Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:18]3[C@H:14]([O:15]C(C)(C)[O:17]3)[CH2:13][S:12]2)=[C:4]([Cl:21])[N:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:18]([OH:17])[C@H:14]([OH:15])[CH2:13][S:12]2)=[C:4]([Cl:21])[N:3]=1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(Cl)nc(Cl)nc43)SC[C@H]2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O[C@H]1[C@H](O)CS[C@H]1n1cnc2c(Cl)nc(Cl)nc21
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2,6-dichloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine, prepared in Step 1, in tetrahydrofuran (20 ml) was added 2 N HCl, followed by stirring the solution overnight. The reaction mixture was neutralized with 1 N sodium hydroxide and carefully concentrated in a vacuum. The concentrate was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (20:1, v/v) as an elution solvent to afford the object compound as a white solid (1.94 g, 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[O:13])[O:9][N:8]=2)[CH:2]=1.[OH-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)=[O:13])[O:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(C(=O)O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
) A mixture of compound (56) (0.001 mol) in methanol (100 ml) was cooled to 0° C. NaOH 1N (0.0288 mol) was added and the reaction mixture was stirred overnight at RT. The reaction mixture was re-cooled to 0° C. 1 N HCl (30 ml) was added and this mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was crystallized from ethanol. The precipitate was filtered off, washed with ethanol, and dried, yielding 0.2 g (5.2%) (±)-4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-α-phenylbenzeneacetic acid (compound 406).
Reaction SMILES: [CH2:1]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[C:14]([C:21]([OH:23])=[O:22])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)(Cl)=O.[OH:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[CH:31][CH:30]=1>>[CH2:1]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:28][C:29]2[CH:44]=[CH:43][C:32]([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[CH:31][CH:30]=2)=[O:17])=[C:14]([C:21]([OH:23])=[O:22])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCc1ccc(C(=O)Cl)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)c(C(=O)O)c1

Procedure:
By customary procedures, 3.5 g of benzyl 4-undecylcarboxybenzoate was prepared from 2.3 g of benzyl 4-hydroxybenzoate and 2.5 g of lauric acid chloride, and this ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2.8 g of 4-undecylcarboxybenzoic acid. The acid was converted to 4-undecylcarboxybenzoic acid chloride by thionyl chloride and the acid chloride was reacted with 1.8 g of benzyl 4-hydroxybenzoate to form benzyl 4-(4-undecylcarboxybenzoyloxy)benzoate. The ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to isolate the benzyl group and obtain 3.0 g of 4-(4'undecylcarboxybenzoyloxy)benzoic acid.
Reaction SMILES: N1C=CC=CC=1N[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OCCC[CH2:48][NH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N+:51]=1[O-].N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[N:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[NH:49][CH2:48][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([CH:22]([CH3:23])[CH3:24])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)C(C(=O)O)c1cccc(OCCCNc2ccccn2)c1
Reactant: [O-][n+]1ccccc1NCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)O)c1cccc(OCCCCNc2ccccn2)c1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of the product from Example 5, Step 3 (720 mg, 3.24 mmol) in DMF (9 mL) was added triphenylphosphine (850 mg, 3.24 mmol). The reaction solution was kept at ambient temperature for 1 hour and a solution of 2-(4-hydroxybutylamino)pyridine N-oxide (590 mg, 3.24 mmol) and diethyl azodicarboxylate (0.51 mL, 3.24 mmol) in DMF (5 mL) was added. The reaction solution was kept at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous solution was back extracted with ethyl acetate. The combined organic solution was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (98:1:1 CH2Cl2:MeOH:NH4OH) to give the desired product, (560 mg, 45% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]1[N:25]=[C:26]([NH:29][C:30]2[N:35]=[CH:34][C:33]([CH2:36][OH:37])=[C:32]([O:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[CH:31]=2)[S:27][CH:28]=1>C1COCC1.CCOCC.[OH-].[Na+]>[CH3:23][C:24]1[N:25]=[C:26]([NH:29][C:30]2[CH:31]=[C:32]([O:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:33]([CH:36]=[O:37])=[CH:34][N:35]=2)[S:27][CH:28]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(CO)cn2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C=O)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of Dess Martin periodane (1.30 g, 3.05 mmol) in THF (5 mL) at 0° C. was added a solution of (6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)pyridin-3-yl)methanol (0.925 g, 2.55 mmol). The mixture was warmed to room temperature and stirred for 30 minutes, diluted with ether and hydrolyzed with 1N NaOH (40 mL). The mixture was extracted with ether, washed with brine, dried, and concentrated to afford 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinaldehyde (0.860 g, 93.5% yield) as a light yellow solid. 