Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:2][O:3][N:4]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Br:5])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CON
Reactant: COC(=O)C(=O)c1ccccc1Br
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1Br

Procedure:
5.2 g (62 mmol) of O-methylhydroxylamine hydrochloride is added to a solution of 10 g (41 mmol) of methyl 2-bromophenylglyoxylate in 30 ml of methanol, and the mixture is refluxed for 2 hours. The mixture is evaporated down, and the residue is taken up in ethyl acetate and washed with water. After drying and evaporating down, there remains 6.9 g (62%) of compound E.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[OH-].[Li+].OO.S(=O)(O)[O-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)C(C)(C)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])O
Agent: OO
Solvent: C1CCOC1
Product: CC1(C)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
6 g (R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-one is added to THF (6 ml). Lithium hydroxide (15.6 ml, 3 mol L−1) is added followed by tetra-butylammonium bromide (0.15 g). This mixture is then added to a mixture of hydrogen peroxide (4.54 g) and THF (12 ml) at 0° C. After 2.5 h, sodium bisulfite solution (12 g, 38-40%) is added. THF is removed in vacuo. Toluene (70 ml) is added and the phases separated. The organic phase is washed with water (15 ml). The phases are separated. The organic phase is concentrated in vacuo and then heptane (60 ml) is added and the mixture cooled to 0° C.). The precipitate is collected by filtration and dried in vacuo to give (R)-5-Biphenyl-4-ylmethyl-3,3-dimethylpyrrolidin-2-one 1H NMR (DMSO): 0.96 (3H), 0.97 (3H), 1.52 (1H), 1.78 (1H), 2.61 (1H), 2.93 (1H), 3.75 (1H), 7.32 (3H), 7.45 (2H), 7.58 (2H), 7.63 (2H), 7.70 (1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: OCCC1CCNCC1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OCCC1CCN(CCCCl)CC1
Yield: 38.9 %

Procedure:
4-Piperidine ethanol (0.9 g, 7.5 mmol), acetone (18 ml, 20 vol), 5M NaOH solution (1.8 ml) and 1-bromo-3-chloropropane (3.54 g, 22.5 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (0.6 g, 37%) as an orange oil.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(O)=O.[Na+]>CCO>[NH2:9][C:8]1[C:3]([N:2]([CH3:12])[CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ncccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ncccc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A stirred mixture of the product from Step 1 (1.05 g, 0.00628 mol), stannous chloride dihydrate (7.09 g, 0.03141 mol) and absolute EtOH (13.9 ml), under nitrogen, was warmed to 80° C. during 30 minutes and kept at that temperature for an additional 30 minutes. The mixture was cooled and kept at ambient temperature for 1 hour. It was then poured onto ice (200 ml), treated slowly with solid NaHCO3 (2.88 g) and adjusted to pH 8 with saturated NaHCO3. This mixture was extracted with EtOAc; the extract was washed with water, dried (Na2SO4) and concentrated to give the titled product (0.738 g), a dark oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]CC)=[O:24].[Li+].[OH-].Cl>C(OCC)(=O)C.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
A mixture of ethyl (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate (0.23 g, 0.63 mmol) and LiOH (0.10 g, 4.20 mmol) in MeOH/H2O (1/1, 20.0 mL) was stirred at ambient temperature for 20 hours. The mixture was acidified with 0.1 M HCl until pH 2-3. The solid was filtered off and dried to give the title compound (0.15 g, 70%): MS (ES−) m/z 336.3 (M−1).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[NH:17]C(=O)C(F)(F)F)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:17][C:10]1[CH:11]=[CH:12][C:13]([CH:15]=[CH2:16])=[CH:14][C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: C=Cc1ccc(NC(=O)C(F)(F)F)c(C(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=Cc1ccc(N)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
N-(2-Benzoyl-4-vinylphenyl)-2,2,2-trifluoroacetamide (b) (0.32 g, 1.0 mmol) was dissolved in a mixture of methanol (38 mL) and water (2.3 mL) and potassium carbonate (0.7 g, 5 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated. Water (20 mL) was added to the residue and the mixture was extracted with chloroform (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel [hexanes:ethyl acetate (9:1)] to produce 2-amino-5-vinylbenzophenone (c) (0.2 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.60 (m, 2H), 7.60-7.40 (m, 5H), 6.72 (d, J=10 Hz, 1H), 6.65 (dd, J=11, 19.6 Hz, 1H), 6.16 (s, br, 2H), 5.56 (d, J=19.6 Hz, 1H), 5.03 (d, J=11 Hz,1H). MS: 224.2 (M+H).
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[S:14]1[C:18]2=[CH:19][CH:20]=[CH:21][C:22]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[C:17]2[N:16]=[CH:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:13][CH:2]([F:1])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:6][CH2:7][N:8]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[S:14][CH:15]=[N:16][C:17]=34)(=[O:25])=[O:24])=[CH:35][CH:34]=2)=[O:32])[CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Reactant: CC(CC1(O)CCNCC1)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added 4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (110 mg 0.57 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (190 mg, 0.57 mmol), DIPEA (367 mg, 2.8 mmol), HATU (261 mg, 0.69 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 5.90-5.61 (m, 1H), 4.36 (s, 1H), 3.57-3.42 (m, 1H), 3.21 (s, 2H), 2.24 (d, J=7.6 Hz, 1H), 2.05 (s, 1H), 1.86-1.77 (m, 2H), 1.36 (dd, J=14.8, 6.3 Hz, 4H), 1.10 (d, J=7.0 Hz, 3H). LC-MS: m/z 510.5 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[CH:10]#[N:11]>[Ni].C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH2:10][NH2:11]
Reactant: Cn1ncc(C=O)c1N
Reactant: C#N
Agent: [Ni]
Solvent: CC(=O)O
Product: Cn1ncc(C(O)CN)c1N

