Azzindani/Open_Reaction_Data huggingface dataset:
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][NH:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 7.0 g. of ethyl p-[(10-phenyldecyl)amino]benzoate (prepared as described in Example 28), 7 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give white crystals, m.p. 80°-87° C. Recrystallization from ethanol gives white crystals, m.p. 96°-98° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]CC2C=CC=CC=2)[C:10]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]O>CC(O)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:31])[CH:13]=[CH:12][C:11](=[O:15])[C:10]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: c1ccc(COc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C=CC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3-tribenzyloxybenzene 8 (2.0 g, 5.0 mmol) in HOAc (30 mL), K3Fe(CN)6 (0.82 g, 2.5 mmol) and 30% H2O2 (1.3 g, 11.5 mmol) were added and the resulting solution stirred at room temperature for 18 h. The solution was diluted with 50 mL CH2Cl2 and the organic layer subsequently washed with H2O, saturated aqueous NaHCO3 and brine. Drying and concentration resulted in a red oil. Purification by radial chromatography (2 mm thickness, EtOAc/hexane, 1:19, v/v) afforded 9 as a red oil. 1H NMR (CDCl3): δ7.36-7.32 (m, 10 H), 6.58 (s, 2 H), 5.20 (s, 4 H). 13C NMR (CDCl3): δ184.1, 145.2, 136.1, 134.6 128.5, 128.4, 128.1, 75.1. Anal. Calcd for C20H18O4: C, 74.99; H, 5.03. Found: C, 75.04; H, 5.06. HRMS (FAB) calcd for C20H16O4 (M+H+): 320.1049. Found: 320.1059.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:6](=[CH:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[CH3:40][N:41]=[C:42]=[O:43]>C1C=CC=CC=1>[N:9]1[S:8][CH:7]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][C:42](=[O:43])[NH:41][CH3:40])[C:10]=12
Reactant: CN=C=O
Reactant: Oc1cccc2csnc12
Agent: C1CN2CCN1CC2
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc2csnc12
Reaction time: 0.08 h

Procedure:
To a solution of 2.0 g. 7-hydroxy-2,1-benzisothiazole, 40 ml. dry benzene, and catalytic amounts of triethylenediamine and stannous octoate was added 2.5 g. methylisocyanate. After about five minutes at room temperature, yellow solid carbamate product crystallized from solution. The mixture was allowed to stand at room temperature overnight, then solvent and excess methylisocyanate were removed by evaporation on a rotatory evaporator. The solid residue was washed with hot hexane and isolated by suction filtration to give 2.6 g. yellow, microcrystalline 2,1-benzisothiazol-7-yl N-methylcarbamate, mp. 145°-148° (dec.) after recrystallization from benzene. This structure was confirmed by ir and nmr. The insecticidal activity of this material was determined exactly as described in Example 12, whereby 2,1-benzisothiazol-7-yl N-methylcarbamate (500 ppm. concentration) destroyed 100 percent of Mexican bean beetle larvae and bean aphids, four of five southern armyworms, and had no effect on two-spotted mites.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(OCC)(=O)C.CCCCCCC>C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.78 g of 7-nitro-1,2,3,4-tetrahydroquinoline (0.01 mol) are dissolved in 15 ml of ethyl acetate. This solution is run into a mixture of 15 ml of ethyl acetate and 0.80 ml of chloroacetyl chloride. A white precipitate forms immediately, and stirring is continued at 30° C. for 2 h (the reaction is monitored by thin layer chromatography (90/10 ethyl acetate/heptane)). After 2 h, since the reaction is incomplete, 0.2 equivalent of chloroacetyl chloride is added and the temperature is raised to 60° C.; the solid formed undergoes dissolution. When the reaction has finished, the medium is cooled and the solvent is evaporated off. 2.46 g of a beige product which corresponds to the expected compound are recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl.[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([O:33][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:3]3[C:4]([Cl:16])=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[Cl:1])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Yield: 63.7 %

