Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](=[O:16])=[O:15].C(=O)([O-])O.C([N+](CCCC)(CCCC)CCCC)CCC.[F:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Cl>C(#N)C>[F:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][O:15][C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)=[O:16]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccccc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.47 g N-Boc-piperazine in 40 ml acetonitrile was saturated with dry carbon dioxide gas at rt. To this solution was added dropwise in 5 min. a solution of 8.50 g (28 mmol) terabutylammonium hydrogencarbonate (dried at 50° C. at 0.1 mbar for 1 h) in 30 ml acetonitrile, and then carbon dioxide gas bubbled into the stirred solution at rt for 1 h. Then 2.90 g (20 mmol) 2-fluorobenzyl chloride was added drop-wise within 5 min. After stirring at rt for 3 h the reaction mixture was evaporated, 150 ml of water added and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and evaporated. Purification by flash chromatography on silica gel with hexane/AcOEt 50:50 provided 4.29 g piperazine-1,4-dicarboxylic acid tert-butyl ester 2-fluoro-benzyl ester as colourless powder. 1H-NMR(CDCl3): 1.46 s, 9H; 3.35–3.55 m, 8H; 5.21 s, 2H; 7.02–7.20 m, 2H and 7.27–7.45 m, 2H. MS (EI): 338.1 M+.
Reaction SMILES: O.[NH2:2]N.[F:4][C:5]([F:12])([F:11])[C:6](OCC)=O.C(O)(=O)C.[CH:17]([NH2:19])=[NH:18]>>[F:4][C:5]([F:12])([F:11])[C:6]1[N:19]=[CH:17][NH:18][N:2]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N=CN
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1nc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Hydrazine monohydrate (4.8 g, 96 mmol) was dissolved in industrial methylated spirits (160 mL) and cooled to 0° C. before ethyl trifluoroacetate (14 g, 100 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added dropwise. The resulting reaction mixture was then warmed to ambient temperature and stirred for 1 hour. After this time, the solvent was removed under vacuum and the residue re-dissolved in industrial methylated spirits (100 mL). Formamidine acetate (9.9 g, 95 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was then added and the reaction mixture heated to 80° C. for 2.5 hours. The reaction was then cooled to ambient temperature and the solvent removed under vacuum. To the residue was then added NaHCO3 (aq.) (100 mL), and the product was extracted with ethyl acetate (2×100 mL), dried over MgSO4, filtered and the solvent removed under vacuum. The crude product was then purified by flash chromatography (1:3 hexane/ethyl acetate), giving ˜10 g of a pale peach oil, which crystallised on standing overnight. The crystals were then filtered, washed with hexane and dried overnight in an oven to afford (I-15a) as colorless crystals (8.73 g, 66% yield): 1H NMR (400 MHz, DMSO-d6): δ 8.81 (1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[F:25].CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][C:21]4[CH:22]=[CH:23][C:24]([F:25])=[C:19]([F:18])[CH:20]=4)=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)c(F)c1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.16 g, 0.65 mmol) and 3,4-difluorophenyl isocyanate (76 μL, 0.65 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless foam after column chromatography with hexane-EtOAc.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[NH:9][NH2:10].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([NH:10][NH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of pent-4-enoic acid 0.1 M in DCM, tert-butyl carbazate (2 eq) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 eq) and the mixture was allowed to stir at RT overnight. DCM was added and the organic solution was washed sequentially with saturated aq. NaHCO3 followed by saturated aq. NaCl and then dried over Na2SO4. Removal of the solvent in vacuo yielded the title compound as colorless oil. This material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ: 7.33 (bs, 1H), 6.51 (bs, 1H), 5.88-5.75 (m, 1H), 5.10-4.99 (m, 2H), 2.43-2.38 (m, 2H), 2.32 (t, J 6.8, 2H), 2.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(CO)CC3)ccc21
