Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=[C:5]2[NH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[NH:4][CH:3]=1
Reactant: COC(=O)c1cnc2c(Cl)c[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cnc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.9 %

Procedure:
Methyl 3-chloro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.10 g, 5.22 mmol) was suspended in 1,4-dioxane (25 mL) and 6 N aqueous hydrochloric acid (8.7 mL) was added. The reaction was allowed to stir at room temperature overnight. The reaction was then concentrated to give the title compound (1.2 g, 100%). +ESI (M+H) 197.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.50 (br. s., 1 H), 8.92 (d, J=1.6 Hz, 1 H), 8.46 (br. s., 1 H), 8.19 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:31][C:32](N(C)C)=O>>[NH2:7][C:6]1[CH:8]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][CH2:12][CH2:15][CH2:31][CH3:32])=[O:18])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)N(C)C
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 144 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
5-Chloro-2-nitroaniline (8.60 g, 50 mmol, commercially available from Aldrich), 1-tert-butoxycarbonyl piperazine (14.0 g, 75 mmol, commercially available from Aldrich)), anhydrous potassium carbonate (6.9 g, 50 mmol) and DMA (60 mL) were combined in a thick walled pressure fitted with a Teflon stirrer bar and sealed with a Teflon screw-top stopper. The reaction mixture was heated to 144° C. with stirring for 24 hours. The reaction mixture was allowed to cool to room temperature, filtered and the recovered solid washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate, and the organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified by silica chromatography eluting with 25% ethyl acetate-hexane which gave 11.8 g of tent-butyl 4-(3-amino-4-nitrophenyl)piperazine-1-carboxylate (80% yield). 1H-NMR (400 MHz, MeOH-d4): 7.95 (d, 1H), 6.37 (dd, 1H), 6.18 (d, 1H), 3.53 (s, 4H) 3.35 (s, 4H), 1.43 (s, 9H). MS (EI): 323 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[CH:21]=[CH2:22]>C(O)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: C=CC(=O)OCC(C)C
Solvent: CCO
Product: CC(C)COC(=O)CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 87.7 %

