Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C@@H:7]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[ClH:34]>CCOCC.O>[ClH:34].[ClH:34].[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C@@H:7]3[CH2:24][NH:25][CH2:26][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1cccnc1)C2=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCc1cc(C)c2c(c1)[C@@H]1CNC[C@H]1N(CCOc1cccnc1)C2=O
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-6-methyl-5-oxo-4-(2-(pyridin-3-yloxy)ethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (20 mg, 0.044 mmol) in 4 mL of ether was added 1 mL of 12 N HCl. The reaction was stirred vigorously for 5 min and then was diluted with 5 mL of water. The reaction was washed with ethyl acetate twice to remove the triphenylphosphine impurity. The aqueous layer was concentrated in vacuo, taken up in water, filtered and lyophilized to afford 8 mg (44%) of the title compound of Example 89 as a light tan powder. 1H NMR (DMSO-D6): δ 9.96-9.90 (broad m, 3H), 8.71 (s, 1H), 8.31-8.26 (m, 1H), 8.03-7.98 (m, 1H), 7.69-7.63 (m, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 4.28-4.23 (m, 1H), 4.20-4.15 (m, 1H), 4.07-4.00 (m, 1H), 3.90-3.84 3.82-3.70 (overlapping m, 2H), 3.55-3.49 (m, 1H), 3.46-3.39 (m, 1H), 3.33-3.26 (m, 1H), 3.21-3.14 (m, 1H), 2.50 (q, 2H, J=7.5 Hz), 2.46 (s, 3H), 1.08 (t, 3H, J=7.7 Hz). LRMS (ESI): 352.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:1][C:2]=3[CH3:7])=[CH:15][CH:16]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccc(O)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(O)cc4)cc3)c2)o1

Procedure:
N-(4-Hydroxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-hydroxybenzylamine using method H. NMR; δH [2H6]—DMSO 9.27,(1H, s), 9.02,(1H, t), 7.98,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.54,,(1H, d), 7.51,(2H, d), 7.13,(2H, d), 6.71,(2H, d), 4.39,(2H, d), 2.56,(3H, s), 2.31,(3H, s), LCMS; retention time 3.03 min, MH+ 400.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([NH:12][CH2:11][CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCC1COc2ccccc2O1
Solvent: ClCCl
Product: c1ccc(CNCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine (4.13 g), benzaldehyde (2.65 g) and methylene chloride (25 ml) is stirred for 3 hours at room temperature and the methylene chloride removed via evaporation. A solution of the residue in ethanol (30 ml) is hydrogenated at atmospheric pressure and room temperature in the presence of methanesulphonic acid (2.4 g) and 10% palladium on charcoal (0.4 g). After the calculated quantity of hydrogen is consumed (510 ml), the solution is filtered, the ethanol is removed via evaporation, the residue is made alkaline with saturated aqueous potassium carbonate, and the resulting solution is extracted with ether. Evaporation of the dried ether extract yields an oily residue of N-benzyl-(2,3-dihydro-1,4-benzodioxin-2-yl)methylamine (5.9 g).
Reaction SMILES: [CH3:1][C:2]1[C:9]2[N:8]3[CH:10]=[CH:11][CH:12]=[C:7]3/[C:6](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)C=O>O>[CH3:1][C:2]1[C:9]2[N:8]3[CH:10]=[CH:11][CH:12]=[C:7]3/[C:6](=[N:13]/[O:14][CH2:15][CH2:16][NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)/[C:5]=2[S:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2c1-n1cccc1/C2=N/OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCNCc1ccccc1
Yield: 64.8 %

