Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([NH:17]C(=O)OC(C)(C)C)=[N:12][CH:13]=[C:14](Br)[N:15]=1.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26].Cl.O1CCOCC1>COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([N:33]2[CH2:32][CH2:31][N:30]([S:27]([CH2:25][CH3:26])(=[O:28])=[O:29])[CH2:35][CH2:34]2)[N:15]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1-c1cc2ccccc2o1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc4ccccc4o3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of tert-butyl N-[3-(benzofuran-2-yl)-5-bromo-pyrazin-2-yl]carbamate, 1-ethylsulfonylpiperazine (164.5 mg, 0.9228 mmol) and 2-methoxyethanol (3 mL) were heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to RT, treated with HCl in dioxane (384.5 μL of 4 M, 1.538 mmol) and allowed to stir at RT for 3 hours. The mixture was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an orange solid (15.5 mg, 12% Yield). 1H NMR (DMSO) d 1.24 (3H, t), 3.11 (2H, q), 3.45 masked signal, 3.51 (4H, m), 6.12 (2H, br s), 7.30 (1H, m), 7.34 (1H, m), 7.47 (1H, s), 7.71 (2H, m), 7.98 (1H, s) ppm; MS (ES+) 388.01
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([O-:30])=[O:29]>CN(C=O)C.O>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:37][C:34]1[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCOc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 16 (1.83 g, 5.75 mmol) in anhydrous DMF (10 mL) were added K2CO3 (2.39 g, 17.3 mmol) and 4-nitrophenol (0.78 g, 5.59 mmol), and the reaction mixture was heated to 80° C. for 16 h. After cooling, the mixture was diluted in water, extracted three times with DCM, and then dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with Hex/EtOAc (1:2) to afford 17 as a yellow oil (1.51 g, 92%): 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=9.1 Hz, 2H), 6.97 (d, J=9.1 Hz, 2H), 4.26-3.65 (m, 12H), 3.37 (s, 3H).
Reaction SMILES: C(Cl)Cl.[C:4]([CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)(=[O:6])[CH3:5].OS(C(F)(F)F)(=O)=O.C[SiH](C)C.[Br:24]N1C(=O)CCC1=O>C(N(CC)CC)C>[Br:24][CH2:5][C:4]([CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)C1CCCO1
Agent: C[SiH](C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)C1CCCO1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a 20-liter glass vessel was added methylene chloride (10.0 liters) followed by acetyltetrahydrofuran (838.0 g, 7.34 moles). The solution was then cooled back to −10° C. and triethylamine was added (854.0 g, 8.44 moles). The vessel was purged with nitrogen and trimethylsilane triflate (1713.0 g, 7.71 moles) was added dropwise at a maximum temperature of −8° C. Addition was typically complete in 45 minutes. After 15 minutes stirring, a sample was removed for TLC and GC analysis, which showed that the reaction was completed. N-bromosuccinimide (1340 g. 7.53 moles) was added to the solution at a maximum temperature of −5° C. over a period of approximately 45 minutes in six portions. After a 30 minute stirring, the solution was sampled for GC and TLC analysis, which showed that the reaction was completed. The solution was then transferred to a 50-liter separating vessel, and 5% sodium bicarbonate (5 liters) was added with caution. The solution was stirred and separated. The upper aqueous phase was discarded, and the methylene chloride phase was washed with water, dried over sodium sulphate, filtered and stored in a freezer before use in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]2[CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[CH2:43][NH2:44]>C(Cl)Cl>[CH:11]1([C:4]2[S:3][C:2]3[NH:1][C:15](=[O:17])[N:44]([CH2:43][C:36]4[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=4[O:34][CH3:33])[C:7](=[O:9])[C:6]=3[CH:5]=2)[CH2:13][CH2:12]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cc(C2CC2)sc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution (300 mL) of methyl 2-amino-5-cyclopropylthiophene-3-carboxylate (4.7 g) in methylene chloride were added triphosgene (3.06 g) and triethylamine (8.