Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Br:23])[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO/N=C(/C(=O)OC)c1ccccc1Oc1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a solution of (E) -methyl-2-[2-(3-methylphenoxy)phenyl]-2-methoxyiminoacetate (4.60 g) in benzene (120 ml), N-bromosuccinimide (2.88 g) and benzoyl peroxide (0.37 g) were added, and the resultant mixture was refluxed for 1 hour, followed by cooling to room temperature. Insoluble materials were removed by filtration and, after removal of the solvent, the residue was purified by silica gel column chromatography to give (E) -methyl-2-[2-(3-bromomethylphenoxy)phenyl]-2-methoxyiminoacetate (4.60 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[C:16]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:16]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Cl)cc3)c3cnccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2nn(C3CCNCC3)c3ccncc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
4-[3-(4-Chlorophenyl)-pyrazolo[4,3-c]pyridin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The solvents were removed in vacuo and the residue was dissolved in 1 M aq Na2CO3 solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo. The residue was purified by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 40% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give 3-(4-chlorophenyl)-1-piperidin-4-yl-1H-pyrazolo[4,3-c]-pyridine (76 mg, 50.2%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)[CH:41]=1>>[ClH:34].[ClH:34].[ClH:34].[ClH:34].[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:13][CH2:14]1)[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(NCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(Cc3ccccc3)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC
Product: Cl

Procedure:
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a tetrahydrochloride which gave the title compound as yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][C@@H:6]1[CH3:21])=[O:4].[I:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:25]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:31]4[C:23]([I:22])=[N:24]3)[C@@H:6]([CH3:21])[CH2:7]2)=[C:12]([F:20])[CH:13]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)c(F)cc1Cl
Reactant: Ic1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A mixture of 2-Chloro-1-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (1.37 g, 4.08 mmol, 1 eq), 3-Iodo-1H-pyrazolo[3,4-b]pyridine (1.0 g, 4.08 mmol, 1 eq), potassium carbonate (2.26 g, 16.4 mmol, 4 eq), and DMF (15 ml) was stirred overnight at 90° C. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and concentrated in vacuo. The crude product was purified by flash chromatography to provide 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g).
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]([F:14])([F:13])[F:12].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CS(C)=O>[C:15]1([N:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:10]3[C:5]([C:6]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:8]=[CH:9]3)=[N:4]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cccc2c(Cl)n(-c3ccccc3)nc12
Reactant: C1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cccc2c(N3CCCCC3)n(-c3ccccc3)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
3-Chloro-2-phenyl-7-trifluoromethyl-2H-indazole (21 mg, 0.07 mmol, compound of formula (XI)) was dissolved in 0.5 ml of DMSO and 100 μl of piperidine (1 mmol) were added. The reaction mixture was stirred overnight at 110° C. After cooling to room temperature, 10 volumes of water were added. The supernatant was removed and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate, 50:50, as eluent) to provide the title compound as a white solid (9 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(Cn3c(C)c(C)c4c(=O)n(C)ncc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (1.06 g) in DMF (90 ml) was dripped into a suspension of 60% sodium hydride-oil (288 mg) in DMF (24 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-methoxybenzoyl)benzyl bromide (2.40 g) in DMF (30 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1-1:2) to provide the title compound as light-yellow powder (1.70 g, yield 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[O:9][C:10]([C:12]1([NH:15]C(OCC2C=CC=CC=2)=O)[CH2:14][CH2:13]1)=[O:11].[H][H].C1CC=CCC=1>[Pd]>[CH3:7][C:4]1([CH3:8])[CH2:5][CH2:6][C:2]([CH3:1])([CH3:26])[CH:3]1[O:9][C:10]([C:12]1([NH2:15])[CH2:14][CH2:13]1)=[O:11]
Reactant: [H][H]
Reactant: CC1(C)CCC(C)(C)C1OC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Product: CC1(C)CCC(C)(C)C1OC(=O)C1(N)CC1
Reaction time: 0.13 h