Procedure:
Add 1 g (3.2 mmol) of (Z)-3-methyl-8-[(2-bromo-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole, 0.53 g (3.8 mmol) of potassium carbonate and 0.51 g (4.8 mmol) of benzylamine in succession to 20 ml of N,N-dimethylformamide. The reaction mixture is heated at reflux for 3 hours then, after cooling, is poured into 100 ml of water and extracted with diethyl ether. The ethereal phase is washed with water, dried over magnesium sulfate, rendered colourless with animal charcoal and then concentrated under reduced pressure to yield 0.7 g of the title product in the form of an oil (base).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33](=[O:35])[CH2:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]3[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=3[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Reactant: CCCCCCCNCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
N-[2-(4-Chlorophenyl)ethyl]-N-heptylamine (0.093 g, 0.366 mmol) was dissolved in DMF (5 ml). (4-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (0.100 g, 0.333 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.118 g, 0.366 mmol) and N-ethyl-N,N-diisopropylamine (0.090 g, 0.699 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of water (2×20 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.112 g of methyl 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (yield 62.7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][NH2:24].[OH-].[NH4+].O>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: NCCc1ccc2ccccc2c1
Reactant: Clc1ncnc2ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc2cc(CCNc3ncnc4ccccc34)ccc2c1
Yield: 26.4 %

Procedure:
A mixture of 1.0 g of 4-chloroquinazoline and 2.0 g of 2-(2-naphthyl)ethyl amine was heated under nitrogen to 165°-170° C. for one hour. The mixture was cooled and then 200 ml of a 50/50 mixture of ammonium hydroxide/water was added. The product was extracted into CH2Cl2, and the resulting solution was treated with charcoal and filtered. The solution was then concentrated to dryness, and the residue was recrystallized from a mixture of pentane and CH2Cl2 to give: 0.480 g of the title product. Yield: 26.7%. M.P. 172°-174° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9](=[O:30])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[C:13]([F:29])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9](=[O:30])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[C:13]([F:29])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)c(F)c1
Reaction time: 0.12 h
Yield: 83.9 %

Procedure:
Methyl 2-[(4-{2-[benzyl(hexyl)amino]-2-oxoethyl}-2-fluorophenoxy)methyl]benzoate (109 mg, 0.222 mmol) was dissolved in THF (2 ml). Lithium hydroxide (10.6 mg, 0.444 mmol) solved in water (1 ml) was added. The mixture was put in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes. It was then acidified with 1% hydrochloric acid, pH˜3, and extracted with ethyl acetate. The organic extract was washed with brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5: 99.5, then 1:99) as eluant gave 89 mg the desired product, yield 84%.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CN)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCc2ccc(OC)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(4-methoxyphenyl)methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (CD3CN) δ 7.50-7.33 (m, 5H), 6.79-6.74 (m, 4H), 6.34-6.26 (m, 1H), 4.08 (d, J=6.7 Hz, 2H), 3.75 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 1.81-1.71 (m, 2H), 1.49-1.38 (m, 2H), 0.97 (t, J=7.5 Hz, 3H); Mass spectrum: M−H+ 399.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[C:21]([CH3:28])[CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[C:21]([CH3:28])[CH:20]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Cc1cc(N)ccc1CC#N
Product: Cc1cc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)ccc1CC#N
Yield: 30.6 %

Procedure:
Following procedure A2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.120 g, 0.47 mmol) was reacted with 2-(4-amino-2-methylphenyl)acetonitrile (0.104 g, 0.71 mmol) to afford the title compound (0.054 g, 45%) as an off-white solid. MW=374.87. 1H NMR (DMSO-d6, 500 MHz) δ 9.31 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.79 (s, 1H), 7.63-7.54 (m, 3H), 7.36 (d, J=8.2 Hz, 1H), 3.99 (s, 2H), 3.01-2.94 (m, 2H), 2.93-2.87 (m, 2H), 2.36 (s, 3H), 2.14 (t, J=7.6 Hz, 2H); APCI MS m/z 375 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Li]CCCC.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C>C1COCC1>[F:10][C:5]1[CH:4]=[CH:3][C:2]([B:20]([OH:21])[OH:19])=[CH:7][C:6]=1[CH2:8][OH:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: OCc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To solution of (5-bromo-2-fluoro-phenyl)-methanol (1.0 eq) in THF (0.1M) at −78° C. was added dropwise n-BuLi (2.5M in Hex; 2.2 eq). The resulting mixture was stirred at −78° C. for 30 min then tri-isopropoxy borane (2.2 eq) was added. The final mixture was stirred 15 min at −78° C. then allowed to warm slowly to room temperature and stirred an extra hour. The reaction was quenched with HCl (10%) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in EtOAc, water (few drops) was added then hexane until a precipitate formed. After 12 h of stirring, the desired compound was isolated by filtration as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[F:11][C:12]1[CH:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:35][CH:34]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([OH:30])[C:21]=1[CH:31]=[O:32].O>CN(C)C=O>[CH2:7]([O:30][C:22]1[C:21]([CH:31]=[O:32])=[C:20]([CH:25]=[CH:24][C:23]=1[C:26]([F:29])([F:27])[F:28])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])=[CH:37][CH:38]=2)=[CH:13][C:12]=1[F:11])[CH:8]=[CH2:9]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)c(F)c2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C=O)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 23.7 %

