Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:18][CH:17]3[CH:10]([O:11][Si:12]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:13][Si:14]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:15][CH2:16]3)[C:9]2([F:32])[F:31])[C:4](=[O:33])[N:3]=1.[C:34](=O)([O:46]C1C=CC([N+]([O-])=O)=CC=1)[O:35][CH2:36][C:37]1[O:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>C1COCC1>[F:32][C:9]1([F:31])[CH:10]2[O:11][Si:12]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[O:13][Si:14]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:23])[CH3:24])[O:15][CH2:16][CH:17]2[O:18][CH:8]1[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:46])[O:35][CH2:36][C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[CH:41]=2)=[N:3][C:4]1=[O:33]
Reactant: O=C(OCc1cc2ccccc2o1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[Si]1(C(C)C)OCC2OC(n3ccc(N)nc3=O)C(F)(F)C2O[Si](C(C)C)(C(C)C)O1
Solvent: C1CCOC1
Product: CC(C)[Si]1(C(C)C)OCC2OC(n3ccc(NC(=O)OCc4cc5ccccc5o4)nc3=O)C(F)(F)C2O[Si](C(C)C)(C(C)C)O1
Temperature: 100 °C
Reaction time: 96 h
Yield: 87.3 %

Procedure:
To a stirred solution of 62 (300 mg, 0.59 mmol) in THF (5 mL) was added benzofuran-2-ylmethyl 4-nitrophenyl carbonate (223 mg, 0.71 mmol). The resulting solution was stirred at 100° C. for 4 days. Solvent was evaporated off in vacuo and the product was purified by preparative HPLC to give 63 (350 mg, 87%) as an oil. m/z=680.0 (M+H), 1359.49 (2M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C[Al](C)C.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[C:30](OC)=[O:31])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:30]([C:26]2[S:27][CH:28]=[CH:29][C:25]=2[NH:24][CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=[CH:14][CH:15]=2)=[O:31])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1sccc1NCc1ccnc2ccccc12
Reactant: Nc1cccc(N)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,3 phenylenediamine (5.43 g, 50.3 mmol) in anhydrous toluene (100 mL) was added AlMe3 (2M in toluene, 7.5 mL, 15.1 mmol) and the solution was stirred at rt overnight. Methyl 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate (3 g, 10.05 mmol) was added and the mixture was stirred at 130° C. for 3 h. The reaction mixture was cooled to rt and the toluene was decanted. To the remaining residue, 50 mL of 2N NaOH and 100 mL of CH2Cl2 were added and the solution stirred for 30 min. The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The toluene and CH2Cl2 layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (50% hexanes:ethyl acetate→100% ethyl acetate) followed by trituration of the solid with CH2Cl2 yielded pure N-(3-aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide as a tan powder. MS (ES): m/z 374.86 (100) [MH+]; 1H NMR (DMSO-d6, 400 MHz): δ 4.98-4.50 (m, 2H), 5.04 (d, J=5.6 Hz, 2H), 6.25 (d, J=7.2 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.79 (d, J=5.6 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 6.96-6.97 (m, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.55 (d, J=5.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.78 (t, J=6.8 Hz, 1H), 8.00-8.05 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.82 (d, J=4.4 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:31]1[CH2:30][CH2:29][CH2:28][CH2:27]C2.BrCC1CCC1.O>C(O)C>[CH:28]1([CH2:27][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccn3)co2)cc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CCC1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(CCC(=O)c3ccccn3)co2)cc1OCC1CCC1

Procedure:
A 0.15 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one obtained in Example 161 and 0.2 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol. A 0.14 g quantity of (bromomethyl)cyclobutane was added thereto, and the mixture was heated and refluxed overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=5:1) to give 50 mg of white powdery 3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](C(OC(C)(C)C)=O)[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].C(O)(C(F)(F)F)=O.C(Cl)[Cl:48]>>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[N:22]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1.[CH3:1][O:2][CH2:3][C:4]([Cl:48])=[O:5]
Reactant: COCC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)Cl
Product: COCC(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (95 mg, 0.18 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid. Product was purified using prep HPLC (method 25-50—70 mins) to afford 2-methoxyacetyl chloride N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide. (45 mg, 59%)
Reaction SMILES: [CH3:1][I:2].[C:3]1([C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH3:21])[N:17]=3)[CH2:13][N:12]=[CH:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[I-:2].[CH3:1][NH+:12]1[CH2:13][CH:14]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)[CH2:15][N:10]([C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11]1
Reactant: CI
Reactant: Cc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Solvent: ClC(Cl)Cl
Product: Cc1noc(C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[NH+](C)C2)n1
Product: [I-]
Reaction time: 12 h
Yield: 99.6 %