Yield: 106.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-piperidine methanol (84 mg, 0.729 mmol), acetic acid (0.168 mL, 2.93 mmol) and sodium triacetoxyborohydride (54 mg, 0.26 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-[4-(hydroxymethyl)piperidinomethyl]indol-2-yl]isoindolinone (39.7 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:17]2[C:16](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CCOC(C)=O>[CH3:26][CH:25]([O:27][C:28](=[O:30])[CH3:29])[C:14](=[N:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:17]=1[C:16](=[O:15])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=Nc2ccccc2)o1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)C(=Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Reaction time: 19.5 h

Procedure:
Piperidine (1 mL) was added to compound 178 (0.161 g, 0.5 mmol) and the reaction mixture was stirred for 19.5 h. The reaction mixture was then concentrated under reduced pressure to give a yellow gum. Trituration with 1:4 EtOAc:hexanes gave a small amount of compound 179 (0.041 g). Flash chromatography (1:4 EtOAc:hexanes) of the filtrate gave only a partially separable mixture of the expected products, the acetoxyquinazolinone compound 179 and the hydroxyquinazolinone (total mass 0.122 g). ESI-MS m/z=408 (MH+). The reaction described above and compound 179 are shown below.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1=[N:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[O:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]1=2
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: ClC1=Nc2ccccc2Oc2ccccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one (1.00 g, 4.74 mmol) and phosphorus oxychloride (40 mL) was stirred for 5 h at reflux. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved into AcOEt and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give an orange oil. The residue was purified by silica gel column chromatography with EtOAc (10%) in hexanes to afford 554 (939 mg, 86%) as a yellow solid. LRMS (ESI): (calc) 229.0 (found) 230.1 (MH)+.
Reaction SMILES: [OH-].[K+].[CH:3]([NH:6][C:7]([C:9]1[S:13][N:12]=[C:11]([CH2:14][CH3:15])[C:10]=1[C:16]([O:18]C)=[O:17])=[O:8])([CH3:5])[CH3:4]>O.C(O)C>[CH:3]([NH:6][C:7]([C:9]1[S:13][N:12]=[C:11]([CH2:14][CH3:15])[C:10]=1[C:16]([OH:18])=[O:17])=[O:8])([CH3:4])[CH3:5]
Reactant: CCc1nsc(C(=O)NC(C)C)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1nsc(C(=O)NC(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
2.8 g of KOH in 30 ml of water are added to 11 g of the ester from Example 5 in 50 ml of ethanol, and the mixture is stirred overnight at room temperature. It is diluted with 150 ml of water and extracted with ether, and the aqueous phase is acidified with concentrated hydrochloric acid. Extraction by shaking with dichloromethane and evaporation give 10 g of 5-isopropylaminocarbonyl-3-ethylisothiazole-4-carboxylic acid of melting point 138°-140° C. (compound No. 3006).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: OC1CCNCC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)N3CCC(O)CC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and 4-hydroxypiperidine gave 176. MS: (ESI+) 497.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][N:11](C(OCC)=O)[CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>C(O)CCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCC=C(c2cccc(OC)c2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: COc1cccc(C2=CCCNC2)c1
Yield: 100.4 %

Procedure:
A solution of 11 g of the product of Step C in 110 ml of n-butanol and 11 g of potassium hydroxide was heated for 6 hours at 120° C. and the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture. The distilled fraction residue was taken up in methylene chloride and the solution was filtered and evaporated to dryness under reduced pressure to obtain 8 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: CON(C)C([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=O.I[C:27]1[CH:36]=[CH:35][C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[N:28]=1.C([Mg]Cl)(C)C.C1C[O:45][CH2:44]C1>>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:44]([C:27]3[CH:36]=[CH:35][C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[N:28]=3)=[O:45])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Ic1ccc2c(n1)CCCC2
