Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[N:2]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccccc1O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccccc1-n1cccc1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, a water cooled reflux condenser, a temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged with (50 g, 0.46 mol) of 2-aminophenol and acetic acid (750 mL) which provided a very dark solution. Stirring was commenced and the vessel was charged with 2,5-dimethoxytetrahydrofuran (59.4 mL, 0.458 mol) dropwise over 2 minutes. The dark mixture was then heated at 100° C. for 15 min. The mixture was allowed to cool to room temperature and was filtered through a pad of Celite to remove residual solids. The filtrate was concentrated under reduced pressure azeotroping with toluene. The residual oil was dissolved in ethyl acetate (1000 mL) and was partitioned with water (500 mL). The organic layer was separated and was washed with water (500 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide 2-(1H-pyrrol-1-yl)phenol (54 g, 74%) as a dark oil. ESI-MS m/z calc. 159.1. found 160.2 (M+1)+. Retention time: 2.67 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.37-7.23 (m, 2H), 7.13-6.97 (m, 2H), 6.91 (t, J=1.9 Hz, 2H), 6.43 (t, J=1.9 Hz, 2H), 5.35 (s, 1H). 3-(1H-Pyrrol-1-yl)pyridin-2-ol was also synthesized using the procedure described above.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[O:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:24][O:23][C:22]1[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]=2[CH:21]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccccc1Oc1ccccc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 72 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-phenoxy-phenyl boronic acid The title compound (120 mg) was obtained as a pale green solid, (yield=72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH3:33][CH:34]([C@@H:36]1[C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:39][C:38](=[O:53])[NH:37]1)[CH3:35]>C1COCC1.C(N(CC)CC)C>[CH3:35][CH:34]([C@@H:36]1[C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:39][C:38](=[O:53])[N:37]1[C:15](=[O:16])[C@@H:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:33]
Reactant: CC(C)[C@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](C(=O)N1C(=O)OC(c2ccccc2)(c2ccccc2)[C@H]1C(C)C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -30 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2.0 g of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoic acid were dissolved in 30 ml of THF and cooled to −30° C. To the cooled mixture, were added successively, 2.3 ml of triethylamine and 780 μl of trimethylacetyl chloride. The mixture was kept at −30° C. for two hours. 308 mg of lithium chloride were added followed by 978 mg of (R)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (Hintermann T., Seebach D., Helv. Chim. Acta, 1998, 81, 2093). The mixture was allowed to warm to room temperature and was kept at that temperature for 18 hours. The reaction mixture was quenched by the addition of one portion of 30 ml of a saturated aqueous ammonium chloride solution. The resulting mixture was extracted with three portions of 30 ml of ether. The combined organic extracts were washed with two portions of 30 ml of 1N hydrochloric solution, one portion of 30 ml of water and one portion of 30 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and the solvent evaporated. The residual yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes to 20% ethyl acetate/hexanes, dry pack), yielding 1.8 g of the titled compound and 0.8 g of the starting acid, 1H NMR (CDCl3): 7.40-7.20 (m, 6H), 7.15-6.95 (m, 6H), 6.77 (dd, J=8.2, 2.0 Hz, 1H), 5.26 (d, J=3.4 Hz, 1H), 4.92 (dd, J=8.8, 6.2 Hz, 1H), 2.15 (m, 1H), 1.97 (m, 1H), 1.70 (m, 1H), 1.58 (br. s, 4H), 1.35-1.25 (m, 6H), 1.23 (s, 3H), 1.20 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.92 (d, J=7.0 Hz, 3H), 0.85 (t, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH2:28]([NH2:31])[CH2:29][NH2:30]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:29][CH2:28][NH2:31])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H cyclopenta[d]pyrimidine (0.5 g, 1.77 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.343 g, 2.659 mmol) followed by ethane-1,2-diamine (0.138 g, 2.30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get the title compound N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)ethane-1,2-diamine (0.35 g, 64.5%) as a dark brown solid. LC-MS (M+H)+=307.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.11-7.08 (2H, m), 6.99-6.95 (2H, m), 5.40 (1H, br s), 4.25-4.22 (1H, m), 3.61-3.57 (2H, m), 2.99-2.98 (2H, m), 2.78-2.62 (3H, m), 2.10-2.09 (1H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:19][CH:20]1[CH2:21][O:22]1