Procedure:
Methyliodide (38 μl, 0.6 mmol) was added to a stirred solution of 1-triphenylmethyl-5(3-methyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (250 mg, 0.6 mmol) in chloroform (lml), in a round bottom flask with a septum, at room temperature. After 12 hours stirring the solvents were evaporated in vacuo giving 330 mg (100%) crude white crystals identified by 300 MHz nmr.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](CBr)=[N:7]1)[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([N:18]=[N+:19]=[N-:20])=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1nc(CBr)c2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(N=[N+]=[N-])c2cccnc21
Temperature: 80 °C

Procedure:
A mixture of (3-(bromomethyl)-pyrazolo[3,4-b]pyridine-1-yl)acetic acid ethyl ester (0.5 Mmol, 1 eq.) and sodium azide (1 Mmol, 2 eq.) in 1 mL of DMF was heated at 80° C. for 1 h. The resultant mixture was cooled to rt, diluted with 150 mL of EtOAc, washed with water (40 mL××3), brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solvent was removed in vacuo to provide 135.2 Mg desired product: HPLC retention time=1.84 minutes (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=261.1, found=261.4.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH3:38])[CH:32]=2)[CH:27]1[C:39]([OH:41])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:44]=[C:45]([CH:47]=[C:48]([F:56])[C:49]=1[C:50]([CH3:55])([CH3:54])[CH2:51][O:52][CH3:53])[NH2:46].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:42][C:43]1[CH:44]=[C:45]([NH:46][C:39]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([O:36][CH2:37][CH3:38])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:41])[CH:47]=[C:48]([F:56])[C:49]=1[C:50]([CH3:54])([CH3:55])[CH2:51][O:52][CH3:53]
Reactant: COCC(C)(C)c1c(F)cc(N)cc1F
Reactant: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
T3P (9.88 mL, 16.80 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.8 g, 5.60 mmol), 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (1.206 g, 5.60 mmol), DIEA (4.89 mL, 28.01 mmol) and DMAP (0.684 g, 5.60 mmol) in ethyl acetate (5 mL), and the mixture was stirred overnight at 60° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.380 g, 4.59 mmol, 82%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20](O)=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.C(Cl)CCl.[CH3:27][NH2:28].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][NH:28][C:20]([C:18]1[NH:19][C:15]2[N:14]=[CH:13][N:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH:7]=3)[C:16]=2[CH:17]=1)=[O:21]
Reactant: CN
Reactant: O=C(O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
A solution of 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (60 mg, 0.2 mmol), EDC (44.6 mg, 0.97 mmol) and DMAP (7.1 mg, 0.06 mmol) in dry DMF (1.5 mL) was stirred at room temperature under nitrogen for 30 minutes. Methylamine (0.5 mL, 0.97 mmol, 2M solution in THF) was then added and the mixture was allowed to stir overnight at rt. After this time, water (5 mL) was added to the mixture which was extracted with DCM (3×15 mL) and the combined organic layers washed with a saturated aqueous sodium chloride (5×10 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo and the resulting crude material purified by preparative TLC (5% MeOH in CH2Cl2) to yield 2.7 mg (4.3%) of N-methyl-1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxamide EXAMPLE 6. 1H NMR (400 MHz, CDCl3): δ=7.95 (br s, 1H), 7.73-7.71 (m, 1H), 7.57-7.42 (m, 6H), 6.59 (br s, 1H), 3.02 (d, J=5.2 Hz, 3H). MS (ES+): m/z 323.31 (100) [MH+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9](/[CH:12]=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:20][Mg]Br.[Cl-].[NH4+]>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C@H:12]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:20])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(OCC2CC2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OCC2CC2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
A solution of (R,E)-N-((5-(cyclopropylmethoxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (6.2 g, 22 mmol) was dissolved into dichloromethane (110 ml). Methyl magnesium bromide (44 ml, 44 mmol, 1.0M in THF) was added to the mixture at −78° C. dropwise. The mixture was stirred for 1 h at −78° C. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 3.2 g (49% yield) of the title compound as a white solid:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[C:24]1([S:30]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine from General Procedure B-3 (500 mg), benzenesulfonyl chloride (0.30 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CO[CH:11](OC)[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:12]=[CH:11][C:4]=2[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2occc2c1
Temperature: 150 °C
Yield: 30.5 %