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1-(2,4-dimethoxyphenyl)methanamine (7.2 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (300 mL), sodium methoxide (6.4 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (8.53 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[C:16](=[N:18][OH:19])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:21][NH:22][C:23]([NH2:25])=[S:24])[C:16](=[N:18][OH:19])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: CC(=NO)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CC(=NO)C(=NNC(N)=S)c1ccc(OCc2ccccc2)cc1
Yield: 66.7 %

Procedure:
A mixture of 4'-benzyloxy-2-hydroxyiminopropiophenone (21.1 g), thiosemicarbazide (7.15 g), methanol (107 ml) and a saturated solution of hydrogen chloride in methanol (2 ml) was refluxed for 65 minutes with stirring. After cooling, the resultant precipitates were collected by filtration, washed successively with methanol, water and methanol, and then dried to give 17.9 g of 4'-benzyloxy-2-hydroxyiminopropiophenone thiosemicarbazone.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C@@H:32]([OH:34])[CH3:33])[N:25]=5)=[CH:22][N:21]([CH2:35][C:36]#[N:37])[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[OH:34][C@@H:32]([CH3:33])[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:19]([C:17]3[CH:18]=[C:13]4[CH:12]=[CH:11][NH:10][C:14]4=[N:15][CH:16]=3)=[N:20][N:21]([CH2:35][C:36]#[N:37])[CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: C[C@H](O)CNc1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)CNc1nccc(-c2cn(CC#N)nc2-c2cnc3[nH]ccc3c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To solution of the {3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-[2-((S)-2-hydroxy-propylamino)-pyrimidin-4-yl]-pyrazol-1-yl}-acetonitrile (C-1-6) (145 mg, 0.28 mmol) in THF (5 mL) at −40° C. was added sodium hydroxide (1.1 mL of a 10 mg/mL solution in MeOH, 0.28 mmol). The mixture was allowed to slowly warm to 0° C. After 2 hr the mixture was diluted with 10 mL THF and stirring continued at 0° C. for 2 hr. Mixture was partitioned between pH 7 phosphate buffer and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4 and reduced to minimum volume. The residue was purified by HPLC to give the [4-[2-((S)-2-Hydroxy-propylamino)-pyrimidin-4-yl]-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-acetonitrile (C-1) in 23% yield. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.78 (br. s., 1H), 8.42 (d, J=2.02 Hz, 1H), 8.22 (s, 1H), 8.05-8.14 (m, 2H), 7.38-7.45 (m, 1H), 6.42-6.56 (m, 2H), 5.74 (br. s., 1H), 5.25 (s, 2H), 3.72 (br. s., 1H), 3.19 (br. s., 1H), 3.04 (br. s., 1H), 0.95 (br. s., 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[C:5]([O:10][CH3:11])[C:4]=1[O:12][CH3:13].C(=O)([O-])[O-:15].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(=O)CC>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:12][CH3:13])[O:15][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)c(OC)c1OC
Reactant: CCOC(=O)CCCBr
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1cc(OC)c(OC)c(OC)c1

Procedure:
9.2 g of trimethoxyphenol, 14 g of potassium carbonate and 10.7 g of ethyl 4-bromobutanoate in 150 ml of 2-butanone are refluxed for 24 hours. The mineral salts are then filtered off and the solvent is distilled off under reduced pressure, enabling the expected compound to be obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH:18]=O)[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C>CN(C)C=O>[CH2:3]([N:10]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13](/[CH:18]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:12]=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCc1c(C=O)cnn1Cc1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(/C=C/C(=O)OCC)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