Procedure:
A stirred solution of 1.0 gram (0.0028 mole) of 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene, 0.6 gram (0.0034 mole) of 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol (known compound), and 0.6 gram (0.0043 mole) of potassium carbonate in 25 mL of DMF was heated at 80° C. for about 18 hours. After this time, the reaction mixture was cooled and 50 mL of water was added. The mixture was then extracted with three 25 mL portions of diethyl ether. The combined extracts were washed with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using mixtures of 1:3 methylene chloride:hexane and 1:1 methylene chloride:hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.87 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([N:27]1[CH2:32][CH2:31][NH:30][C@H:29]([CH3:33])[CH2:28]1)=[CH:22][CH:21]=[CH:20]2.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH:4]3[C:9]4[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=4[CH2:7][CH2:6][O:5]3)[C@H:29]([CH3:33])[CH2:28]1)=[CH:22][CH:21]=[CH:20]2
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Reactant: N#Cc1ccc2c(c1)CCOC2CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-(2-oxoethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.454 g, 2.26 mmol) in methanol (30 mL) was added (3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine (0.61 g, 2.49 mmol), and the mixture stirred for 10 min. Sodium cyanoborohydride (0.157 g, 2.49 mmol) and acetic acid (0.25 mL) were added and the mixture stirred for 18 h. A further portion of sodium cyanoborohydride (0.20 g) was added and the reaction stirred for 6 h. The mixture was quenched with water, and the solvent removed in vacuo. Water was added and the mixture extracted with chloroform, the organic extracts dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by preparative LC-MS to yield the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[OH-:42].[Na+].[BH4-].[Na+]>C1COCC1.O.C1COCC1.[Hg](OC(C)=O)OC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)([OH:42])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Reactant: [OH-]
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCN(C(=O)CCCCC(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
To a solution of 6,6-bis-(4-fluoro-phenyl)-1-[4-(3,4,5,-trimethoxy-benzoyl)-piperazin-1-yl]-hex-5-en-1-one (1.62 g, 2.87 mmol) in dry THF (20 ml) a solution of Hg(OAc)2 (0.9 g, 2.87 mmol) in water:THF (1:1, 6 ml) was added. The mixture was then refluxed overnight. NaOH (3M, 3 ml) was added followed by addition of NaBH4 (54 mg, 1.43 mmol). The mixture was stirred for 4 hrs and separated organic layer was saturated with NaCl
Reaction SMILES: O=P(Cl)(Cl)Cl.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.N1C=NC=N1>N1C=CC=CC=1>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:8][CH:9]=1
Reactant: Oc1ncnc2ccccc12
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: c1ccc2ncncc2c1

Procedure:
Intermediates of formula (3) wherein L is 1,2,4-triazol-1-yl, can be prepared, for example, by adding POCl3 dropwise to a mixture of a 4-hydroxyquinazoline (1 equiv.) of formula (9) and 1,2,4-triazole (3 equiv.) in pyridine at room temperature.
Reaction SMILES: ClC1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][CH:34]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:51]=[C:50]([N:52]3[CH2:55][C:54](NCC)(C(N)=O)[CH2:53]3)[N:49]3[C:62](=[O:67])[N:63](CC)[N:64]=[C:48]3[C:47]=2[C:68]2[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=2)=[CH:42][CH:41]=1>>[N:52]1([C:50]2[N:49]3[C:62](=[O:67])[N:63]([CH2:28][C:29]4[CH:34]=[N:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:64]=[C:48]3[C:47]([C:68]3[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=3)=[C:46]([C:43]3[CH:44]=[CH:45][C:40]([Cl:39])=[CH:41][CH:42]=3)[N:51]=2)[CH2:53][CH2:54][CH2:55]1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CCC3)n12

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with 5-(chloromethyl)-2-(trifluoromethyl)pyridine, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.483 min, [M+H]30 =571.
Reaction SMILES: Cl[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=2)[N:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.ClC1C=CC(C2C(C3C=CC=CC=3)=NN3C(=O)N(CC4C=NC(C(F)(F)F)=CC=4)N=C3C=2)=CC=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:3]2[C:2]([C:36]3[C:31]([F:30])=[N:32][CH:33]=[CH:34][CH:35]=3)=[N:7][N:6]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=4)[N:10]=[C:5]3[CH:4]=2)=[CH:28][CH:27]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: OB(O)c1cccnc1F
Agent: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3)nn12
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3cccnc3F)nn12
Yield: 40.9 %