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Product: O=C(c1ccc2c(n1)CCCC2)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 327 mg (0.81 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 4 mL THF and 527 mg (2.03 mmol) of 2-iodo-5,6,7,8-tetrahydro-quinoline in 2 mL THF with 1.01 mL 2M isopropylmagnesium chloride. Yield: 28 mg of a white powder. LC-MSD, m/z for C25H20BrN3O2 [M+H]+=474.0, 476.0; HPLC retention time: 2.5 min.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[Br-:21].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: BrCCCc1ccccc1
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Solvent: ClC(Cl)Cl
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 60.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0688 g, 0.225 mmol) and (3-bromopropyl)benzene (0.070 mL, 0.460 mmol) in 1MeOH/1 CHCl3 (4.0 mL) were reacted to give the desired product (0.0685 g, 62.3%). EI-MS m/z 424 (M+) Rt (1.97 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3C4C=CC=CC=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[C:26]12(CS(O)(=O)=O)C(C)(C)[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=O.[CH3:41][C:42](C)(C)C([O-])([O-])[O-]>C(#N)C>[CH3:41][C:42]1[N:8]([CH3:9])[C:7]2[C:2]([N:1]=1)=[C:3]([N:10]1[CH2:11][CH2:12][CH:13]([N:16]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[NH:18][C:17]3=[O:25])[CH2:14][CH2:15]1)[N:4]=[CH:5][N:6]=2
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(C)(C)C([O-])([O-])[O-]
Solvent: CC#N
Product: Cc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Yield: 385 %

Procedure:
To 1-{1-[5-amino-6-(methylamino)pyrimidin-4-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (150 mg, 0.442 mmol) in acetonitrile (2 mL) was added camphorsulfonic acid (4.9 mg, 0.02 mmol) and trimethylorthoacetate (2 mL, 16.6 mmol). The mixture was heated at reflux for 15 h, then was cooled to ambient and was purified by preparative-HPLC to afford 1-[1-(8,9-dimethyl-9H-purin-6-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one as a beige solid (28 mg, 0.077 mmol, 17% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[C:11]3[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:46]>>[ClH:46].[ClH:46].[C:30]1([C:15]2[C:16]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClCCl
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of tert-butyl 4-(1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.440 g, 0.881 mmol) in DCM (5 mL) was added to TFA (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness and dried under vacuum for 1 hour. TFA (3.39 mL, 44.0 mmol) was then added, and the mixture was stirred at 65° C. for 4 hours. The reaction was then concentrated to dryness, and the resulting residue was dissolved in DCM (3 mL). HCl in ether (2 mL, 2N) and ether (10 mL) were then added, and the resulting solid was collected by filtration to give 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.29 g, 75%). MS ESI (+) m/z 280.1 detected.
Reaction SMILES: N1CCCCC1.Br[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>CCCCC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCCC
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1cccs1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a mixture of piperidine (10 mL, 93.9 mmol), 2-bromothiophene (3.21 g, 19.7 mmol), and (trimethylsilyl)acetylene (2.13 g, 21.7 mmol) was added Pd(PPh3)4 (0.03 g, 0.026 mmol), followed by CuI (0.01 g, 0.05 mmol) and PPh3 (0.015 g, 0.057 mmol). The reaction mixture was heated at the reflux temperature for 45 min., and was allowed to cool to room temperature. The resulting dark brown slurry was diluted with pentane (20 mL) and water (20 mL) and the aqueous layer was extracted with pentane (2×20 mL). The organic layers were washed with a saturated NH4Cl solution (4 mL) and a 3M HCl solution (4 mL), dried (MgSO4) and concentrated under reduced pressure to give 2-(2-thienyl)-1-trimethylsilylacetylene (2.79 g, 79%) as a reddish brown oil: GC-MS m/z (rel abundance) 180 (M+, 30%); 1H NMR (CDCl3) δ 0.15 (s, 9H), 6.79 (m, 1H), 7.15 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:22][CH2:21][CH2:20][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCN1CCCC1)CCCC2=O
