Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:35])[Cl:34])[CH:27]=[C:26]([Cl:36])[C:9]=1[O:10][CH2:11][C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:34])[Cl:35])[CH:27]=[C:26]([Cl:36])[C:9]=1[O:10][CH2:11][C:12]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=1)=[CH2:1]
Reactant: O=C(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
189 mg of potassium tert-butylate and 532 mg of methyltriphenylphosphonium bromide are heated in 8 ml of toluene for 3 hours at 80° C. The reaction mixture is cooled to 50° C. and a solution of 500 mg of 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-tri-fluoromethyl-phenoxy)-propan-2-one in 5 ml of toluene is added in the course of 5 minutes. After 2 hours at 80° C., the reaction mixture is filtered, diluted with ethyl acetate and washed with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=O)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:48][C:47](=[CH2:49])[CH2:46][CH:45]1[C:50](O)=O)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:48][C:47](=[CH2:49])[CH2:46][CH:45]1[C:50]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:43])([CH3:38])([CH3:39])[CH3:40]
Reactant: C=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: C=C1CC(c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1

Procedure:
This compound was made using the same procedure used to make [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester using 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI+: calc'd for C25H34BN3O4: 451.26 (M+); Found: 452.33 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C=O)C>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc(Br)ccc1OC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-n2ccnc2)ccc1OC
Reaction time: 18 h

Procedure:
5-Bromo-2-methoxybenzoic acid, methyl ester (5 g, 20.4 mmol), imidazole (1.4 g, 20.6 mmol), and potassium carbonate (2.9 g, 20.7 mmol) were heated to 145° C. in DMF under N2 as cuprous iodide (1.5 g, 7.9 mmol) was added in portions. The reaction was stirred at this temperature for 18 h, allowed to cool, and filtered through a celite plug. The filtered salts were washed extensively with methanol, the filtrate concentrated in vacuo, and the residue taken up in ethyl acetate, washed with water, brine, and dried. Chromatography on SiO2, elution with methanol/ethyl acetate/hexanes (1:1:3) gave 3 g (63%); IR(KBr, υ=cm−1) 3430, 1726, 1512, 1232, 1068; 1H NMR (300 MHz, DMSO-d6) δ 3.80 (3H, s), 3.85 (3H, s), 7.07 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.69 (1H, s), 7.76 -7.82 (2H, m) 8.18 (1H, s); MS(DCl)m/z: 233 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O)=[O:15].O>C(OCC)(=O)C.[Al].[Ni]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CO
Reactant: N#Cc1ccc(Cl)cc1C(F)(F)F
Agent: [Ni]
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 100 °C
Yield: 87 %

Procedure:
Add 4-chloro-2-trifluoromethyl-benzonitrile to formic acid (96%) (15 mL) and water (3 mL). Add nickel-aluminum alloy (1260 mg). Heat at 100° C. overnight. Dilute with ethyl acetate and filter through Celite®. Extract the filtrate with 1 N sodium hydroxide and saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate to give 4-chloro-2-trifluoromethylbenzaldehyde (555 mg, 87%): 1H NMR (400 MHz, MeOH-d4) δ 10.29 (m, 1H), 8.10 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=1.6 Hz), 7.85 (dd, 1H, J=8.4, 1.6 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1.[Cl:19][C:20]1[C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN1C(=O)CCC1>[ClH:19].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]4[C:25]([C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=5[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.039 g, 0.16 mmol), 4-chloro-N-(2,4-difluorophenyl)nicotinamide (0.043 g, 0.16 mmol) and p-toluenesulfonic acid monohydrate (Aldrich, 0.024 g, 0.13 mmol), in anhydrous NMP (1 mL), was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 160° C. After one hour, the reaction mixture was partitioned between chloroform and brine. The aqueous layer was extracted twice with chloroform, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to an off-white solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4 N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.015 g, 18%) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[C:3](=O)[CH2:4][CH3:5].[O-:13][C:14]#[N:15].[K+].C(=O)(O)[O-].[Na+]>Cl>[CH2:4]([C:3]1[NH:15][C:14](=[O:13])[O:1][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:5]
Reactant: N#C[O-]
Reactant: CCC(=O)C(O)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Product: CCc1[nH]c(=O)oc1-c1ccncc1
Yield: 47.3 %