Sodium hydride (60%, oily, 2.25 g) was added to a mixture of 1-benzyl-5-propyl-1H-pyrazole-4-carbaldehyde (12.60 g), ethyl diethylphosphonoacetate (10.69 g), and N,N-dimethylformamide (150 ml) at 0° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-(1-benzyl-5-propyl-1H-pyrazol-4-yl)propenoate (11.90 g, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=O)[CH3:2].[C:13]1([CH3:21])[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=1.[ClH:22].[CH2:23](OCC)C>>[O:5]1[C:6]2=[CH:12][CH:11]=[CH:10][C:9]2=[CH:7][CH:8]=[C:4]1[CH:1]1[C:2]2[C:16](=[CH:17][CH:18]=[C:13]([CH3:21])[CH:14]=2)[CH2:15][CH2:19][N:20]1[CH3:23].[ClH:22].[O:5]1[C:6]2=[CH:12][CH:11]=[CH:10][C:9]2=[CH:7][CH:8]=[C:4]1[CH:1]1[C:2]2[C:16](=[CH:17][CH:18]=[C:13]([CH3:21])[CH:14]=2)[CH2:15][CH2:19][N:20]1[CH3:23]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: Cc1cccc(CN)c1
Reactant: CCOCC
Agent: Cl
Product: Cc1ccc2c(c1)C(c1ccc3cccc-3o1)N(C)CC2

Procedure:
Racemic 4-benzofuran-2-yl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline was prepared from 2-acetylbenzofuran and 3-tolylmethylamine as described in Example 26. This racemic compound (105 mg) was separated on semi-prep chiral HPLC (chiralcel OD-H, 1×25 cm, eluent: 3% ethanol in heptane, flow: 4 ml/minute, 500 μl injections, 5 mg/injections). The resulting free bases were dissolved in ethyl acetate and treated with a 2 M solution of HCl in diethyl ether (2 equiv) to give (+)-4-benzofuran-2-yl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride salt (39 mg, 100% AUC HPLC, 99.4% AUC chiral HPLC): 1H NMR (300 MHz, Acetone-d6) δ7.63-7.70 (m, 1H), 7.20-7.47 (m, 6H), 7.00-7.08 (m, 2H), 5.31-5.43 (m, 1H), 4.43-4.62 (m, 2H), 3.70-3.88 (m, 2H), 3.01 (s, 3H); EI MS m/z=277 [C19H19NO]+, [α]25D+20° (c 1.0, MeOH, free base) and (−)-4-benzofuran-2-yl-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride salt (40 mg, 100% AUC HPLC, 100% chiral HPLC): 1H NMR (300 MHz, Acetone-d6) δ7.63-7.69 (m, 1H), 7.21-7.47 (m, 6H), 7.00-7.10 (m, 2H), 5.32-5.45 (m, 1H), 4.43-4.66 (m, 2H), 3.67-3.90 (m, 2H), 3.02 (s, 3H); EI MS m/z=277 [C19H19NO]+; [α]25D−17° (c 1.0, MeOH, free base).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH:9]([OH:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]1CCCN(C)C1(C)C.ICC>CO>[CH2:14]([N:11]1[CH2:12][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C@H:9]([OH:13])[CH2:10]1)[CH3:15]
Reactant: CC1CCCN(C)C1(C)C
Reactant: OC1CNCC(c2ccccc2)C1
Solvent: CO
Solvent: CCI
Product: CCN1C[C@@H](O)C[C@@H](c2ccccc2)C1

Procedure:
5-Phenyl-3-piperidinol (5.2 g), tetramethylpiperidine (8.3 ml) and iodoethane (1.97 ml) was stirred at room temperature in methanol (100 ml) for 48 hours. The methanol was removed under reduced pressure and excess 2 M NaOH added. The oil was extracted with ether and washed with brine. After drying (MgSO4) the ether was removed and the product crystallised affording, after recrystallisation from cyclohexane, 3.2 g of pure title compound which could be converted to the hydrochloride salt m.p. 182°-4° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:15]1([CH2:21][NH:22][CH2:23][CH3:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:15]1([CH2:21][N:22]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH3:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCNCC1CCCCC1
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC1CCCCC1)c1nc2cc(F)ccc2cc1C=O
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-7-fluoroquinoline-3-carbaldehyde (200 mg, 0.95 mmol), N-(cyclohexylmethyl)-N-ethylamine (140 mg, 0.99 mmol) and potassium carbonate (140 mg, 1.0 mmol) in toluene (3 mL) is stirred and refluxed for 14 hours. The reaction mixture is cooled to room temperature and then diluted with water and ethyl acetate. The organic layer is washed with 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 2-[N-(cyclohexylmethyl)-N-ethylamino]-7-fluoroquinoline-3-carbaldehyde.