Procedure:
A solution of 20 (0.782 g, 3.14 mmol), isobutyl acrylate (0.56 mL, 3.89 mmol) and ethanol (5 mL) was shaken at 75° C. for 2 h, then evaporated to dryness to give 1.04 g of 11e as a viscous yellow oil that was used without further purification. The structure was confirmed by 1H NMR. (Propanoate esters 11b, 11c, and 11f were similarly prepared (see synthesis of cyclopentyl acrylate in the Scheme 6). Isopropyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate (11d). Sodium hydride (60% dispersion in mineral oil, about 15 mg) was added to a stirred solution of 11b (1.20 g, 3.5 mmol) in 2-propanol (15 mL). Although after 1 h there was no insoluble solid, TLC showed evidence of degradation to the acid 1a, and the mixture was then stirred for an additional 48 h. The mixture was concentrated, suspended in a small amount of 1:1 heptane:ethyl acetate, filtered to remove insoluble solid (323 mg, a) and purified by flash chromatography to yield 560 mg (43%) of 11d. The structures were confirmed by 1H NMR and LC/MS. (Propanoate ester 11f was similarly prepared (this represents a second method for preparing 11f.) Cyclopentyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate, oxalic acid salt (11f-Ox). A solution of oxalic acid (190 mg, 2.11 mmol) in ethanol (3 mL) was added in one aliquot to a stirred solution of 11f (885 mg, 2.26 mmol) in warm ethanol (5.5 mL). The mixture became solid after 10 seconds of stirring. The solid mass was broken up and after 1.5 h of stirring, the solid was collected by suction filtration and washed with ethanol. After drying, the oxalate salt 11f-Ox was obtained as white powder (961 mg, 96%). 1H NMR, MS, and elemental analyses were consistent with the structure of the product. (The oxalate salt of 11d was similarly prepared.) Ethyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate, HCl salt (11c-HCl). 2 M HCl/ether (1.45 mL) was added to a stirred solution of 11c (812 mg, 2.32 mmol) in isopropyl ether (40 mL). After stirring for 30 min, the resulting precipitate was filtered, washed with isopropyl ether, and recrystallized from boiling H2O (2 mL) to give 608 mg of the hydrochloride salt of 11c-HCl as a creamy white powder. The structure was confirmed by 1H NMR, MS, and elemental analysis. (The HCl salt of 11e was similarly prepared.)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:8])[CH3:7].[C:30]([O-])(=[O:32])C.[Na+]>CN(C=O)C>[C:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][C:21]([CH:30]=[O:32])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1ccc(N(c2ccccc2)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
DMF (2.63 g, 0.036 mol) was added to a three-neck flask (50 mL) equipped with a condenser, CaCl2 drying tube, and a glass stopper and cooled in an ice bath. Phosphorus oxychloride (1.8 g, 0.012 mol) was then added dropwise, and the resulting mixture stirred for 5 minutes and then allowed to warm slowly to room temperature. A solution of 4-(N,N-diphenylamino)benzyl acetate (1.88 g, 0.0059 mol) in DMF (20 mL) was then added dropwise. After addition was complete, the mixture was heated to 70° C. and stirred overnight. The mixture was then poured over ice (20 g) and the product obtained by filtration after slowly neutralizing the solution in an ice bath with saturated sodium acetate solution to pH 6. After washing with deionized water and drying, the product was recrystallized by dissolving in a small quantity of chloroform and pouring into excess hexane to yield the desired product (1.21 g, 60%). m.p. 86-89° C.; 1H NMR δ: 2.12(s, 2H, CH3), 5.09 (s, CH2), 7.0-7.37 (m, 12H, phenyl), 7.65-7.70 (d, 2H, phenyl), 9.81 (s, 1H, CHO). Analysis: Calculated for C22H19NO3: C, 76.52%; H, 5.51%; N, 4.06%. Found: C, 76.27%; H, 5.72%; N, 4.01%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:36]1[N:35]=[CH:34][C:33]2=[CH:32][CH:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[N:38]2[N:37]=1
Reactant: COc1cc([C@H]2CC[C@H](N3CCOCC3)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc([C@H]2CC[C@H](N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 120 °C

Procedure:
Into an 8-dram vial, 2-methoxy-4-[trans-4-(morpholin-4-yl)cyclohexyl]aniline (0.125 g, 0.430 mmol), Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (98 mg, 0.26 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-{2-methoxy-4-[trans-4-(morpholin-4-yl)cyclohexyl]phenyl}-7-(2-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine as a yellow solid (65 mg, 48%). LCMS (E/I+) 514.23 (M+H). NMR 1H (DMSO-d6)-9.71 (bs, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=8.03 Hz), 7.81 (d, 1H, J=7.74 Hz), 7.60 (s, 1H), 7.46 (t, 1H, J=7.74 Hz), 7.22 (d, 1H, J=8.32 Hz), 7.10 (t, 1H, J=7.74 Hz), 6.98 (d, 1H, J=4.64 Hz), 6.94 (d, 1H, J=4.64 Hz), 6.89 9 s, 1H), 6.69 (d, 1H, J=8.33 Hz), 4.02 (d, 2H, J=12.02 Hz), 3.87 (s, 3H), 3.79 (s, 3H), 3.70 (t, 2H, J=11.78 Hz), 3.46 (d, 2H, J=12.02v), 3.28 (bs, 1H), 3.15 (q, 2H, J=11.54 Hz), 1.97-2.10 (m, 4H), 1.47-1.64 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[C:36]2[C:32](=[CH:31][C:30]([NH:29][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:46][CH2:47][CH2:48][N:49]5[CH2:53][CH2:52][CH2:51][CH2:50]5)[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Yield: 94.9 %