Procedure:
Potassium carbonate (148 mg, 1.07 mmol) and allyl bromide (0.091 ml, 1.1 mmol) were successively added to a solution of allyl (3′-fluoro-4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (476 mg, 0.975 mmol) obtained in Example (12-4) in N,N-dimethylformamide (5 ml), and the mixture was stirred at 50° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1) to give allyl (4′-{[3-(allyloxy)-2-formyl-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate (122 mg, yield: 24%).
Reaction SMILES: [CH3:1]OC1C=C(NC2N=C(NC3C=CC(C(OC)=O)=C(OC)C=3)C(F)=CN=2)C=CC=1C(OC)=O.[CH3:34][C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[C:37]([CH3:44])[C:36]=1[OH:45].C(=O)([O-])[O-].[K+].[K+].IC>>[CH3:34][C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[C:37]([CH3:44])[C:36]=1[O:45][CH3:1]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(OC)c3)n2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c(C)cc([N+](=O)[O-])cc1C

Procedure:
In a manner analogous to the preparation of N2,N4-bis[3-methoxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,6-dimethyl-4-nitrophenol (1.67 g, 10 mmol), potassium carbonate (13 g, 0.1 mol) and iodomethane (2.5 mL, 50 mmol) gave 2,6-dimethyl-1-methoxy-4-nitrobenzene. Hydrogenation of 2,6-dimethyl-1-methoxy-4-nitrobenzene gave 3,5-dimethyl-4-methoxyaniline.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[CH:12][C:11]2[C:14](=[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[O:15][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[C:9]=1[Cl:33].[CH:34](O)(C)C>>[Cl:33][C:9]1[C:10]2[CH:16]([C:17]([CH:22]=[CH:21][CH3:34])=[CH:18][CH:19]=[CH2:20])[O:15][C:14](=[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[C:11]=2[CH:12]=[N:13][C:8]=1[NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5]
Reactant: NCC(O)CO
Reactant: CC(C)O
Reactant: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c1cnc(Cl)c2Cl
Product: C=CC=C(C=CC)C1OC(=C2C(=O)Nc3ccccc32)c2cnc(NCC(O)CO)c(Cl)c21
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 3-amino-propane-1,2-diol (225 mg, 2.47 mmol) in 4 mL of isopropanol is treated with 3-(6,7-Dichloro-1-phenyl-1H-furo[3,4-c]pyridin-3-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.25 mmol) in one portion. The reaction mixture is heated to reflux overnight, cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, gradient elution 5% MeOH/Chloroform to 15% MeOH/Chloroform). The product containing fractions are concentrated to give the title compound as a yellow solid (56 mg, 50%).
Reaction SMILES: I[CH2:2][C:3]1[N:4]([CH3:16])[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:8]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].O>CN(C)C=O>[CH3:16][N:4]1[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:8]=[C:3]1[CH2:2][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1c(CI)nc(-c2ccncn2)cc1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CN2C(=O)c3ccccc3C2=O)nc(-c2ccncn2)cc1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a solution of 14.80 g (45.11 mmol) of 2-iodomethyl-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 30 ml of anhydrous dimethylformamide was added 16.71 g (90.21 mmol) of potassium phthalimide. The resulting mixture was stirred at 130° C. for 3 h. After cooling, water was added and the resulting mixture was stirred for 12 h at 0° C. The precipitate was filtered, heated in ethyl acetate and the precipitate was filtered. The product was dried to give 5.3 g (30%) of pure compound as a brown solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:34][C:35]1[S:39][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][N:12]([S:40]([C:38]2[S:39][C:35]([Br:34])=[CH:36][CH:37]=2)(=[O:42])=[O:41])[CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(c1ccc(N2CCNC[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(Br)s3)C[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
The 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (147 mg, 0.404 mmol) was dissolved in CH2Cl2 (10 mL) was cooled to 0° C. To this solution was added triethylamine (124 μL, 0.889 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (127 mg, 0.485 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was concentrated and absorbed onto silica gel. The crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-((2S)-2-benzyl-4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (105 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(N(C(C)C)CC)(C)C>CC#N>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: BrCCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Temperature: 25 °C