1H NMR (DMSO d6) δ 11.28 (bs, 1H), 10.40 (s, 1H), 8.75 (s, 1H), 8.09 (d, 1H), 7.98 (d, 1H), 7.92 (d, 1H), 7.55-7.68 (m, 3H), 7.49 (d, 1H), 6.62 (s, 1H), 6.26 (bs, 1H), 2.13 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.N1C=CN=C1.[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35]O>C(Cl)Cl>[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][Br:20]
Reactant: BrBr
Reactant: COC(=O)COCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COCCCCBr
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Triphenylphosphine (5.59 g, 21.3 mmol), bromine (1.1 mL, 21.5 mmol) and imidazole (1.41 g, 20.7 mmol) were sequentially added to a solution of (4-hydroxy-butoxy)-acetic acid methyl ester (2.88 g, 17.8 mmol) in CH2Cl2 (15 mL) at 0° C. under nitrogen. After 1 h, the mixture was filtered through basic alumina, rinsing with 5% EtOAc/Hexane (40 mL). The filtrate was concentrated and the residue was purified by flash column chromatography (0%→20% EtOAc/Hexane) to afford 2.02 g (51%) of (4-bromo-butoxy)-acetic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][O:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:6]1)=[O:4].N12CCCN=C1CCCCC2.BrC(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[O:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1COC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COC(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4,5-dihydro-4-(methoxycarbonyl)-2-oxazolyl]-1-piperidinecarboxylate (i.e. the product of Example 7, Step B) (2.89 g, 9.26 mmol) in 100 mL of dichloromethane at 0° C. was added 1.52 mL (10.18 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the reaction mixture was stirred for 10 minutes at 0° C. Bromotrichloromethane (1 mL, 10.18 mmol) was added dropwise over 7 minutes, and the reaction mixture was stirred for 6 h at 0° C. The mixture was washed with saturated aqueous ammonium chloride (2×50 mL), the aqueous phase was extracted with ethyl acetate (2×25 mL), and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 25-75% of ethyl acetate in hexanes as eluant to give 1.41 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[F-].[K+].[F:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1B(O)O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[F:24])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1ccc(B(O)O)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(Cl)nn2)c(F)c1
Temperature: 120 °C

Procedure:
To a solution of 3,6-dichloropyridazine (2.0 g, 13.42 mmole) in 1,4-dioxane (20 ml) are added Pd2(dba)3 (0.21 g, 0.2 mmole), P(tBu)3 (0.122 g, 0.6 mmole) in 1,4-dioxane (1 ml), KF (2.57 g, 44.3 mmole) and 2-fluoro-4-methylbenzeneboronic acid (step 31.1, 2.68 g, 17.45 mmole). The resulting mixture is heated at 120° C. for 48 h. The reaction mixture is filtered through celite and washed pad with EtOAc. The filtrate is washed with H2O, dried over MgSO4 (anhydrous) and evaporated under reduced pressure to give a brown solid, which is purified by chromatography, affording the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].O1CCCC1.B(F)(F)F.CCOCC.[BH4-].[Na+]>CCOCC.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 0.38 h
Yield: 98.4 %

Procedure:
(3,4-Dinitrophenyl)-morpholin-4-yl-methanone (0.750 Kg, 2.67 mol, 1.0 wt) and tetrahydrofuran (7.50 L, 10.0 vol) were charged to a flask under nitrogen and cooled to 0 to 5° C. Borontrifluoride etherate (0.713 L, 5.63 mol, 0.95 vol) was added at 0 to 5° C. and the suspension was stirred at this temperature for 15 to 30 minutes. Sodium borohydride (0.212 Kg, 5.60 mol, 0.282 wt) was added in 6 equal portions over 90 to 120 minutes. (A delayed exotherm was noted 10 to 15 minutes after addition of the first portion. Once this had started and the reaction mixture had been re-cooled, further portions were added at 10 to 15 minute intervals, allowing the reaction to cool between additions). The reaction mixture was stirred at 0 to 5° C. for 30 minutes. Reaction completion was determined by 1H NMR analysis (d6-DMSO). Methanol (6.30 L, 8.4 vol) was added dropwise at 0 to 10° C. to quench the reaction mixture (rapid gas evolution, some foaming). The quenched reaction mixture was stirred at 0 to 10° C. for 25 to 35 minutes then warmed to and stirred at 20 to 30° C. (exotherm, gas/ether evolution on dissolution of solid) until gas evolution had slowed. The mixture was heated to and stirred at 65 to 70° C. for 1 hour. The mixture was cooled to 30 to 40° C. and concentrated under vacuum at 40 to 45° C. to give crude 4-(3,4-dinitro-benzyl)-morpholine (0.702 Kg, 98.4%) as a yellow/orange solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([F:15])(F)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[F-].CO[CH2:21][N:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:23][Si](C)(C)C>C(#N)C>[CH2:1]([N:8]1[C:9](=[O:16])[C@:10]2([F:15])[C@@H:11]([CH2:21][N:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23]2)[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1CC(F)(F)C(=O)N1Cc1ccccc1