Procedure:
The objective was to build the 3,4,5-trihydro-1,3-diazepin-5-ol moiety using as a template the 5-amino-1-methylpyrazole-4-carboxaldehyde, 6. This aldehyde may be readily prepared from the partial reduction and in situ hydrolysis of the corresponding nitrile, compound 5. ##STR5## The presentation of the aldehyde 6 involved the reduction of nitrile 5 with an activated form of Raney nickel (see Dominquez et al, J. Org. Chem. 1961, 26, 1625; T-1 Raney Nickel) in 70% aqueous acetic acid. Through a modification of the Kiliani-Fischer cyanohydrin homologation sequence, it was proposed to add hydrogen cyanide in this aldehyde and subsequently to reduce the nitrile portion of the resulting cyanohydrin 7. ##STR6## This transformation would provide the 5-amino-4-(β-amino-α-hydroxyethyl)-1-methylpyrazole, intermediate 8. This intermediate would be subsequently ring closed with triethylorthoformate to afford the requisite 4,5,6-trihydro-1-methylpyrazolo[5,4-d] [1,2] diazepin-4-ol, compound 9. ##STR7##
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of benzyl piperazine-1-carboxylate (0.5 g, 2.270 mmol) and TEA (0.949 mL, 6.81 mmol) in THF (10 mL) was added methyl 2-bromoacetate (0.230 mL, 2.497 mmol) dropwise. The reaction was stirred at 65° C. After 1 hour, the reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to generate benzyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate as a clear oil (0.61 g, 92% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9].[NH2:16][NH2:17]>C(O)C>[C:10]1([C:6]2[CH:5]=[N:17][N:16]=[C:2]3[NH:3][N:4]=[C:8]([NH2:9])[C:7]=23)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(-c2ccccc2)cnnc1Cl
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2nncc(-c3ccccc3)c12

