Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1.Br[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1
Reactant: OB(O)c1ccc(F)c(-c2ccnnc2)c1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccnnc4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-4-yl)phenylboronic acid (100 mg, 0.46 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (117 mg, 0.46 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 5% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-(pyridazin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid: δH (400 MHz, CDCl3) 1.63 (6H, s), 7.11 (1H, d, J 7), 7.43-7.48 (1H, m), 7.64-7.69 (2H, m), 7.71-7.74 (1H, m), 7.88 (1H, s), 8.54 (1H, d, J 7), 9.33 (1H, dd, J 5 and 1), 9.46-9.47 (1H, m); m/z (ES+) 350 (M++H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11](CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].S([O-])(=O)(=O)C.FC1C=CC(CCCO)=CC=1>>[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[N:35]([CH2:11][CH2:10][CH2:9][C:3]3[CH:2]=[CH:7][C:6]([F:8])=[CH:5][CH:4]=3)[N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: CS(=O)(=O)[O-]
Agent: OCCCc1ccc(F)cc1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CCCc2ccc(F)cc2)c1=O
Yield: 90.1 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and the mesylate derivative of 3-(4-fluorophenyl)-1-propanol {J. Med. Chem., 19, 461 (1976)} were reacted to yield the title compound as a yellow oil (yield: 90.1%). The mesylate derivative was prepared in accordance with the procedure of Example 1 (9).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[BrH:10].CS(C)=O>C(O)(=O)C.O>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1ccccc1O
Reactant: Br
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1cc(Br)ccc1O
Reaction time: 1 h
Yield: 103 %

Procedure:
To a stirred solution of 2-ethylphenol (8.97 g, 73.4 mmol) in acetic acid (100 ml) was added hydrobromic acid (48 wt. % solution in water; 50 ml, 442 mmol), DMSO (50 ml, 705 mmol) dropwise, and the mixture was stirred for 1 hour. The mixture was diluted with water, and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo to give title compound (15.2 g, 99% yield). The compound was used for next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>CO>[C:18]1([CH3:23])[C:17]([NH:16][CH:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)C(=CO)c1ccccc1Br
Solvent: CO
Product: CCOC(=O)C(=CNc1ccccc1C)c1ccccc1Br
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a solution of ethyl 2-(2-bromophenyl)-3-hydroxyacrylate (1 g, 3.88 mmol) in methanol (10 mL) was added o-toluidine (0.416 g, 3.88 mmol) via syringe at room temperature. After being stirred for 18 hours at the same temperature, solvent was removed under reduced pressure to give the crude product of ethyl 3-(o-toluidino)-2-(2-bromophenyl)acrylate (1.326 g, 95%), which was used in the next step without further purification. LRMS (M+H+) m/z: calcd 359.05. found 359.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].[F-:17].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([F:17])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: [F-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)F

Procedure:
CBZ-Ala (1 mmole) in dry CH2Cl2 is kept under nitrogen and treated with cyannuric fluoride (8 mmol) and pyridine (1 mmole) to form the corresponding CBZ-Ala-F.
Reaction SMILES: [Cl:1]C1C=CC(C#N)=C(N2CCOCC2)N=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19](N2CCOCC2)[N:18]=1.P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>C(#N)C>[Cl:1][C:19]1[N:18]=[C:17]([Cl:16])[CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1ccc(Cl)nc1N1CCOCC1
Reactant: N#Cc1ccc(Cl)nc1N1CCOCC1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: NC(=O)c1ccc(Cl)nc1Cl
Yield: 91 %