Procedure:
To a mixture of tert-butyl 5-(7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g, 0.118 mmol) in CH2Cl2 (4 mL) was added TFA (6 mL). The resultant mixture was stirred at RT for 1.25 h, upon which the volatiles were removed in vacuo and the residue was triturated with Et2O to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)-2-morpholinoacetamide (0.090 g, 0.112 mmol, 95%). MS 623.2 (M+1). HPLC retention time 3.806 mins.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:3][CH:2]=1.[NH3:26]>CO.CCOCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([NH2:26])=[O:17])=[CH:3][CH:2]=1
Reactant: COC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: NC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
A solution of methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyrate (39 g, 120 mmol) in 600 mL of MeOH was saturated with NH3. The solution was periodically treated with additional NH3 over a 24 h period. The solution was degassed with a stream of nitrogen and the solution was concentrated to leave a yellow solid. The solid was slurried in ether and filtered to leave the title compound: MS (M+H): 325 (base peak).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-:29].[NH4+]>CCOCC>[ClH:29].[F:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH2:5][C:17]1([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH:15]([N:13]([CH3:12])[CH3:14])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1ccc(F)cc1F
Product: Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
0.29 g (11.9 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.47 g (11.9 mmole) of 2,4-difluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.30 g (9.9 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.78 g of crude base (49.9% of theory) were obtained. The aqueous solution was extracted three times with 15 ml of ether and 15 ml of dichloromethane each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.31 g of crude base (36.7% of theory) were obtained. The hydrochloride was precipitated from both bases according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. 0.95 g of 1-(2,4-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (20.2% of theory) was obtained from the first base, and 1.27 g of 1-(2,4-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (32.4% of theory) with a melting point of 178° C. was obtained from the second base.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si](C(C)(C)C)(C)C)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[F:36][C:37]([F:60])([F:59])[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]([C:49]3[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=3)[S:47][CH:48]=2)=[CH:40][CH:39]=1>>[OH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]1[NH:8][C@@H:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([NH:1][S:55]([C:52]3[CH:53]=[CH:54][C:49]([C:46]4[S:47][CH:48]=[C:44]([C:41]5[CH:42]=[CH:43][C:38]([C:37]([F:60])([F:59])[F:36])=[CH:39][CH:40]=5)[N:45]=4)=[CH:50][CH:51]=3)(=[O:57])=[O:56])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Product: O=S(=O)(Nc1ccc(C[C@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1

Procedure:
The title compound was prepared from tert-butyl (2R,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4b) and 4-{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}benzenesulfonyl chloride (i-6) according to the procedure of Example 212, step A. The crude product was purified by preparative TLC plate eluting with 40% ethyl acetate in hexane to afforded the product (8.1 mg, 81%). mlz (ES) 865 (MH)+, 765 (M-Boc)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH:7]=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[CH:15][CH:16]=1>C1COCC1.CCOCC>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH:7]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[CH:16]=1)[OH:8]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: O=Cc1cc(Cl)sc1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1cccc(Cl)c1)c1cc(Cl)sc1Br
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-5-chlorothiophene-3-carbaldehyde from Example 1, Step 3 (2.50 g, 11.1 mmol) in THF/ether at −78° C. was added 3-chlorophenylmagnesium bromide (26.6 mL, 0.5M in THF) in 2 min. and the mixture was stirred at −78° C. for 5 min., quenched with saturated NH4Cl/water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (10-20% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH:36]=4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Reaction time: 0.67 h