Procedure:
3-Chloro-5-phenyl-pyridazine-4-carbonitrile obtained from Step B was suspended in 1 mL ethanol with 23 μL hydrazine and the mixture was refluxed for several hours. The solvent was then evaporated and the title product was purified by silica gel chromatography (1:9 methanol/dichloromethane): MS (ES+) 212 (M+H); HPLC 1.121 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH:5]([OH:38])[CH2:6][CH:7]([OH:37])[CH:8]=[CH:9][C:10]1[N:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:17])[CH3:16]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH:5]([OH:38])[CH2:6][CH:7]([OH:37])[CH2:8][CH2:9][C:10]1[N:11]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)CC(O)CC(O)C=Cc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(O)CC(O)CCc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid methyl ester (1.190 g, 2.21 mmol) in MeOH (50 ml) was added Pd—C (0.1 g). The reaction vessel was evacuated, flushed with nitrogen and then filled with hydrogen (via balloon). Reaction was stirred at 25° C. for 4 hrs. Reaction was then flushed with nitrogen and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography (30-40% EtOAc/Hex) to afford 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid methyl ester (0.792 g, 66%): MS(APCI+) 540.2 m/z (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.O1CCCC1.C[Si](C)(C)[C:35](F)([F:37])[F:36].[I-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23]4([C:35]([F:37])([F:36])[CH2:26]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 115 °C
Yield: 79 %

Procedure:
To a 10 mL microwave tube charged with tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate (0.475 g, 1.27 mmol) and tetrahydrofuran (4 mL) was added trimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide (0.42 g, 2.79 mmol). The reaction mixture was heated at 115° C. for 1 hour. After cooling to ambient temperature, additional trimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide (0.42 mg, 2.79 mmol) were added. The reaction was heated at 115° C. for another 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.426 g, 79%) as a colorless oil: MS (ES+) m/z 369.1 (M−55).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].CO.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([C:19]1[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:24]
Reactant: O=Cc1ccccc1Cl
Reactant: Fc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: OC(c1ccccc1Cl)c1cccnc1F
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
Add diisopropylamine-(286.6 g, 2.83 mol) to a −63° C. solution of n-butyllithium (2.47 M in hexanes, 917 mL, 2.27 mol) while maintaining the temperature below −38° C. Add tetrahydrofuran (1.20 L) while maintaining the temperature below −43° C. To the resulting solution add 2-fluoropyridine (200.0 g, 2.06 mol) while maintaining the temperature between −66° C. and −57° C. Stir the resulting solution between −72° C. and −57° C. for 45 min. To this solution add a solution of 2-chlorobenzaldehyde (318.5 g, 2.27 mol) in tetrahydrofuran (125 mL) while maintaining the temperature between −70° C. and −39° C. Stir the resulting solution between −73° C. to −50° C. for 1 h, and then add methanol (198 g, 6.18 mol). Allow the solution to warm to −30° C. and stir for 30 min. Add the resulting solution to a −13° C. mixture of toluene (1.20 L) and 3 N hydrochloric acid (1.85 L, 5.55 mol). Separate the layers and extract the aqueous layer with toluene (1.2 L). Extract the combined organic layers with water (1.8 L), and then concentrate this solution at 60° C. under reduced pressure to an approximate weight of 910 g. Cool the solution to 25° C. Crystallization will occur. Stir the resulting slurry for 1 h. Add cyclohexane (2.0 L) over a period of 5 min, and then stir the resulting slurry for 14 h. Collect the resulting solid by filtration and wash the solid with cyclohexane (500 mL). Dry the solid under vacuum at 45° C. for 4 h to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 6.17 (d, J=4.80 Hz, 1H) 6.35 (d, J=4.80 Hz, 1H) 7.29-7.38 (m, 2H) 7.42 (t, J=7.71 Hz, 1H) 7.41-7.46 (m, 1H) 7.61-7.67 (m, 1H) 7.75-7.88 (m, 1H) 8.16 (d, J=4.55 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](C(O)=O)=[CH:7][C:6]=2[CH:13]=1>CN1CCCC1=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: [Cu]
Solvent: CN1CCCC1=O
Product: Clc1ccc2occc2c1
Temperature: 250 °C
Yield: 418.7 %