Reaction SMILES: Cl.NC[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].[CH:35]([N:38](CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:38][CH2:35][C:5]1[CH:4]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:23])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]([CH3:14])=[N:10]2)=[O:29]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.45 g, 1.4 mmol) in acetonitrile (10 mL), was added 3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.2 mmol). The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as an off-white solid (290 mg, 46% yield); HPLC, Waters Symmetry C18, 5 am, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.45 min (99.6%); mp, 177-179° C.; 1HNMR (DMSO-d6) 2.16-2.18 (m, 1H, CHH), 2.56-2.84 (m, 6H, CHCH2, CH3), 4.59 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=5, 9 Hz, 1H, CH), 7.58-8.14 (m, 6H, Ar), 9.34 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.91, 23.41, 30.61, 42.47, 56.54, 120.01, 124.04, 126.66, 127.56, 129.20, 130.77, 131.32, 134.17, 134.37, 137.71, 145.88, 154.65, 160.42, 164.00, 169.45, 172.60. LCMS MH=473, 475; Anal Calcd For C22H18N4O4Cl2+1.0CH2Cl2: C, 53.78; H, 4.10; N, 11.40, Cl, 14.43. Found: C, 53.44; H, 4.11; N, 11.27; Cl, 14.80.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].C[C@@H]1CCCN[C@@H]1CN1C(=O)C2C(=CC=CC=2)C1=O.[Br:44]C1C=CC(C)=CC=1C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[Br:44])=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting with 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-bromo-5-methylbenzoic acid. ESI-MS (m/z): 325, 327 [M]+, [M+2]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:25][C:26]1[S:30][C:29]([NH2:31])=[N:28][N:27]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[F:35][C:33]1[CH:32]=[C:24]([CH:23]=[C:22]([F:21])[CH:34]=1)[CH2:25][C:26]1[S:30][C:29]([NH:31][C:16]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C@@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)=[O:18])=[N:28][N:27]=1
Reactant: Nc1nnc(Cc2cc(F)cc(F)c2)s1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(Cc4cc(F)cc(F)c4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2.2 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (7.91 mmol, 1 eq.) are placed in 30 mL of dimethylformamide at room temperature. 1.98 g of 5-(3,5-difluorobenzyl)[1.3.4]thiadiazol-2-ylamine (8.70 mmol, 1.1 eq.), 4.42 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (9.49 mmol, 1.2 eq.) and 2.76 mL of diisopropylethylamine (15.81 mmol, 2 eq.) are successively added. The reaction mixture is stirred for 6 days at room temperature, poured into water and extracted with ethyl acetate. The organic phase is washed three times with water and once with brine. The organic phase is concentrated and the residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 7% to 30%. 1.5 g of methyl cis-4-{4-[5-(3,5-difluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}cyclohexanecarboxylate are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][CH:30]([NH2:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:32][CH:30]([CH3:31])[CH3:29])[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CC(C)N
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 2 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). 2-Propanamine (0.022 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further 2-propanamine (0.022 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, 2-propanamine (0.02 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time 2-propanamine (0.022 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was re-purified by Mass Directed Automated Preparative HPLC (Method E, using Waters Atlantis column 100 mm×19 mm, 5 um). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (2.1 mg).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]([C:35](Cl)=[O:36])[CH2:29][C:28]2=[O:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:24].[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]([C:35]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:36])[CH2:29][C:28]2=[O:38]
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CC(=O)c3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a suspension of 2.0 g of 4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride in 150 ml of methylene chloride was added 4.3 ml of triethylamine with vigorous stirring in an atmosphere of nitrogen. After stirring for 20 minutes, the mixture was cooled to -10° C. in an ice and salt bath and 50 ml of methylene chloride solution containing 1.9 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride was added dropwise to it. The reaction mixture was stirred at -10° C. for an hour and a half and subsequently at room temperature for two hours and a half and poured into a saturated aqueous solution of sodium bicarbonate. The resulting aqueous mixture was extracted with diethyl ether and the extract was washed with a saturated aqueous solution of sodium chloride followed by drying over anhydrous magnesium sulfate and distilling off the solvent. The residue was purified by column chromatography through silica gel and 1.60 g of the desired compound was obtained from the fractions eluted with a 10:3 mixture of ethyl acetate and triethylamine. To a solution of the product dissolved in methylene chloride was added a two molar quantity of a 4N 1.4-dioxane solution of hydrogen chloride and the mixture was concentrated. The residue was recrystallized from a mixture of ethanol and acetone to afford the title compound, melting at 250°-255° C. (dec.).