Procedure:
1-Hydroxy-1-(4-pyridyl)butan-2-one (26.4 g, 0.16 mol) was dissolved in 350 ml of 2N HCl. Potassium cyanate (38.9 g, 0.48 mol) was added portionwise to this solution over a period of one hour with stirring. After the addition was complete, concentrated hydrochloric acid was added until the pH of the solution was one. After an additional hour the reaction mixture was made basic by addition of sodium bicarbonate solution and the resulting mixture was stirred overnight. The resulting solid precipitated was collected and recrystallized twice from 50% aqueous ethanol to yield the title compound (14.4 g, 47% of theoretical yield), m.p. 287°-289° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH3:19].CCOC(C)=O.CCCCCC>CC(C)=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:18][CH3:19])[C:5]([F:9])=[CH:4][C:3]=1[F:10]
Reactant: Oc1cc(Br)c(F)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOc1cc(Br)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 97C (2.0 g, 10 mmol) in acetone (30 mL) was added K2CO3 (4.1 g) and iodoethane (2.4 mL). The mixture was stirred at rt overnight. After TLC (10% EtOAc/Hexane) indicated the reaction was complete, the mixture was diluted with diethyl ether, washed with water and brine. The organic layer was dried over MgSO4 and concentrated to give 97D as an colorless oil (1.7 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (t, J=7.03 Hz, 3H) 4.07 (q, J=7.03 Hz, 2H) 6.94 (dd, J=10.77, 8.13 Hz, 1H) 7.11 (dd, J=8.35, 6.59 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:8]=[CH:9][CH:10]=1.[N-:37]=[C:38]=[O:39].[Na+]>>[C:38]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:39])[NH2:37]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc(OCCO)c2)C(OCc2ccc3ccccc3c2)C1
Reactant: [N-]=C=O
Agent: [Na+]
Product: NC(=O)OCCOc1cccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 24(m), by reacting 2,2,2-trichloro-ethyl (3RS,4RS)-4-[3-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with sodium isocyanate there was obtained 2,2,2-trichloro-ethyl (3RS,4RS)-4-[3-(2-carbamoyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; Rf : 0.40 (SiO2, methylene chloride:methanol=9:1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH:7]=[CH:6]2.[ClH:34].B(Br)(Br)Br>ClCCl.C(#N)C.O>[ClH:34].[N:21]1([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:9]3[C:8]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[CH:12][C:3]([OH:2])=[CH:4]4)=[CH:28][CH:27]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 54.5 %

Procedure:
Dissolve 1-(2-(4-(6-methoxy-2-(thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine (100 mg, 0.22 mmol) in dichloromethane and treat with HCl (1M in ether; 220 μL, 0.22 mmol). Concentrate in vacuo to give a yellow solid and add dichloromethane (7.3 mL). Cool the resulting solution to 0° C. and add boron tribromide (1M in dichloromethane; 870 μL, 0.87 mmol). Stir the resulting mixture at 0° C. for 2.5 hours. Quench the mixture with saturated aqueous sodium bicarbonate and allow to warm to room temperature. Separate the layers and extract the aqueous layer with 20% methanol in dichloromethane (10 mL×3). Dry combined organic layers (Na2SO4), filter and concentrate in vacuo to give a yellow residue. Purify the residue by silica gel flash chromatography to give an off-white foam. Suspend the foam in ACN and add HCL (5M in water; 1 mL). Freeze the resulting solution and lyophilize to obtain the title compound (50.5 mg, 0.12 mmol): mass spectrum (m/z): 446 (M+1-HCl).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([C:23](O)=[O:24])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][CH3:29].B.C1COCC1>C1COCC1>[OH:24][CH2:23][C:18]12[CH2:22][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:26])[N:3]([CH2:27][CH2:28][CH3:29])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:15][CH2:16][CH2:17]1)[CH2:21][CH2:20][CH2:19]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Agent: B
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CO)(CCC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane 1-carboxylic acid (700 mg) was taken in THF (25 ml). BH3.THF (1M, 3.5 ml) was added and stirred at rt overnight. Next day the reaction was quenched with MeOH. Solvent was removed by rotavap. Diluted with water and extracted with ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated. Yield 690 mg. Mass (ES+ 389)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15])(=O)C>S(=O)(=O)(O)O.C1COCC1.CCOCC>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:15]
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A solution of N-acetyl dimethyl oxindole (500 mg, 2.5 mmol) in 3 N sulfuric acid solution (7 mL) and THF (7 mL) was refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with ether. The ethereal layer was washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 30% EtOAc in hexanes) to give dimethyl oxindole as a red solid (228 mg, 57%).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([S:1][C:2]2[NH:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: Sc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)cc1
Temperature: 0 °C
Yield: 86 %