Procedure:
To a degassed solution of the title compound from Example 12 Step D (365 mg, 0.551 mmol) in EtOAc (10 mL) was added platinum(IV) oxide (125 mg). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 40 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. Purification by flash chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 665.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1 H), 8.12 (s, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.79 (br s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.19-7.16 (m, 3H), 6.97 (d, J=8.5 Hz, 1H), 5.09 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 4.30-4.18 (m, 2H), 2.82-2.78 (m, 2H), 2.67-2.62 (m, 1H), 2.35 (s, 3H), 1.83-1.80 (m, 2H), 1.66-1.57 (m, 2H), 1.49 (s, 9H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[N:12]([C:13]=2[N:14]=1)[CH2:11][CH:10]([N:15]([CH3:26])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:9][CH2:8]3.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH3:33][OH:34]>C(Cl)Cl>[CH3:33][O:34][C:27](=[O:31])[C:28]([C:6]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:14][C:13]=2[N:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:15]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:26])[CH2:11]2)=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C1CCc2cc3ccc(Cl)nc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reactant: CO
Solvent: ClCCl
Product: COC(=O)C(=O)c1c2n(c3nc(Cl)ccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-N-(2-chloro-6,7,8,9-tetrahydro-pyrido[3,2-b]indolizin-8-yl)-4-fluoro-N-methyl-benzenesulfonamide (0.31 g) in 15 mL of CH2Cl2 cooled at 0° C. was added 0.15 mL of oxalyl chloride. After stirring for 30 min at 0° C., 6 mL of dry MeOH was added and stirring was continued for 20 min. The resulting solid was collected by filtration to give 0.28 g of the title compound as a white solid. (containing trace of MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:30][CH:26]3[O:27][CH2:28][O:29][CH:25]3[CH2:24]2)[CH:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][CH:23]4[CH2:24][CH:25]5[O:29][CH2:28][O:27][CH:26]5[CH2:30]4)[C:10]=3[C:17]=2[CH3:18])=[O:21])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NCCCN1CCCC1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CC4OCOC4C3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN2CCCC2)sc2ncnc(Nc3ccc(F)cc3OC3CC4OCOC4C3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.15 g 4-[4-fluoro-2-(tetrahydro-cyclopenta[1,3]dioxol-5-yloxy)phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid, 0.045 g 1-(3-aminopropy)pyrrolidine, 0.159 g HATU and 0.097 ml TEA in 15 ml DMF was stirred at rt for 1 hour. The reaction mixture was poured on water, extracted with DCM, dried and filtered. The filtrate was concentrated. The residue was triturated with diisopropylether.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH2:13]O)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:58]1[CH:62]=[C:61]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=2)[N:60]=[CH:59]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:72]CCl>>[ClH:72].[C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH2:13][N:60]3[C:61]([CH2:63][C:64]4[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=4)=[CH:62][N:58]=[CH:59]3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2ccccc2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3ccccc3)cn2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-phenyl-6-hydroxymethylpyridine (192 mg, 1.04 mmol) and diisopropylethylamine (0.360 mL, 2.07 mmol) in dichloromethane (8 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.180 mL, 1.07 nmuol) and the mixture stirred at -78° C. for 1 hour. To this mixture was added a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (441 mg, 1.04 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 4 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (10 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, EtOAc and then 5% MeOH in CH2Cl2). The amine was converted to the HCl salt by treatment with 1.0M HCl in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid. FAB HRMS exact mass calcd for C23H19N4 351.160972 (MH+); found 351.161206.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[OH:15][CH2:14][CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCO
Yield: 40 %

Procedure:
25.9 g (170 mmol) vanillin (Aldrich), 33.3 g (266 mmol) 2-bromoethanol (Aldrich), 35.2 g (255 mmol) potassium carbonate (Sigma-Aldrich), and 20 g molecular sieves (Aldrich) were combined in a 1 liter round bottom flask equipped with magnetic stirrer and nitrogen inlet. Acetone (600 ml) (Chromesolv for HPLC, >99.9%, Sigma-Aldrich) was added and the reaction mixture was refluxed for 16 hours using an external glycerol heating bath set to 65° C. The solids were filtered and the solvent was removed via rotary evaporation to yield a yellow oil. White crystals were obtained by recrystallization in ethyl alcohol at −20° C. (40% yield).