Additional DIPEA (0.9 mL, 5.47 mmol) was added. It was stirred overnight at reflux. The mixture was cooled to RT and poured into rapidly stirred water at 0° C. It was basified to pH 10 with 10 N NaOH (aq.) to give an orange solution. The solution was extracted with DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow orange solid (398 mg, 57%). m/z (ESI, +ve) 286.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Br[CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24]>C(#N)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C:2]([NH:1][C:23](=[O:24])[CH:22]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: O=C(Cl)C(Br)Cc1ccccc1
Reactant: CC(N)(CO)c1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(CO)(NC(=O)C=Cc1ccccc1)c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A solution of (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (1.5 g, 6 mmol) and triethylamine (1.01 ml, 7.3 mmol) in acetonitrile (31 ml) was cooled to 0° C. A solution of (RS)-2-bromo-3-phenyl-propionyl chloride (CAS 42762-86-7) (1.637 g, 6.6 mmol) in acetonitrile was added dropwise. After complete addition the reaction mixture was left to warm to room temperature. After 1 hour the reaction mixture was evaporated under reduced pressure and directly purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. Besides the N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide (0.233 g, 10% of theory), the (2RS)-bromo-N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide (mixture of diastereoisomers 3:2) was obtained as a white solid (1.985 g, 71.5% of theory). Mass (calculated) C18H18Br2FNO2 [459.156]; (found) [M+H]+=457, [M+2-H]+=459, [M+4-H]+=461.