Yield: 72.6 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-(pyrrolidin-1-yl)ethanamine 0.24 g (2.1 mmol) was reacted to give 0.21 g (73%) of the titled compound as a white solid.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:3]1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:31](OCC)(=O)C>C1COCC1.C(OCC)C>[CH3:31][C:9]1[CH:8]=[C:7]([O:11][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH:6]=[C:5]2[C:10]=1[NH:2][CH:3]=[C:4]2[CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2cn(C)c3ccc(O)cc23)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: -4 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a suspension of 1-methyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indole (2.52 mmol, 0.616 g) in THF (6.4 mL) at room temperature was added 60% sodium hydride (3.03 mmol, 0.121 g). After stirring 15 minutes, benzenesulfonyl chloride (2.77 mmol, 0.490 g) was added. Reaction stirred at room temperature for 24 hours. Reaction then treated with ethyl acetate (25 mL) and washed with water (2×25 mL) then brine (25 mL). The organic phase was dried over sodium sulfate, filtered, concentrated in vacuo to afford an oil. The oil was subjected to normal phase radial chromatography, 4 mm plate eluting with 9:1 chloroform:2M ammonia in methanol. Fractions containing product combined, concentrated in vacuo to afford an oil. The oil was dissolved in diethyl ether. The solution was cooled at −4° C. which resulted in crystal formation. Crystals collected by filtration to afford 0.639 g (66%) of the title compound: mp=118° C.; mass spectrum (ion spray): m/z=385 (M); 1H NMR (DMSOd6): 7.85-7.77 (m, 3H), 7.67-7.62 (m, 2H), 7.12 (d, J=2.20 Hz, 1H), 6.69 (d, J=2.20 Hz, 1H), 6.60 (d, J=1.46 Hz, 1H), 2.77-2.68 (bd, 2H), 2.43 (m, 1H), 2.37 (s, 3H), 2.19 (s, 3H), 1.92 (m, 2H), 1.71-1.62 (m, 2H), 1.52 (m, 2H); Calculated for C21H24N2O3S: C, 65.60; H, 6.29; N, 7.29. Found: C, 65.64; H, 6.45; N, 7.19.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](O)=[O:17].CO>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH2:16][OH:17]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
LiAlH4 (1.0 m in THF, 5.0 mL, 5.0 mmol) was slowly added to a solution of indole-2-carboxylic acid (403 mg, 2.5 mmol) in dry THF (18 mL) at 0° C. The resultant yellow solution was warmed to room temperature and stirred for 18 hours. MeOH (0.5 mL) was added and the solution concentrated under reduced pressure (3×). The resultant orange syrup was partially dissolved in CHCl3 (150 mL) and washed consecutively with H2O (10 mL) and NH4Cl (10 mL). The aqueous layer was extracted with CHCl3 (2×25 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2) afforded the desired alcohol (250 mg, 68%) as a yellow solid. 1H NMR (CDCl3) δ 4.84 (s, 2H), 6.42 (d, 1H, J=0.9 Hz), 7.11-7.20 (m, 2H), 7.36 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.5 Hz), 8.31 (br s, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[BH3-][C:13]#[N:14].[Na+].[CH3:16]COC(C)=O.C([O-])(O)=O.[Na+]>CC#N.C=O.O.C(O)(=O)C>[CH3:16][N:14]([CH3:13])[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cncc(N)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cncc(N(C)C)c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 37 %

Procedure:
To a stirring solution of 283 mg (1.86 mmol) of methyl 5-aminonicotinate in 19 mL of CH3CN and 19 mL of 37% formaldehyde in H2O was added 353 mg (5.62 mmol) of NaCNBH3, and 50 drops of acetic acid. The solution was stirred at r.t. for 18.5 h and 40 mL of EtOAc and 40 mL of sat. NaHCO3 solution was added. The layers were separated, and the organic layer was washed with 25 mL of sat. NaHCO3 and 25 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (0.5% MeOH/CHCl3) resulted in 124 mg of methyl 5-(dimethylamino)nicotinate as a yellow oil in 37% yield.