Procedure:
The title compound (41 mg, 42%) as a yellow solid was prepared from 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (88 mg, 0.2 mmol) and 2-fluoropyridin-3-ylboronic acid (56 mg, 0.4 mmol) according to the procedures described for 7-(4-chlorophenyl)-6-phenyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 9). LC/MS (method A): retention time=3.38 min, (M+H)+=501. 1H NMR (CDCl3, 400 MHz): δ 8.84 (s, 1H), 8.14 (d, J=1.96 Hz, 1H), 7.97-8.01 (m, 1H), 7.68-7.76 (m, 2H), 7.46 (s, 1H), 7.34 (d,J=8.56 Hz, 2H), 7.04 (d,J=8.56 Hz, 2H), 6.89 (dd,J=8.56, 2.93 Hz, 1H), 5.34 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[N:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:31][C:26]1[CH:25]=[N:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:22]=2)[N:27]=1
Reactant: Cc1cnc2cc(N)ccc2n1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)cnc3c2)cc1
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (115 mg, 0.528 mmol) in dichloromethane (3 mL) was added pyridine (100 μL, 1.26 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoxaline (80 mg, 0.50 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (168 mg, 95%), single spot at Rf 0.72 (ethyl acetate). mp 135.6-136.2° C., HPLC purity 99+% (tR 2.23 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.66 (1H, s), 7.89 (1H, di-J=9.2 Hz), 7.77 (2H, d, J=8.4 Hz), 7.67 (1H, d, J=2.5 Hz), 7.54 (1H, dd, J=8.9, 2.5 Hz), 7.22 (2H, d, J=8.4 Hz), 2.71 (3H, s), 2.56 (2H, t, J=7.7 Hz), 1.58 (2H, sextet, J=7.7 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 340.25 (M−). FAB-MS (MH+, C18H19N3O2S): calcd 342.1276, found 342.1290.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:34](S(C(F)(F)F)(=O)=O)[S:35]([C:38]([F:41])([F:40])[F:39])(=O)=[O:36]>ClCCl.N1C=CC=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([O:21][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:34])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (200 mg, 0.43 mmol) in dichloromethane (10 mL) and pyridine (0.35 mL) was added Tf2O (0.1 mL, 0.87 mmol) at −78° C. The temperature was slowly raised to 0° C. The mixture was stirred at 0° C. for 2 hours, quenched with slowly addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to provide a brown colored solid. The obtained residue was purified by flash chromatography to provide the desired product (200 mg, 77%). LCMS-ESI+ (m/z): 602.0, 604.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-fluorophenyl)methanol (74.3 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was washed with toluene, and recrystallized from IPA-IPE to give the title compound (49.6 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][N:5]([CH2:10][OH:11])[N:4]=1
Reactant: C=O
Reactant: FC(F)(F)c1cc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: OCn1ccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
The mixture of 4.08 g of 3-(trifluoromethyl)-1H-pyrazole, 2.00 g of paraformaldehyde and 1 ml of triethylamine was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 4.31 g of 3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)C(=O)OC(C)(C)[O:13][C:12]2=O)=[CH:6][CH:5]=1.[O:30]1[C:35]2=[CH:36][CH:37]=[CH:38][C:34]2=[CH:33][CH:32]=[C:31]1[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12](=[O:13])[N:39]([C:31]2[O:30][C:35]3=[CH:36][CH:37]=[CH:38][C:34]3=[CH:33][CH:32]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC2(Cc3ccc(Br)cc3)C(=O)OC(C)(C)OC2=O)cc1
Reactant: c1ccc(Nc2ccc3cccc-3o2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(CC(Cc2ccc(Br)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Yield: 56.1 %

Procedure:
A solution of 4-[5-(4-Bromobenzyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester (1.35 g, 2.93 mmol) and 4-benzofuran-2-ylphenylamine (736 mg, 3.52 mmol) in dry NMP (10 mL) was heated at 220° C. for 5 min in the microwave. The reaction mixture was diluted with water then extracted with EtOAc. After concentrating, the crude material was purified by flash chromatography on silica gel (ISCO cartridge, 40 g), eluting with a gradient of zero to 35% ethyl acetate in hexane over 30 minutes to afford 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-bromophenyl)-propyl]-benzoic acid methyl ester (935 mg, 56%). 1H NMR (300 MHz, DMSO-d6): δ 9.92 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.64-7.17 (m, 13H), 3.81 (s, 3H), 3.10-2.93 (m, 3H), 2.85-2.71 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 1.62 (6H, s), 4.50 (1H, s), 7.08 (1H, d, J 7), 7.41 (1H, t, J 9), 7.53-7.64 (4H, m), 7.72 (1H, dd, J 8 and 1), 7.84 (1H, s), 7.86 (1H, s), 8.86 (1H, d, J 7); m/z (ES+) 373 (M++H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH:9]=O)[CH3:8].[CH:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+].CNC>ClCCCl>[CH3:8][N:7]([CH:9]=[C:12]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:16])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCCCC=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCC(C=O)=CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
To a solution of phosphorus oxychloride (2.330 mL, 25.00 mmol, Aldrich) in 1,2-dichloroethane (5.0 mL) at 0° C. was added DMF (7.74 mL, 100 mmol, EMD) in 1,2-dichloroethane (10.0 mL) during the course of 10 min. The mixture was stirred at 0° C. for 20 min and then warmed up to room temperature. After stirring at room temperature for 3 hrs, valeraldehyde (2.66 mL, 25.0 mmol, Aldrich) in 1,2-dichloroethane (5.0 mL) was added dropwise (5 min) and the resulting mixture was stirred at room temperature for 50 min and at 85° C. for 50 min. The cooled reaction mixture was poured into a mixture of ice and K2CO3 (7.5 g) followed by addition of saturated K2CO3 aqueous solution until the pH of the mixture was around 10. To the above mixture, dimethyl amine (8.0 mL, 40 wt. % solution in water, Aldrich) was added and the reaction mixture was heated at 80° C. for 1 hr, cooled and evaporated under reduced pressure to remove 1,2-dichloroethane. The resulting mixture was then heated at 95° C. for 1 hr, cooled to room temperature and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was distilled under reduced pressure (1 torr at 145-155° C. of oil bath) to yield the title compound (200 mg, 5.7%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1 H), 6.48 (s, 1 H), 3.13 (s, 6 H), 2.30-2.45 (m, 2 H), 1.32-1.53 (m, 2 H), 0.93 (t, J=7.42 Hz, 3 H).