Procedure:
Experimental procedure for synthesis of 6-chloro-2-morpholin-4-yl-nicotinonitrile (3) is the same as that described in synthesis of (D46). The reaction of 6-chloro-2-morpholin-4-yl-nicotinamide (2) (2.49 g) with phosphorus oxychloride (2.7 mL, 29 mmol) and pyridine (4.7 mL, 58 mmol) in acetonitrile (60 mL) gave a crude black oil upon workup. The black oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with CH2Cl2 (300 mL) followed by the addition of silica gel (20 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (60 g, 230-400 mesh) and eluted with 10% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (1.97 g, 91% isolated yield over 2 steps with respect to 1.85 g of compound 1). TLC eluted with 50% EtOAc/hexanes and rendered with UV lamp gave Rf=0.8; 1H NMR 400 MHz (CDCl3) δ 7.69 (d, J=8.2 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 3.85-3.77 (8H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9])=C.Cl.O1CCOCC1>CO.C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (57.0 mg, 0.109 mmol) in anhydrous MeOH (5.5 mL) and anhydrous THF (2.7 mL) under N2 was added 4 M HCl in dioxane (817 μL, 0.327 mmol, 3.0 eq), and the reaction mixture was stirred at room temperature. After 1 h the solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and methanol (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Trituration from DCM-hexane afforded the title compound as a tan solid (32.9 mg, 60.8%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 8.32 (d, J=5.9 Hz, 1H), 7.70-7.41 (m, 3H), 7.20 (dd, J=8.50 Hz, 1H), 6.26 (t, J=9.6 Hz, 1H), 4.78 (br s, 1H), 3.87 (dd, J=6.31 Hz, 2H), 3.70-3.39 (m, 3H), 1.27 (br s, 1H), 1.18-1.03 (m, 2H), 0.90-0.67 (m, 2H); LC-MS (method C): [M+H]+=497.0, RT=0.57 min.
Reaction SMILES: C(CC[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[CH3:21])#N.[OH-].[K+]>Cl>[CH3:21][C:6]1[NH:5][C:13]2[C:8]([C:7]=1[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Cc1c(Cc2cccnc2)c2ccccc2n1CCC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1[nH]c2ccccc2c1Cc1cccnc1
Reaction time: 24 h
Yield: 54.5 %

Procedure:
1-(2-Cyanoethyl)-2-methyl-3-(3-pyridylmethyl)indole (1.0 g) was dissolved in concentrated hydrochloric acid (10 ml) and the solution was allowed to stand at room temperature for 24 hours. The solution was cautiously basified by addition of dilute KOH solution with cooling to give an oil which gradually solidified. The solid was filtered off, washed with water and crystallised from isopropanol/water to give 1-carbamoylethyl)-2-methyl-3-(3-pyridylmethyl)indole (0.44 g), m.p. 145°147°.
Reaction SMILES: O1[CH:6]2[CH:2]1[C:3](=[O:14])[CH2:4][CH:5]2[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[CH2:15]([SH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.[Cl-].[NH4+]>CO>[CH2:15]([S:22][C:2]1[C:3](=[O:14])[CH2:4][CH:5]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCS
Reactant: O=C1CC(OC2CCCCO2)C2OC12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCCCSC1=CC(OC2CCCCO2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
2,3-Epoxy-4-tetrahydropyranyloxycyclopentan-1-one (200 mg) and 121 mg of n-heptylmercaptan were dissolved in 5 ml of methanol, and 158 mg of triethylamine was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was treated by a customary procedure to afford 280 mg of a crude product. The crude product was chromatographed on a thin layer plate with cyclohexane/ethyl acetate (=6/4) to afford 80 mg of 2-n-heptylthio-4-tetrahydropyranyloxycyclopent-2-en-1-one in a yield of 26%. The product had the following characteristics.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:13])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 69 was prepared from 1-(4-chlorophenyl) cyclopropanecarboxylic acid and N{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.45 (s, 1H), 7.36–7.34 (m, 5H), 7.24 (t, 1H, J=8.0 Hz), 6.94 (d, 1H, J=7.6 Hz), 5.69 (br s, 1H), 3.25 (dd, 2H, J=6.8, 12.8 Hz), 2.87 (d, 2H, J=11.6 Hz), 2.44 (m, 1H), 2.35 (t, 2H, J=7.2 Hz), 2.29 (t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=11.2 Hz), 1.80–1.74 (m, 4H), 1.63–1.59 (m, 6H), 1.03–1.00 (m, 5H); ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-((6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (32 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 22 mg (yield 30%) of the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>CN(C)C=O.[Cl-].[Na+].O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C#N)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of methyl cyanoacetate (24.75 g; 0.25M) in dimethylformamide (70 ml) was added dropwise over 40 minutes to a stirred suspension of sodium hydride (8.25 g; 0.275M) in dimethylformamide (250 ml) at 0° under nitrogen atmosphere. The solution was stirred for 0.5 h, then a solution of 2-fluoronitrobenzene (17.65 g; 0.125M) in dimethylformamide (70 ml) added. After stirring for 16 h at room temperature, the red solution was poured onto excess brine, and extracted with ether (×6). The aqueous layer was then acidified with hydrochloric acid (5M) until the red colour was discharged. The resultant solution was extracted with ether (×4) and the combined organic extracts washed with brine, dried and evaporated to afford the title compound as a yellow oil (26.7 g; 97%) which slowly solidified.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1>O>[F:27][C:25]([F:26])([F:28])[S:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:7][C:4]2[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=2)=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(N)cc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccc(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 190 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
A mixture of 0,277 mol of 1,4-benzenediamine, 0,017 mol of methyl 2-hydroxy benzoate and 10 grams of potassium carbonate is stirred for 1 hour at 190° C. Then there are added 0,049 mol of 1-chloro-4-(trifluoromethylsulfonyl)benzene and stirring at 190° C. is continued for 3 hours. The reaction mixture is cooled and stirred in 2000 ml of water. The precipitated product is filtered off, washed with water, dried and crystallized from a mixture of ethanol and water, yielding 2.3 grams of N-[4-(trifluoromethylsulfonyl)phenyl]-1,4-benzenediamine. (interm. 6)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:23]1([CH2:22][C:13]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: N#CC1CCCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC1(Cc2ccccc2)CCCCCC1
Yield: 55.8 %