Procedure:
To a solution of 5-chloro-1-benzofuran-2-carboxylic acid (0.2 g) in 1-methyl-2-pyrrolidinone (2 ml) was added copper granules (0.2 g). The reaction mixture was heated at 250° C. for 3.5 min in a microwave. The reaction vessel was cooled to room temperature and the mixture combined with four other similar mixtures and the combined mixtures partitioned between water and diethyl ether. The organic layer was washed with water and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.65 g) as a yellow oil.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:73][N:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][C:59]([F:62])([F:61])[F:60])=[CH:53][C:52]=2[N:63]([CH3:72])[S:64]([C:67]1[S:68][CH:69]=[CH:70][CH:71]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.CSC>ClCCl.O>[CH3:72][N:63]([C:52]1[CH:53]=[C:54]([O:58][C:59]([F:62])([F:60])[F:61])[CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:73][N:74]3[CH2:79][CH2:78][O:77][CH2:76][CH2:75]3)[CH2:45][N:46]=1)=[CH:57]2)[S:64]([C:67]1[S:68][CH:69]=[CH:70][CH:71]=1)(=[O:65])=[O:66]
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a solution of triphenylphosphine oxide (670 mg) in dichloromethane (15 mL) was added trifluoromethanesulfonic anhydride (340 mg) under ice-cooling, and the mixture was stirred for 10 min. A solution of N-[2-(benzylthio)-3-morpholinopropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (400 mg) and dimethylsulfide (40 mg) in dichloromethane (15 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio). The obtained compound was further purified by preparative HPLC to give the title compound (150 mg, yield 44%) as white crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 165-166° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.O>CS(C)=O>[Cl:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:25][CH2:24]1
Reactant: Clc1cccc(Cl)c1N1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FC(F)(F)c1ccc2nc(N3CCN(c4c(Cl)cccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of the benzoimidazole from step (c) above (75 mg, 0.34 mmol), the piperazine from step (a) above (90 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.58 mmol, Aldrich) in DMSO (2 mL) was stirred at 80° C. for 24 h. The mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×10 mL) and brine (5 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexane to give the title compound as a white solid. M.p. 263-265° C. MS (ESI, pos. ion) m/z: 415 (M+1).
Reaction SMILES: [O:1]1[C:5]([CH3:12])([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]1[CH2:3][OH:4].[OH:13][CH2:14][CH2:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[OH:13][CH2:14][CH2:15][N:16]([CH3:17])[CH:2]([C:5]([CH3:12])([OH:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][OH:4]
Reactant: CNCCO
Reactant: CC(C)CCCC1(C)OC1CO
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)(O)C(CO)N(C)CCO
Yield: 85 %

Procedure:
A solution of 17.2 g of 2,3-epoxy-3,7-dimethyl-1-octanol, 15.0 g of (2-hydroxyethyl)methylamine and 20 ml of toluene was refluxed for 4 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure to give 21.0 g (yield 85%) of 2-[(2hydroxyethyl)methylamino]-3,7-dimethyl-1,3-octanediol Compound (60)]. The physical constants of Compound (60) are as follows.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[O:11][CH2:10][CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[O:15]1[CH2:16][CH2:17][N:12]([C:4]2[C:5]3[O:11][CH2:10][CH2:9][O:8][C:6]=3[N:7]=[C:2]([C:26]3[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[N:3]=2)[CH2:13][CH2:14]1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OCCO2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCCO3)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (114 mg, 0.44 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (196 mg, 0.88 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) and cesium carbonate (430 mg, 1.32 mmol) in dioxane (5 mL) and water (0.5 mL) was degassed and then heated at 100° C. for 2 hours. Further 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (100 mg, 0.44 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) were added and the mixture heated at 100° C. for a further 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-10% methanol in DCM) then triturated with diethyl ether affording 101 (37 mg, 27%). LCMS: RT=2.75 min, [M+H]+=317. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.01 (2H, s), 4.42-4.36 (2H, m), 4.25-4.18 (2H, m), 3.70 (8H, s).