Agent: [F-]
Agent: [Li+]
Solvent: CC#N
Product: O=C1[C@@H]2CN(Cc3ccccc3)C[C@]2(F)C(=O)N1Cc1ccccc1

Procedure:
To a solution of 1-benzyl-3,3-difluoropyrrolidine-2,5-dione (325 mg, 1.44 mmol) in acetonitrile (3.6 mL), LiF (56 mg, 1.50 eq) and a stir bar were added. The reaction mixture was sonicated for 2.5 hr at rt. N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.4 mL, 1.59 mmol, 1.10 eq) and LiF (37 mg, 1.44 mmol, 1 eq) were added and continued to sonicate for 0.5 hr. The reaction mixture was concentrated and the salt was removed by filtration. The crude residue was purified by column chromatography and eluted with 2 to 20% EtOAc/heptane and purified further with 2 to 10% EtOAc/heptane. The desired fractions were faintly ultraviolet active but were visualized with KMNO4 stain. The title compound was isolated as a yellow oil (196 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.43 (m, 10 H) 4.57-4.75 (m, 2 H) 3.63 (s, 2 H) 3.56-3.65 (m, 1 H) 3.33-3.41 (m, 1 H) 3.13 (d, J=9.29 Hz, 1 H) 2.74 (dd, J=9.35, 7.03 Hz, 1 H) 2.57-2.70 (m, 1 H). m/z (APCI+) for C20H20FN2O2 339.20 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].C(N(CC)C(C)C)(C)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](O)=[O:43].C(Cl)CCl>CN(C=O)C>[NH2:8][C:7]1[N:6]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:5]2[N:4]=[C:3]([C:22]2[CH2:23][CH2:24][N:25]([C:42]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)=[O:43])[CH2:26][CH:27]=2)[C:2]=1[Br:1]
Reactant: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C(O)c1cccs1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)c(C2=CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (0.035 mmol) was charged to a 20 mL scintillation vial. Then DMF (1 ml), N,N-diisopropylethylamine (0.14 mmol, 25 μL), thiophene-2-carboxylic acid (0.039 mmol, 5 mg), and EDC (0.039 mmol, 7.4 mg) were added, respectively. The resulting reaction mixture was stirred at room temperature for 18 hours. Upon completion, the reaction mixture was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield (4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone (m+H=531.06, retention time=3.74 min). Also recovered was the dehalogenated product, (4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone (m+H=453.24, retention time=3.51 min).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1)#[N:2].[CH2:15]([Mg]Br)[CH3:16].[OH-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:2][C:1]1([C@@H:3]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4]2)[CH2:16][CH2:15]1
Reactant: CC[Mg]Br
Reactant: N#C[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Reaction time: 0.5 h

Procedure:
(3R)-3-Cyano-1-benzylpyrrolidine (1.40 g) was dissolved in tetrahydrofuran (21.0 mL) under an argon atmosphere. Titanium(IV) tetraisopropoxide (2.40 mL) and ethylmagnesium bromide (5.00 mL, 3 mol/L solution in ether) were added to the solution at room temperature. After 0.5 h, trifluoroboron-diethyl ether complex (1.90 mL) was added dropwise to the mixture, and the resultant mixture was stirred at room temperature. After 4 h, 2 mol/L aqueous sodium hydroxide (30 mL) was added to the reaction mixture, followed by stirring for 0.25 hours. The product that precipitated was collected through filtration and then extracted. The formed aqueous layer was again extracted with ethyl acetate, and the organic layers were combined together, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby the target compound as a crude product (1.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:17])[NH:13][C:14]([CH3:16])=[N:15][C:6]3=[C:5]([C:18]([F:21])([F:20])[F:19])[C:4]=2[CH:3]=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1.CN(CCN(C)C)C>[CH2:23]([C:5]1([C:18]([F:19])([F:21])[F:20])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[NH:8][C:7]2[C:12](=[O:17])[NH:13][C:14]([CH3:16])=[N:15][C:6]1=2)[CH2:24][CH2:25][CH3:26]
Reactant: [Li]CCCC
Reactant: Cc1nc2c(C(F)(F)F)c3cc(Cl)ccc3nc2c(=O)[nH]1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCC1(C(F)(F)F)c2cc(Cl)ccc2Nc2c1nc(C)[nH]c2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
