Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:9]1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:28]([NH2:31])[CH2:29][NH2:30]>>[ClH:26].[ClH:26].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:9]1[NH:30][CH2:29][CH2:28][NH2:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=S(=O)(c1ccccc1)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Solvent: O
Product: Cl
Product: NCCNc1c(S(=O)(=O)c2ccccc2)c2ccccc2n1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A suspension of 1-benzyl-2-chloro-3-phenylsulfonylindole (1.0 g, 2.6 mmol) in ethylene diamine (10 ml) was heated at 80° for 1 hour. Water was added to the solution and the aqueous phase was decanted from the gummy material which separated after standing for 20 min. To this gum was added excess ethereal hydrogen chloride followed by dichloromethane. The gelatinous solid which formed was collected by filtration, washed with ethyl acetate and dried to give a solid. This solid was recrystallized from dichloromethane to give the title compound.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.Br[CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[CH:23]=1.C(N(CC)CC)C.CN(C=O)C>CCOC(C)=O>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][C:22]4[CH:31]=[CH:30][C:25]5[C:26](=[O:29])[O:27][CH2:28][C:24]=5[CH:23]=4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1OCc2cc(CCBr)ccc21
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc5nonc5c4)C(=O)C3)ccc21
Temperature: 60 °C

Procedure:
A mixture of 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one (54 mg, 0.22 mmol), 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one (105 mg, 0.44 mol), Triethylamine (0.15 mL, 1.1 mmol), and DMF (1.5 mL) was heated to 60° C. for 24 hours. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by prep-TLC (5% MeOH in DCM) to deliver the title product. LC-MS (IE, m/z): 407 [M+1]+.
Reaction SMILES: [P:1]([O:5][CH2:6][CH:7]([OH:10])[CH:8]=[O:9])([OH:4])([OH:3])=[O:2].C(O)[CH:12]([OH:19])[CH2:13][O:14]P(O)(O)=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[P:1]([O:5][CH2:6][C@@H:7]([OH:10])[C@@H:8]([OH:9])[C@@H:12]([OH:19])[CH:13]=[O:14])([OH:4])([OH:3])=[O:2]
Reactant: O=P(O)(O)OCC(O)CO
Reactant: O=CC(O)COP(=O)(O)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: O=C[C@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Temperature: 30 °C

Procedure:
Crude cell extracts were prepared in 100 mM Tris/HCl at pH 7.8. Determination of TKT activity required application of several coupling enzymes. RPI and RPE served as coupling enzymes to provide the substrates ribulose 5-phosphate and xylulose 5-phosphate from ribose 5-phosphate (R5P) supplied in the assay. Online monitoring at 340 nm was enabled by further conversion of glyceraldehyde 3-phosphate as product of the TKT reaction by triosephosphate isomerase and glycerophosphate dehydrogenase (TPI/GDH). In contrast to the above mentioned procedure, two distinct mastermixes were prepared. Mix A contained buffer, TPI, RPI, RPE and NADH in a total volume of 650 μl, mix B contained buffer, TPP, MgCl2 and cell extract in a total volume of 300 μl. Both were pre-warmed for 10 min at 30° C. Ribose 5-phosphate was provided in the cuvette and the reaction was started by subsequent addition of mix B and mix A. The final reaction mix contained 50 mM Tris/HCl (pH 7.8), 0.5 mM NADH, 1 U RPI, 0.5 U RPE, 1 U TPI/GDH, 10 mM MgCl2, 0.2 mM TPP, 20 mM R5P and 50 μl of crude cell extract.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H][H]>[Pd].CC1CCCCC1>[CH3:2][O:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: COc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC1CCCCC1
Solvent: O
Product: COC1CCC(=O)CC1

Procedure:
0.5 g of borax and 0.5 g of water were mixed and 6 g of a catalyst which was moist with water (water content=50 %) and comprised 5% by weight of palladium on carbon were then mixed in. The resulting mixture was added to a solution of 100 g of p-methoxyphenol in 150 g of methylcyclohexane and this reaction mixture was hydrogenated in a stirred reactor at from 150 to 180° C. and from 3 to 8 bar of hydrogen pressure until no more hydrogen was absorbed. After a hydrogenation time of 72 minutes, 96.2% by weight of the p-methoxyphenol had reacted and p-methoxycyclohexanone had been formed in a yield of 83% by weight.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CCCCN(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCCCN(CC2CC2)C1=O

Procedure:
A solution of tert-butyl [3-(cyclopropylmethyl)-2-oxo-1,3-diazepan-1-yl]acetate from Step D (240 mg, 0.85 mmol) in CH2Cl2 (5 mL) and CF3CO2H (2 mL) was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo and the residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=227 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].CCOC(C)=O.O>CN1CCN(C)C1=O.[Cu]I>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([C:24]#[N:25])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: O=C1c2cc(Br)ccc2C[C@@H]2CN(Cc3ccccc3)CCN12
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Temperature: 190 °C
Reaction time: 1.38 h