Reactant: CC(CCc1ccccc1O)Cc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(CCc1ccccc1OCC1CO1)Cc1ccccc1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 1(a), 0.98 g of 2-(3-methyl-4-phenylbutyl)phenol (prepared as described in Preparation 13), 0.46 of potassium t-butoxide and 0.56 g of epibromohydrin were reacted in 10 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 1.0 g (yield 83%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C#C>N1C=CC=CC=1>[C:10]([O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCC(O)CCCC
Reactant: O=C(Cl)c1ccccc1
Agent: C#C
Solvent: c1ccncc1
Solvent: O
Product: C#CCC(CCCC)OC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λ max. 3240 (terminal acetylene) and 1730 cm-1 (benzyloxy group).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11]C=O)=[CH:7][N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]([O:31][CH3:32])([O:29][CH3:30])OC>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:26]([O:29][CH3:30])[O:31][CH3:32])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(CC=O)cn1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(CC(OC)OC)cn1
Yield: 78.5 %

Procedure:
A mixture of 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (prepared as in Example 42, 330 mg, 1.83 mmol), p-toluenesulfonic acid monohydrate (35 mg, 0.184 mmol), trimethyl orthoformate (3 mL, 137 mmol), and methanol (10 mL) was heated under reflux for 90 min. The mixture was concentrated in vacuo to dryness, and the residue was further concentrated in vacuo to dryness from toluene (10 mL). The resulting residue was shaken with methylene chloride (25 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous phase was back-extracted with methylene chloride (10 mL). Each extract was washed with a saturated aqueous sodium chloride solution (5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylic acid methyl ester (325 mg, 78%) as a yellow oil.
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([NH:43][C:44]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:18][C:12]=2[Cl:11])=[S:45])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 53%).
Reaction SMILES: C(C1C=CN=C(C(O)=[O:13])C=1)CC(C)C.C(C1C=CN=C(C(O)=O)C=1)CCCC.[CH2:29]([CH:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:32][CH3:33])[CH3:30].OO>C(O)(=O)C.C(Cl)Cl>[CH2:29]([CH:31]([C:34]1[CH:35]=[CH:36][N+:37]([O-:13])=[CH:38][CH:39]=1)[CH2:32][CH3:33])[CH3:30]
Reactant: CC(C)CCc1ccnc(C(=O)O)c1
Reactant: CCC(CC)c1ccncc1
Agent: CCCCCc1ccnc(C(=O)O)c1
Agent: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)c1cc[n+]([O-])cc1
Yield: 95 %

Procedure:
4-Isopentylpyridine-2-carboxylic acid, compound 10b (R9=1-ethyl-propyl), was made by employing Method P. To 4-(1-ethyl-propyl)-pyridine (8.5 g, 57 mmol) in acetic acid (30 mL), hydrogen peroxide (17.8 g, 30%, 57 mmol) was added. The resulting reaction mixture was refluxed overnight. The residue obtained on removal of solvent was dissolved in DCM (100 mL), dried over MgSO4. After filtering, the solvent was removed to obtain a brown liquid, 4-(1-ethyl-propyl)-pyridine-N-oxide (9 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH2:39](Br)[CH:40]=[CH2:41].C(O)C>CN(C=O)C>[CH2:41]([N:34]1[CH2:35][CH2:36][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([N:8]7[CH2:12][CH2:11][CH2:10][C:9]7=[O:13])=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:32][CH2:33]1)[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: C=CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3
Yield: 11 %

Procedure:
This was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and allyl bromide using a similar procedure to Example 19, except that DMF was used as solvent in place of ethanol. This gave the title compound as a white foam (11%) which was converted to its hydrochloride salt, crystallising from acetone as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])[CH:2]=[CH2:3].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCCCCC>[CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCc1ccc2ccccc2c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 2-(2-propenyl)-1-naphthol (Example 118 Part A; 101.9 g, 0.550 mole), t-butyldimethylsilyl chloride (100.0 g, 0.660 mole), and imidazole (93.6 g, 1.375 mole) in N,N'-dimethylformamide was stirred at room temperature for 6.5 hours. It was then poured into saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with hexane. The residue was distilled at reduced pressure to provide the title compound (155.2 g, 95%), bp 135°-140° (0.1 torr).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:31]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>C1COCC1>[OH:33][C:31]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)([C:7]1[CH:8]=[N:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)[CH3:32]
Reactant: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.65 mL, 4 mmol) was added dropwise to a mixture of 4-bromo-1-trityl-1H-pyrazole (1.5 g, 3.8 mmol) in THF (15 mL) cooled to −78° C. Then the mixture was stirred at −78° C. for 1 hour. After methyl 4-acetylbenzoate (0.71 g, 3.8 mmol) in THF (1 mL) was added, the mixture was stirred at −78° C. for 2 hours, and then quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by chromatography on silica gel to afford methyl 4-[1-hydroxy-1-(1-trityl-1H-pyrazol-4-yl)ethyl]benzoate. MS ESI calc'd. for C32H29N2O3 [M+H]+ 489. found 489.
Reaction SMILES: O(C1C=C(C=CC=1)N)C1C=CC([NH2:6])=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.[C:38]1(=[O:48])[O:43][C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>CN1CCCC1=O>[CH:46]1[CH:47]=[C:39]([C:38]([NH2:6])=[O:48])[C:40]([C:41]([OH:43])=[O:42])=[CH:44][CH:45]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(Oc2cccc(N)c2)cc1
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminatedimide polymer with theoretical number average molecular weight of 11,600 g/mole. 3,4'-Oxydianiline (ODA) (25.0 mmole, 5.0062 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (25.0 mmole, 7.3084 g) were dissolvedin N-methylpyrrolidinone (NMP) ( ~ 35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. 3,3',4,4'-Biphenyl tetracarboxylic dianhydride (BPDA) (47.87 mmole, 14.0845 g) and phthalic anhydride (PA) (4.260 mmole, 0.6310 g) were slurried in NMP (~ 35 mL) and were added to the solution. Afterwashing with ~ 38 mL of NMP to provide a 20% solids content reaction, an exotherm of 10°-15° C. was observed. The exotherm quickly subsided and the reaction was stirred at 25° C. for 16 hours to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ninh) of the phthalamide acid-terminated polyamide acid was 0.41 dL/g in NMP at 25° C. To imidize, toluene (30 mL) was added and the reaction was heated at 160° C. for 24 hours. After cooling to 25° C., the polymer was still soluble. The solution was poured into water to precipitate a powder which was washed twice in water and dried at >100° C. to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was soluble in NMP and had a glass transition temperature of 219° C. A film cast from the polyamide acid solution and dried one hour each at 100°, 225°, and 371° C. had a Tg of 223° C. and was tough and creasible.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C:23]1[C:27](B(O)O)=[CH:26][N:25]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:27]4[C:23]([CH3:22])=[N:24][N:25]([C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:26]=4)=[CH:4][CH:5]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:16][CH:17]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B(O)O
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1

Procedure:
4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine hydrochloride was reacted with 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LC/MS: (PS-B3) Rt 2.78 min [M+H]+594. *This starting material can be made by the method described in EP1382603
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(CO)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), 3-(hydroxymethyl)benzeneboronic acid (0.555 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 16.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate) followed by trituration with acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 449 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a white solid, mp 186-187° C.