Procedure:
N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester is dissolved in absolute alcohol at 0° C. in an ultrasound bath. Palladium on carbon (10%) is added. The hydrogen source, 1,4-cyclohexadiene, is added, and ultrasound is commenced for eight minutes. The slurry is then filtered through a bed of Celite with ethyl alcohol. The solvent is removed by rotary evaporation to yield 1-aminocyclopropylcarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20](OC)=[O:21])[C:5]2[C:6]3[C:17](=O)[CH2:16][N:15]4[C@:11]([CH3:19])([CH2:12][CH2:13][CH2:14]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1.C(O)(=O)C.O.[NH2:29][NH2:30].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:30][N:29]=[C:17]3[CH2:16][N:15]4[CH2:14][CH2:13][CH2:12][C@:11]4([CH3:19])[C:7]4[NH:8][C:9]([CH:10]=1)=[C:5]2[C:6]=43
Reactant: NN
Reactant: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CN1CCC[C@]31C
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12CCCN1CC1=NNC(=O)c3cc(F)cc4[nH]c2c1c34
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A solution of compound (R)-methyl 9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate (90 mg), acetic acid (0.54 g), and hydrazine hydrate (0.28 g) in methanol (30 mL) was heated at reflux. After 5 h, the reaction was cooled and water (5 mL) was added. The mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL) and dried over MgSO4. The mixture was filtered, and the filtrate was evaporated to dryness, and the residue was purified by Pre-TLC using CH2Cl2 as eluent to give 80 mg of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.30 (d, 1H, J=9.6 Hz), 7.20 (d, 1H, J=10.2 Hz), 3.76 (d, 1H, J=16.4 Hz), 3.34 (d, 1H, J=16.4 Hz), 2.99-3.02 (m, 1H), 2.54-2.58 (m, 1H), 2.35-2.40 (m, 1H), 1.90-1.94 (m, 1H), 1.73-1.75 (m, 1H), 1.48 (s, 3H), and 1.43-1.45 (m, 1H). MS (ESI) m/e [M+1]+ 299.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[CH:25]=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([C:29]([O:31]C)=[O:30])[C:21]=3[CH:20]=[CH:19][C:18]2=[O:33])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[CH:25]=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([C:29]([OH:31])=[O:30])[C:21]=3[CH:20]=[CH:19][C:18]2=[O:33])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.5 %

Procedure:
466 mg of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylate was dissolved in a mixture of 7 mL of methanol, 5 mL of tetrahydrofuran and 3 mL of water. To this mixture, 0.77 mL of 5 mol/L sodium hydroxide was added and stirred at room temperature for 1 hour. To the reaction mixture, hydrochloric acid was added to make acidic, the resulting solid was filtered and dissolved in chloroform. The chloroform solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 553 mg of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (4.4 g, 31.2 mmol) in EtOH (32 mL) was added at 0° C., 2-phenylethanamine (4.11 mL, 32.8 mmol). Mixture went from light yellow to bright orange instantly and it was stirring overnight at RT. Another equivalent of 2-phenylethanamine was added (4.11 mL, 32.8 mmol) and the mixture was heated to 50° C. overnight. Water was added (20 ml) and the resulting orange solid was isolated by filtration to afford 6.99 g of 2-nitro-N-phenethylbenzenamine (Yield: 92%) as an orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[O:11]1[CH:13]([CH3:14])[CH2:12]1>>[OH:11][CH:13]([CH3:14])[CH2:12][NH:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC1CO1
Product: Cc1cc(C)c(NCC(C)O)c(C)c1
Yield: 45.1 %

Procedure:
2,4,6-Trimethylaniline is reacted with 1,2-epoxy-propane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxy-propyl)-2,4,6-trimethyl-aniline with a yield of 45.1%; b.p.: 130°-135° C./0.4 mm Hg.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.C[C:18]1[NH:19][C:20](C)=[CH:21][CH:22]=1>C1C=CC=CC=1>[C:1]1([C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:13]2[NH:12][CH:16]=[CH:15][CH:14]=2)[O:11]1)=[O:10].[C:1]1([C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:22]2[CH:21]=[CH:20][NH:19][CH:18]=2)[O:11]1)=[O:10]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: Cc1ccc(C)[nH]1
Reactant: c1cc[nH]c1
Solvent: c1ccccc1
Product: O=C1OC(c2cc[nH]c2)c2ccccc21
Product: O=C1OC(c2ccc[nH]2)c2ccccc21

Procedure:
Rees et al. in further studies, ibid., pp. 687-91 (1965), reported that the condensation of phthalaldehydic acid could be extended to pyrroles and found that phthalaldehydic acid reacted with pyrrole and 2,5-dimethyl pyrrole in boiling benzene in the absence of an external catalyst to give high yields of 2-phthalidyl-pyrole and 3-phthalidyl-pyrrole, respectively. In these reactions, it was observed that pyrrole tended to substitute in the 2-position when possible to yield the 2-phthalidyl derivative. In a further extension of the reactions, the authors found that naphthalaldehydic acid, though less reactive than phthalaldehydic acid, behaved in a similar manner and could be condensed with indole under fusion conditions to yield 3-naphthalidylindole.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][CH2:31][S:32][CH3:33])[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:40])(C)C>CC(CC)=O>[ClH:40].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][CH2:31][S:32][CH3:33])[C:9]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Agent: COc1ccc(C(=O)N2CCC3(CC2)N[C@@H](CCSC)C(=O)N3Cc2ccccc2)c(OC)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1-benzyl-8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (290 mg, 0.6 mmol) was dissolved in ethyl methyl ketone (2 mL), and water (6 μL) and TMSCl (80 μL) were added and the mixture was stirred overnight. The precipitated solid matter was isolated by filtration and dried in vacuo. The product 1-benzyl-8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 105 mg (95%).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH2:31])[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8].Br[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C1CCCCC1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH:31][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=2)[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8]
Reactant: Cc1ccc(Br)nc1
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 120 °C