Procedure:
Mixture of (R)-2-benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (25 mg, 0.067 mmol), CuCN (12.9 mg, 0.14 mmol) and CuI (3.7 mg, 0.29 mmol) in 1,3-dimethyl-2-imidazolidinone (1.5 mL) was stirred at 190° C. for 83 min in microwave. The reaction was cooled to RT and added EtOAc (20 mL) and H2O (5 mL). Filtered off the precipitate and rinsed with EtOAc (50 mL). The organic layer was separated and washed with brine (5 mL), dried over MgSO4, and conc in vacuo to give crude product. Purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to yield crude product as a yellow oil. MS (ESI) 318 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 5-methyl-3-(2-methyl-5-nitrophenylsulfonyloxy)phenol (1.46 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.6 g, 8.0 mmol) and 1,3-propanediol (2.3 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (2.0 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (80 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a yellow oil (920 mg, 48%). 1H-NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.37 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.25 (s, 3H), 1.99 (m, 2H), 1.58 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].Cl[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([CH:1]=[O:2])[C:4]=1[O:13][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: COC(=O)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C=O)c1OCC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A mixture of 3.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.31 g of t-butyl chloroacetate, 12.0 g of potassium carbonate and 40 ml of dimethylformamide is heated at 70° C. for 2.5 hours. After cooling, the reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in trifluoroacetic acid and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with ether to give 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:41])[CH2:38][N:39]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH3:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CNCC(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.61 g; 2.66 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (66) (0.75 g; 2.22 mmol), N,N-diisopropylethylamine (0.63 g; 4.87 mmol) and PyBOP (1.38 g; 2.66 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (60%→80% ethyl acetate in hexanes) affording the desired product (67) as a clear oil. CIMS: MH+ 550
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:8][CH2:9][CH2:10][C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:14]=3[O:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.[OH2:42]>ClCCl>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8]([CH2:9][CH2:10][C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:14]=3[O:13][CH:12]=2)(=[O:39])=[O:42])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)COc1cccc2c(CCSC(c3ccccc3)c3ccccc3)coc12
Solvent: ClCCl
Product: O=C(O)COc1cccc2c(CCS(=O)(=O)C(c3ccccc3)c3ccccc3)coc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
(3-(2-(diphenylmethyl)thioethyl)benzofuran-7-yloxy)acetic acid (126 mg) was dissolved in dichloromethane (2 ml) and the obtained solution was cooled to 0° C. To this solution, m-chloroperbenzoic acid (143 mg) was added and the resulting mixture was stirred for 2 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium thiosulfate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/2+5% acetic acid) using silica gel to obtain the desired compound (97 mg, yield: 72%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>C(Cl)Cl.CCOCC>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
Diisopropylethylamine (0.23 mL, 1.30 mmol) was added to a suspension of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (prepared as in Example 2, Step 1, 0.165 g, 0.43 mmol) in CH2Cl2 (10 mL). The mixture was cooled to 0° C. in an ice bath, and isopropyl chloroformate (1.0M in toluene, 0.48 mL, 0.48 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, and stirred for 1.5 h, then diluted with ether, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column eluted with 45 to 50% EtOAc/hexane to give 0.152 g (82%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.97 (d, 2H, J=8.3 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.64 (d, 2H, J=8.8 Hz), 7.04 (d, 2H, J=8.8 Hz), 4.90-4.80 (m, 1H), 4.20-4.10 (m, 2H), 3.90 (d, 2H, J=6.1 Hz), 3.13 (s, 3H), 2.95-2.75 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 432 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]2[NH:9][C:10]([NH:12][C:13]3[C:14]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:35]>C1COCC1>[C:1]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]=[C:10]([NH:12][C:13]3[C:14]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][CH:16]=[CH:17][CH:18]=3)[N:11]([CH3:35])[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1ccc2[nH]c(Nc3cccnc3Oc3ccccc3C(C)(C)C)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(Nc2cccnc2Oc2ccccc2C(C)(C)C)nc2ccc(C(C)(C)C)cc21
Reaction time: 0.18 h

Procedure:
5-tert-Butyl-N-(2-(2-tert-butylphenoxy)pyridine-3-yl)-1H-benzo[d]imidazol-2-amine (Example 6, 50 mg, 0.121 mmol) was dissolved in THF (2 mL). At 0° C., NaH (2.6 mg, 0.109 mmol) was added and the mixture stirred for 11 min. ICH3 (15 mg, 0.109 mmol) was then slowly introduced. The solution turned purple. After 15 min additional stirring, the solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel (eluting with a continuous gradient of MeOH from 0% to 5% in CH2Cl2). tR=6.265 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C27H32N4O [M+H]+ 429.2654. found 429.2636.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]4[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cnc(N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)nc1
Temperature: 120 °C