Procedure:
Obtained by operating as in example 27b, from 195 mmoles of lithiated diisopropylamine (25.6 g (252.9 mmoles) of diisopropylamine treated with 122 ml (195 mmoles) of n-butyllithium 1.6M in hexane) in 300 ml of dry tetrahydrofuran, 24 g (195 mmoles) of commercial cycloheptanecarbonitrile and 24.6 g (195 mmoles) of benzyl chloride. After distillation, there is obtained 23.2 g (yield=55.8%) of a yellow viscous liquid. b.p.16 =190°-7° C.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]3[N:21]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:22]=[C:23]([CH2:25][C:26]([CH3:33])([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH2:28])[N:24]=3)=[O:19])=[CH:13][CH:12]=2)=[N:9][CH:10]=1>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]3[N:21]([S:34]([N:37]([CH3:38])[CH3:39])(=[O:35])=[O:36])[CH:22]=[C:23]([CH2:25][C:26]([CH3:33])([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH2:28])[N:24]=3)([OH:19])[CH3:1])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (0.50 mL, 1.49 mmol) was added to a 0° C. solution of 2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide (780 mg, 1.49 mmol) in tetrahydrofuran (10 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded 2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([O:24][CH3:25])[C:8]=1[NH2:9].O>N1C=CC=CC=1>[Br:6][C:7]1[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:16])[F:17])[CH:11]=[C:10]([O:24][CH3:25])[C:8]=1[NH:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(Br)c1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(Br)c1NS(C)(=O)=O
Reaction time: 8 h