Procedure:
Acetonitrile (100 ml) suspension of 2-mercaptoimidazole (5.0 g) and 4-chloronitrobenzene (8.7 g), potassium carbonate (8.3 g) was stirred under refluxing for 1 day. The reaction mixture was poured into ice-water. The deposited solid matters were collected by filtration, washed with water and diethyl ether. The thus obtained solids were dried, there was obtained 2-(4-nitrophenylthio)imidazole (9.5 g, yield: 86%) as yellow powdery product.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH3:7][N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](Cl)=[O:10]>CCOC(C)=O.CCCCCCC>[N:2]1([O:1][C:9](=[O:10])[N:8]([CH3:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccnn1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)On1ccnn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-1,2,3-triazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (80%, oil). HPLC-MS m/z=219.1 (M+1), Rt: 2.50 min. Mp 105-106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:32][CH:29]2[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:27][CH2:28]2)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)c(F)c2)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared as a white solid from 2-fluoro-4′-(methylsulfonyl)-4-biphenylol (0.25 g, 0.94 mmol), N-Boc-4-piperidinemethanol (0.21 g, 0.94 mmol) and Ph3P (0.25 g, 0.94 mmol) in THF (6 mL) followed by diisopropyl azodicarboxylate (0.20 g, 94%, 0.94 mmol) in THF (2 mL) in a manner similar to Example 1, Step 2. The crude product was triturated with hot hexane containing 1% of MeOH to give 20 mg of the title compound as a white solid. The filtrate was purified by chromatography on a silica gel column eluted with 3:4 EtOAc/hexane to give additional 0.34 g (overall 83%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.99 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=7.4 Hz), 7.50-7.40 (m, 1H), 6.90-6.80 (m, 2H), 4.20-4.10 (m, 2H), 3.91 (d, 2H, J=6.4 Hz), 3.14 (s, 3H), 2.90-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 486 (M+Na).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:31](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.CO>[CH3:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(C(=O)c2ccc(Oc3nccnc3N3CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)-phenyl)methanone as prepared according to Scheme 3, (0.2 g, 0.5 mmol) in DMF (1 mL) was added cesium carbonate (0.2 g, 0.7 mmol) and iodomethane (0.04 mL, 0.6 mmol). The resulting mixture was stirred at RT overnight. LC/MS showed complete conversion. Compound crashed out in MeOH. Filtered the resulting orange solid and rinse with copious amounts of MeOH. Solids were dried by vacuum pump overnight to afford (1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 416.1.(M+1). IC50 (uM) ++++.
Reaction SMILES: N1CC(OCC2C=CC(C3SC4C(=NC=CC=4OC4C=CC(NC(NC5CC5)=O)=CC=4F)C=3)=NC=2)C1.C([O:40][CH2:41][C:42]([N:44]([CH2:49][C:50]1[CH:51]=[N:52][C:53]([C:56]2[S:64][C:63]3[C:58](=[N:59][CH:60]=[CH:61][C:62]=3[O:65][C:66]3[CH:67]=[N:68][C:69]([NH:72][C:73]([NH:75][CH:76]4[CH2:78][CH2:77]4)=[O:74])=[CH:70][CH:71]=3)[CH:57]=2)=[CH:54][CH:55]=1)[CH2:45][CH2:46][O:47][CH3:48])=[O:43])(=O)C>>[CH:76]1([NH:75][C:73](=[O:74])[NH:72][C:69]2[N:68]=[CH:67][C:66]([O:65][C:62]3[CH:61]=[CH:60][N:59]=[C:58]4[CH:57]=[C:56]([C:53]5[N:52]=[CH:51][C:50]([CH2:49][N:44]([CH2:45][CH2:46][O:47][CH3:48])[C:42](=[O:43])[CH2:41][OH:40])=[CH:55][CH:54]=5)[S:64][C:63]=34)=[CH:71][CH:70]=2)[CH2:77][CH2:78]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)COC(C)=O
Agent: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(COC5CNC5)cn4)sc23)c(F)c1)NC1CC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)CO