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.10 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 2-chloro-5-ethylpyrimidine (27 mg, 0.20 mmol). The mixture was heated in a microwave at 120° C. for 10 min. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-chloro-N2-(4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 522.2 (M+H+).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[OH:5][CH:6]([CH3:16])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:15])[CH3:14]>C(O)C.CO.CCOCC>[OH:4][CH:2]([CH3:3])[CH2:1][N:8]([CH2:7][CH:6]([OH:5])[CH3:16])[CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC1CO1
Reactant: CC(O)CNCCNCC(C)O
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: CC(O)CNCCN(CC(C)O)CC(C)O
Yield: 55 %

Procedure:
(V-a): Propylene oxide (181.6 g, 0.3 mol) in 25 mL of absolute ethanol was added dropwise for 4.5 hours to a solution of N,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) (55 g, 0.3 mol) in 50 mL each of absolute ethanol, methanol and distilled water at 80° C. The reaction mixture was cooled and concentrated to give a milky white viscous suspension. The suspension was dissolved in ether and dried over anhydrous sodium sulfate. Unreacted (IV-a) precipitated and was removed by filtration. Ether was removed from the clear filtrate to produce a viscous liquid. Fractional distillation of the oil produced N,N,N'-tris(2-hydroxypropyl)ethylenediamine[bp. 140° C. at 0.15 mm; yield 55 percent; IR(neet); 3350(broad OH); NMR(CDCl3): δ 3.8(broad m,3H); 2.5(broad m,10H); 1.1(d,9H)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>C(#N)C>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CNCCN1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reaction time: 3 h

Procedure:
A solution of Example 500A (500 mg, 4.99 mmol) in acetonitrile (25 mL) at room temperature was treated with BOC2O (1198 mg, 5.49 mmol), stirred for 3 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5 ethyl acetate/methanol to provide the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[C:2]#[C:3]C.C([Li])CCC.[CH3:21][O:22][C:23]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]([N+:35]([O-:37])=[O:36])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:39])([CH3:38])[O:28]2.CCOCC>C1COCC1.O=[Mn]=O>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][C:33]([C:32]2[C:23]([O:22][CH3:21])=[C:24]3[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=2)[O:28][C:27]([CH3:39])([CH3:38])[CH:26]=[CH:25]3)=[O:34])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1c(C=O)cc([N+](=O)[O-])c2c1C=CC(C)(C)O2
Reactant: CC#CCOc1ccc(OC)c(OC)c1
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(OCC#CC(=O)c2cc([N+](=O)[O-])c3c(c2OC)C=CC(C)(C)O3)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 4-but-2-ynyloxy-1,2-dimethoxybenzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 ml of 1.6 M solution in THF, 8.86 mmol) at −78° C. After 30 min., 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde (2.17 g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. The resulting crude material is dissolved in dichloromethane (20 mL) and MnO2 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to afford 4-(3,4-dimethoxy-phenyoxy)-1-(5-methoxy-2,2-dimethyl-8-nitro-2H-chromen-6-yl)-but-2-yn-1-one.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH2:32]=O>C(O)=O>[O:11]=[C:10]1[N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[CH2:32][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:4][CH:5]=1
Reactant: C=O
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Solvent: O=CO
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CN2C(c3ccc(Cl)cc3)C(c3ccccc3)CN12

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide in 5 ml of formic acid was added 0.57 g of formalin. The mixture was heated at reflux for 30 minutes and then partitioned between dichloromethane and water. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the expected compound, mp 184°-187° C.
Reaction SMILES: [C:1]([C:5]12[CH2:11][CH:9]([CH2:10]1)[CH2:8][CH:7]([C:12]([O:14]C)=[O:13])[CH2:6]2)([O:3]C)=[O:2].O.[OH-].[Li+]>O1CCCC1.C(O)(C)C.O>[C:1]([C:5]12[CH2:11][CH:9]([CH2:10]1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]2)([OH:3])=[O:2]
Reactant: COC(=O)C1CC2CC(C(=O)OC)(C2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC2CC(C(=O)O)(C2)C1
Yield: 379.1 %

Procedure:
A stirred solution of 1,3-dicarbomethoxybicyclo[3.1.1]heptane (1.90 g, 8.95 mmol) in tetrahydrofuran (25 mL) and isopropanol (8 mL) was treated with a solution of lithium hydroxide hydrate (2.1 g, 50 mmol) in water (25 mL), and the mixture was heated to 60°-70° C. for 3 h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was cooled on an ice bath and acidified with 6N hydrochloric acid (10 mL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum to afford 6.25 g (86%) of subject material as a white solid. No MS could be obtained. 1H NMR (CDCl3) δ 2.40-2.50 (m, 2H), 1.90-2.00 (m, 4H), 1.80-1.90 (m, 2H), 1.70-1.80 (m, 2H).