8-Chloro-2-methyl-10-(trifluoromethyl)-pyrimido[5,4-b]quinolin-4(3H)-one (13, 82 mg, 0.261 mmol) was suspended in THF-TMEDA (10:1, 1.74 mL) and cooled to −78° C. under a N2 atmosphere. n-BuLi was added dropwise and the reaction slowly became homogeneous. The reaction mixture was stirred at −78° C. for 20 minutes, then the ice bath was removed and the reaction allowed to warm to rt. After stirring for 90 min, the reaction was quenched with sat. aq. NH4Cl and was partitioned between EtOAc and H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated. Chromatography (SiO2, 60% EtOAc-hexane) provided the desired material 14 (17 mg, 17%). Rf 0.39 (50% EtOAc-hexane). 1H NMR (CDCl3, 300 MHz) δ 11.63 (br s, NH), 7.53 (s, 1H), 7.22 (dd, J=2.2, 8.4 Hz, 1H), 6.87 (br s, NH), 6.82 (d, J=8.4 Hz, 1H), 2.86 (m, 1H), 2.48 (s, 3H), 2.14 (m, 1H), 1.34 (m, 2H), 1.01 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); 19F NMR (CDCl3, 300 MHz) δ−75.21. ESI-HRMS 372.1099 (M++H, C17H17ClON3F3 requires 372.1091).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:36]=[CH:35][C:30]5[N:31]=[C:32]([CH3:34])[NH:33][C:29]=5[CH:28]=4)[N:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.CO.C(OCC)C>[CH3:34][C:32]1[NH:33][C:29]2[CH:28]=[C:27]([NH:26][C:22]3[N:21]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[N:15][CH:16]=4)[CH:25]=[CH:24][N:23]=3)[CH:36]=[CH:35][C:30]=2[N:31]=1
Reactant: Cc1nc2ccc(Nc3nccc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)n3)cc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cc1nc2ccc(Nc3nccc(-c4ccc(N5CCNCC5)nc4)n3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
A solution of 4-(2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrid-5-yl)-N-(2-methylbenzimidazol-5-yl)-2-pyrimidineamine (70 mg, 0.14 mmol) in a mixture of dichloromethane (5 ml) and methanol (3 ml) was treated with hydrogen chloride (5 ml of a 1M solution in diethyl ether, 5.00 mmol) then stirred for 18 h at room temperature. The precipitate which formed was collected by filtration then subjected to column chromatography (silica, 0.88 ammonia solution-methanol-dichloromethane, 1:5:94) to afford the title compound (19 mg) as a yellow solid m.p. 245-250°. δH (d6DMSO) 2.45 (3H, s), 2.80 (4H, m), 3.38 (4H,m), 6.91 (1H, d, J 9.0 Hz), 7.24 (1H, d J 5.2 Hz), 7.35 (2H, s), 8.11 (1H, s), 8.25 (1H, m), 8.39 (1H, d, J 5.2 Hz), 8.93 (1H, d, J 2.2 Hz), 9.41 (1H, br s) and 11.50 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:21]=[CH:22][C:23]4[NH:24][C:33]([C:32]5[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)=[N:1][C:4]=4[CH:5]=3)=[O:20])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(-n2ccnc2)cc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4ccc(-n5ccnc5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 209 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-imidazol-1-ylbenzoyl)aniline and 4-methoxybenzaldehyde. [M+H]+ calcd for C24H19N5O2: 410.05; found: 410.00.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([I:11])[CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.O>C(O)C.[Zn]>[I:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]2
Reactant: CCOC(=O)c1[nH]c2ccc(I)cc2c1I
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(I)ccc2[nH]1
Reaction time: 0.75 h

Procedure:
Ethyl 3,5-diiodo-1H-indole-2-carboxylate (12.1 g, 26.4 mmol) was suspended in 250 mL of absolute ethanol, to which concentrated aqueous hydrogen chloride (22.0 mL, 264 mmol) was added. Zinc dust (17.3 g, 264 mmol) was added portionwise over 30 minutes. After stirring for 45 minutes, two additional portions of zinc were added slowly (5.2 and 4.4 g, 146 mmol). After stirring for 30 minutes, the mixture was poured into water and extracted four times with ethyl acetate. The combined organic extracts were washed once with aqueous saturated NaHCO3 and once with aqueous saturated NaCl. The organic extract was dried with Na2SO4, filtered and concentrated in vacuo. The residue was crystallized three times from hexanes and ethyl acetate, providing the title compound. The mother liquor was columned by flash chromatography (0 to 8% ethyl acetate in hexanes) to provide an additional amount of the title compound. HRMS (ES) exact mass calculated for C11H10INO2 (M+Na+): 377.9648. Found 377.9649.
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[C:10](=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[CH3:10][O:9][C:7]1[CH:8]=[CH:2][C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: Cc1cc(O)ccc1O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Product: COc1ccc(O)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a 1 L glass reaction vessel, methylhydroquinone (1.2 moles, 148.97 g) and diphenyl carbonate (1.29 moles, 277.63 g) were added. After heating the system to about 180° C., the system underwent Segments 1 through 5 and then skipped to Sement 11. After about 2 hours, the polymer crystallized at about 270° C. when about 90 wt % phenol had evolved. The solidified polymer could not be stranded.