Procedure:
Sodium tert-butoxide (135 mg, 1.41 mmol)) was added to a suspension of ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 16) (450 mg, 1.28 mmol), 2-bromo-5-methylpyridine (439 mg, 2.55 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (40 mg, 0.102 mmol) and tris(dibenzyldieneacetone)dipalladium(0) (47 mg, 0.051 mmol) in anhydrous toluene (4.5 mL). The mixture was heated under microwave irradiation to 120° C. for 1 h in a sealed vial. The mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient) to give a residue. This residue was dissolved in a mixture of EtOAc (0.6 mL) and cyclohexane (0.4 mL). The solution was treated with cyclohexane (3 mL) to give an emulsion, which was allowed to stand at room temperature over a weekend. The solution was decanted from the precipitated dark brown oil and concentrated to dryness under a stream of nitrogen to give an oil. This oil was triturated with cyclohexane (2×3 mL), the residual gum isolated by decanting off the cyclohexane, dissolved in EtOAc and concentrated to dryness under a stream of nitrogen to give crude ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate as a pale brown foam (240 mg) which was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.C1(C(N)C2CCCCC2)CCCCC1.[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc2[nH]ncc2cc1Br
Agent: NC(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2nn(COCC[Si](C)(C)C)cc2cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 5-bromo-6-methyl-indazole (500 mg, 2.37 mmol) in THF (6 mL) was added dicyclohexylmethylamine (0.63 mL, 3.0 mmol), followed by SEM-chloride (0.50 mL, 2.8 mmol) via syringe. The reaction mixture was stirred at room temperature for 3 hours. EtOAc (20 mL) was added followed by 0.5N aqueous NaOH (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed consecutively with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (0-33% EtOAc/heptane) to provide the title compound (639 mg, 79% yield). MS (ES+) 343.1 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 5.70 (s, 2H), 3.62 (t, J=8.10 Hz, 2H), 2.52 (s, 3H), 0.95 (t, J=8.30 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:17][CH3:18]>C(#N)C>[I-:17].[CH3:18][N+:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:10]([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=1
Reactant: C[Si](C)(C)Cn1cc(-c2ccccc2)nn1
Reactant: CI
Solvent: CC#N
Product: C[n+]1nn(C[Si](C)(C)C)cc1-c1ccccc1
Product: [I-]

Procedure:
4-phenyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (1.0 g, 4.32 mmol) and iodomethane (5 ml, 80 mmol) were added to a vial. The reaction was heated for 19.5 hours. and 5 mL ACN was added. The reaction was heated for another 2 hours. The precipitate was filtered, rinsed with ether and dried in vacuo overnight. The following 3-methyl-4-phenyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCCC1=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:43][CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 105 °C
Yield: 90.1 %

Procedure:
Sulfone 9.1 (2.24 g, 5.4 mmol) was combined with N-tert-butoxycarbonyl-4-aminomethylpiperidine (5.6 g, 16.2 mmol) and 1-methyl-2-pyrrolidinone (9 mL). The mixture was heated to 100-110° C. for 2 hours at which time it was cooled to room temperature and ethyl acetate was added. The resultant white solid was filtered and washed with ethyl acetate to give 2.3 g of 3-(2-chlorophenyl)-7-[(1-tert-butoxycarbony-piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (MH+=473). Hydrogen chloride gas was bubbled into 2.1 g of the protected amine which was suspended in 1,4-dioxane (22 mL), and the suspension stirred for 1 hour, concentrated in vacuo and dried to give the intermediate 3-(2-chlorophenyl)-7-[(piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:6]([O:5][C:1]([NH:2][N:3]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of t-butyl carbazate (2.0 g, 15.1 mmol) in 99% ethanol (20 ml) was added benzaldehyde (1.6 g, 15.1 mmol) and the mixture was stirred for 30 min. Then the mixture was cooled to 0° C. and the precipitate was separated and washed with cold ethanol and dried in vacuo to give 2.7 g (81%) of N'-benzylidenehydrazinecarboxylic acid tert-butyl ester.