Procedure:
A solution of 4-bromophenol (17.3 g, 100 mmol) in dimethylformamide (40 ml) was treated with bromoacetaldehyde dimethyl acetal (16.9 g, 100 mmol) and potassium carbonate (13.8 g, 100 mmol) and heated at 150° C. for 16 h. The mixture was cooled, poured into water (500 ml) and extracted with diethyl ether (3×100 ml). The combined organic extracts were dried (MgSO4), concentrated, and filtered through a plug of silica gel eluting with 10% diethyl ether in hexane. The resulting oil (15 g) was added to a solution of polyphosphoric acid (~12 g) in toluene (100 mL) and heated at 80° C. for 16 h. The mixture was cooled and the toluene layer was decanted off and washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4), concentrated and the residue distilled to give 5-bromobenzofuran (6 g) as a colourless oil, bp. 98° C./1 mmHg; δH (DMSO-d6) 6.96 (1H, m, ArH), 7.45 (1H, m, ArH), 7.59 (1H, m, ArH), 7.91 (1H, m, ArH), and 8.05 (1H, m, ArH).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]([C:25]1[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=1)[CH3:24])=[N+]=[N-].O>C1COCC1>[F:31][C:29]1[CH:30]=[C:25]([C@@H:23]([NH2:20])[CH3:24])[CH:26]=[C:27]([F:33])[C:28]=1[F:32]
Reactant: C[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
Triphenylphosphine (1.23 g) was added to a solution of 5-((S)-1-azidoethyl)-1,2,3-trifluorobenzene (858 mg) in THF (20 ml) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for five minutes. Thereafter, water (2.5 ml) was added to the reaction solution, which was then stirred at 60° C. for 2.5 hours. The reaction solution was returned to room temperature, followed by extraction with 2 N hydrochloric acid (twice). The hydrochloric acid extraction layer was washed with ethyl acetate and then made basic with a 5 N sodium hydroxide solution, followed by extraction with methylene chloride (twice). The methylene chloride layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 348 mg of the title compound. Further, the following operation was performed in order to collect the title compound remaining in the ethyl acetate dilution of the reaction solution. Diethyl ether was added to the dilution, followed by extraction with water. The water extraction layer was washed with diethyl ether and then made basic with a 5 N sodium hydroxide solution, followed by extraction with methylene chloride (twice). The methylene chloride layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 413 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH2:27][CH3:28])[C:10]2=[O:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH2:27][CH3:28])[C:10](=[O:29])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([S:31]([C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32])[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(S(=O)(=O)c1cccc(C(=O)O)c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To a mixture of Example 50 (100 mg, 0.23 mmol) and 3-(chlorosulfonyl)benzoic acid (57 mg, 0.26 mmol) in THF (5 ml) was added DIEA (45 μl, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours then concentrated under vacuum. The residue was partitioned between EtOAc and water. The pH was adjusted to pH=2. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The obtained solid was chromatofraphed over silica gel using DCM/MeOH (80/20) to yield the above-titled compound (63 mg), mp=145° C. 1H NMR (CDCl3): 8.63 (1H, s), 8.41 (1H, d, J=7.5 Hz), 8.17 (1H, d, J=7.4 Hz), 7.77 (1 H, t, J=7.7 Hz), 7.62 (2H, d, J=7.7 Hz), 7.18-7.26 (3H, m), 6.60 (2H, s), 3.4-4.2 (7H, m), 1.45 (3H, t, J=6.8 Hz).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12](C1C=CC(N)=CC=1)C1C=CC(N)=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.C1(=O)OC(=O)C2=CC=CC=C12>CN1CCCC1=O>[CH:8]1[CH:7]=[C:3]([C:4]([NH2:5])=[O:6])[C:2]([C:1]([OH:11])=[O:12])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Agent: O=C1OC(=O)c2ccccc21
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminated imide oligomer with theoretical number average molecular weight of 12,000 g/mole. 4,4'-Oxydianiline (4,4'-ODA) (8.00 mmole, 1.6020 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (32.00 mmole, 9.3547 g) were dissolved in N-methylpyrrolidinone (NMP) (~35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. Pyromellitic dianhydride (PMDA) (38.51 mmole, 8.3994 g) and phthalic anhydride (PA) (2.980 mmole, 0.4414 g) were added to the solution with enough NMP to total 79.2 g (20% solids). The reaction was stirred at 25° C. for 6 h to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ηinh) of the phthalamide acid-terminated polyamide acid was 0.36 dL/g in NMP at 25° C. To imidize, toluene (40 mL) was added and the reaction was heated at 160° C. for 24 h. After cooling, a powder precipitated which was washed twice in water and dried ~230° C. in a vacuum to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was insoluble in NMP and had a glass transition temperature 218° C. and a small Tm at 331° C. A film cast from the polyamide acid solution and dried 1 hour each at 100, 225, and 371° C. had a Tg of 240° C. and was tough.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl.CO.CN(C)C=O>[N:19]([CH2:17][C@@H:13]1[C@H:14]([OH:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@H](O)C1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 13 h
Yield: 85.1 %

Procedure:
(3R,4S)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (2.33 g), sodium azide (1.81 g), triphenylphosphine (2.67 g) and N,N-dimethylformamide (46 mL) were mixed together. While the mixture was chilled in an ice water bath, carbon tetrabromide (3.38 g) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 13 hours and then at 60° C. for 3 hours. Subsequently, methanol (3 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: hexane=2:1) to give (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup (2.18 g).