Procedure:
To a solution of N-hydroxyphthalimide (2.0 g) and 1,3-dibromopropane (2.49 ml) in 50 ml of dry CH3CN was added diisopropylethylamine (4.27 ml). The mixture was stirred at room temperature. After 4 hours the volatiles were removed in vacuo. The residue was triturated with Et2O to provide 2.53 g of while solid, homogeneous by TLC.
Reaction SMILES: [OH:1][CH:2]([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])Cl)[CH3:17].O>CN(C)C=O>[CH2:10]=[C:6]([CH2:7][CH2:8][CH3:9])[CH:2]([O:1][Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:16][CH3:17])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(O)C(=C)CCC
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(O[Si](CC)(CC)CC)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 30.0 g. of 4-hydroxy-5-methylene-1-octyne and 31.02 g. of imidazole in 80 ml of dimethylformamide at 0° C., is added 40.9 g. of triethychlorosilane. The mixture is stirred at room temperature for 30 minutes, poured into cold water and extracted with petroleum ether. The petroleum ether is removed and the residue is distilled. The product is recovered in the fraction boiling at 103°-106° C. (1.5 mm.).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]2[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]12)=[O:4].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:11]1([C:8]2[N:7]3[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:30][CH2:31]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3)CC1)CC=C2c1ccccc1

Procedure:
A mixture of 3.8 g of 4-(chloroacetyl)-4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3carbonitrile, 2.5 ml of N-benzylpiperazine and 1.6 g of sodium carbonate in 165 ml of toluene was reacted as described in Example 146, giving 4 g of the desired product, mp 156-158.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N:17]1([C:14]([C:11]2[CH:10]=[N:9][C:8]([Cl:7])=[CH:13][N:12]=2)=[O:16])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: C1CNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cnc(Cl)cn1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Oxalyl chloride (1.55 mL, 17.5 mmol), followed by DMF (2 drops), was added to a mixture of 5-chloropyrazine-2-carboxylic acid (CAS no. 36070-80-1, Intermediate 33) (2.31 g, 14.6 mmol) in DCM (40 mL). The reaction was stirred at RT for 2 hours after which time the volatiles were removed under reduced pressure. The residue was taken up DCM (40 mL) and azetidine (1.08 mL, 16.03 mmol) and triethylamine (4.46 mL, 32.06 mmol) added. The mixture was stirred at RT for 72 hours. The volatiles were removed under reduced pressure and ethyl acetate (100 mL) added to the residue. The organics were washed with water (100 mL), citric acid (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of 50-100% ethyl acetate in isohexane, to afford the product (2.38 g, 82%). 1HNMR δ (400 MHZ, CDCl3): 2.35-2.42 (2H, m), 4.26 (2H, t), 4.67 (2H, t), 8.52 (1H, d), 9.09 (1H, d); m/z 198 (M+H)+.