Procedure:
Add 2.5 g (22 mmole) of methanesulfonyl chloride dropwise to 5.5 g (15 mmole) of 2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)-6-methoxyaniline in 30 ml of pyridine below 10° C. Allow to stand overnight. Pour into H2O and decant. Dissolve the oil in Et2O, wash with 1N HCl and extract with 1N NaOH. Acidify the NaOH with HCl and extract with Et2O. Dry and concentrate. Chromatograph the oil on silica gel, eluting with CHCl3. Recrystallize from CH2Cl2 to obtain 2'-bromo-4'-(hexafluoro-2-hydroxy-2-propyl)-6'-methoxymethanesulfonanilide; m.p. 38°-41° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=13)[N:18]=[CH:17][N:16]([C@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[OH:32])[C:15]2=[O:33]>C1COCC1.ClCCl.O.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:32][C@@H:27]1[C@@H:26]([N:16]2[C:15](=[O:33])[C:14]3[C:19](=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]4=[C:12]([CH2:2][C:3]4[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=4)[CH:13]=3)[N:18]=[CH:17]2)[CH2:31][CH2:30][O:29][CH2:28]1
Reactant: O=c1c2cc(Br)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: COc1ccc(CCl)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(chloromethyl)-2-methoxy pyridine (0.158 g, 0.999 mmol) in 0.5 mL of THF under an atmosphere of nitrogen was added Rieke Zn (1.3 mL, 1.0 mmol, 0.76 M in THF). The mixture was heated to reflux for 18 h, then cooled to 0° C. A solution of 6-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (see Example 1, 0.125 g, 0.333 mmol) in 0.5 mL of THF was added, followed by bis(tri-tert-butylphosphine)palladium(0) (5.1 mg, 0.010 mmol). The mixture was warmed to rt. After 2 h, the reaction was diluted with dichloromethane and water, and the aqueous layer was extracted with additional dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 418.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.94-8.92 (m, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.91-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.29 (dd, J=2.4 Hz, 8.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.86-4.79 (m, 1H), 4.28 (s, 2H), 4.23-4.06 (m, 3H), 3.85 (s, 3H), 3.58-3.53 (m, 1H), 3.31 (t, J=10.3 Hz, 1H), 2.96 (d, J=6.7 Hz, 1H), 2.30-2.20 (m, 1H), 2.01-1.97 (m, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH2:7][N:8]1[C@H:11]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:10]([CH:32]([OH:34])[CH3:33])[C:9]1=[O:35])=[O:6])[CH:2]=[CH2:3].Cl>[Zn].O1CCCC1>[OH:34][CH:32]([C@@H:10]1[C@@H:11]([SH:12])[N:8]([CH2:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:9]1=[O:35])[CH3:33]
Reactant: C=CCOC(=O)CN1C(=O)[C@H](C(C)O)[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCOC(=O)CN1C(=O)[C@H](C(C)O)[C@H]1S

Procedure:
Add 500 mg of (3S,4R)-1-(allyloxycarbonylmethyl)-3-(1-hydroxyethyl)-4-(triphenylmethylthio)azetidin-2-one and 20 ml tetrahydrofuran to a 50 ml flask. Add zinc dust and 10% hydrochloric acid in small portions over 1 hour until all of the starting material is reacted. Recover the product by filtering off the excess zinc and removing the solvent to crystallize the title product.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:12](OC)=[O:13])[CH:11]=2)[C:5]([CH3:8])=[CH:6][N:7]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([CH2:12][OH:13])[CH:11]=2)[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1cc2c(C)ncc(C)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ncc(C)n2nc(CO)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of methyl 4,7-dimethylpyrazolo[1,5-a]pyrazine-2-carboxylate (62 mg, 0.30 mmol) in DCM (5 mL) was cooled to 0° C. Diisobutylaluminium hydride (DIBAL-H) (1 M in cyclohexane, 1 mL, 0.33 mmol) was added to the above solution dropwise over 5 min. After addition, the mixture was stirred at 0° C. for 1 h. Saturated aqueous ammonium chloride solution (2 mL) was added to quench the reaction. Then 5 mL of saturated sodium bicarbonate aqueous solution was added. The mixture was extracted with DCM (3×15 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, evaporated, and chromatographed on silica gel using 5% MeOH in DCM as eluent to give 41 mg (77% yield) of the title compound as a yellow solid. ESI MS: m/z 178.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 6.77 (s, 1H), 4.98 (d, J=6.0 Hz, 2H), 2.71 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=O.Cl.CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:31][NH:32][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone, methylamine-hydrochloride, TBTU, HOBt and N-ethyl-N,N-diisopropylamine in DMF.