Procedure:
Compounds 411-412 (examples 260-261) were prepared in one step by reacting the amine precursor 401 (table 31), similarly to compound 30 (scheme 13). Compound 413 (example 262) was obtained similarly to compound 31 (scheme 13). Compounds 414-415 (examples 263-264) were prepared in two steps by reacting the corresponding amine precursors 402 (table 31) and 405 (scheme 76), similarly to compound 31 (scheme 13).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9]O.[Br-:11].[Br-:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Br:11][CH2:9][CH2:8][C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH2:2][Br:12]
Reactant: [Br-]
Reactant: OCCc1sccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: BrCCc1sccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
2.0 g of the compound obtained in Example 2 was dissolved in 40 mL of dichloromethane, and the resulting solution was cooled to below 5° C. 13.4 g of triphenylphosphine dibromide was added thereto, and the resulting mixture was warmed to room temperature, stirred for 4 hours, and concentrated by evaporation under reduced pressure. To the residue, 5 mL of ethyl acetate and then 15 mL of n-hexane were added. The resulting mixture was stirred for 1 hour at room temperature and 2 hours at below 5° C., filtered and condensed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to obtain 2.9 g (yield of 80%) of the title compound as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:7]([C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[C:10]([F:13])([F:12])[F:11])=[O:9])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Product: Cc1nc(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c(C(F)(F)F)o1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-methyl-5-trifluoromethyloxazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (58% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.98, 6.99, 3.75-3.95, 3.50-3.59, 2.55, 1.51, 0.71-0.80, 0.45-0.49, 0.06-0.12. MS (ES+) m/z 453 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]2[CH2:9][CH2:10][C@H:11](N)[C:12]3[C:19]([C:6]2=[C:5]([O:23][CH3:24])[C:4]=1[O:25][CH3:26])=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[C:14](=[O:15])[CH:13]=3.N([O-])=[O:28].[Na+]>>[OH:28][CH2:11][C@H:10]1[CH2:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:25][CH3:26])=[C:5]([O:23][CH3:24])[C:6]=2[C:19]2=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[C:14](=[O:15])[CH:13]=[C:12]12
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](N)CC2
Reactant: O=N[O-]
Agent: [Na+]
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](CO)C2

Procedure:
10 g of N-desacetylthiocolchicine are treated with sodium nitrite to give 4 g of 5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-methylthio-8H-cyclo-hepta[a]naphthalen-8-one, according to the process described in J. Med. Chem., 36, 544, 1993. The resulting product is treated for 12 hours under reflux in acetonitrile with 26 g of α-bromotetraacetylglucose in the presence of 85 g of mercuric cyanide. Salts are filtered off and the solution is evaporated to dryness, taken up with 70% acetone and treated for two hours with 15% sodium carbonate. The mixture is neutralized, extracted with ethyl acetate and chromatographed on silica gel eluting with a methylene chloride-ethanol 9:1 mixture. 2.1 g of product are obtained, M+ a m/z 536.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH2:16]([N:18]([CH2:26][CH3:27])[CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:25][CH:22]1[CH2:21][CH2:20][CH:19]([N:18]([CH2:26][CH3:27])[CH2:16][CH3:17])[CH2:24][CH2:23]1
Reactant: CCN(CC)C1CCC(N)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(Br)cc23)CC1
Yield: 92 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (116 mg, 0.408 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (138 mg, 0.812 mmol) to afford the desired product (157 mg, 51%) as an off-white solid: ESI MS m/z 418 [C21H28BrN3O+H]+.