Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[CH3:31][C:32](OC(C)=O)=[O:33]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:32](=[O:33])[CH3:31])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 45.7 %

Procedure:
To a solution of N-cyclobutyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine (12.0 g, 29.2 mmol) in acetone (200 mL) and dioxane (300 mL) was added Ac2O (30 mL, 318 mmol) and Pd/C (1.80 g, 16.91 mmol). The reaction was then stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. Then the mixture was filtered through a pad of Celite™, washing with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallized with PEEtOAc, lyophilized and washed with PEEtOAc (5:1) to give pure title compound (6.1 g). 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.57-1.74 (m, 2H), 1.85-1.95 (m, 2H), 1.97-2.08 (m, 4H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.19-2.30 (m, 2H), 2.58 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.88 (t, J=10.5 Hz, 2H), 3.23-3.33 (m, 2H), 3.70 (dt, J=11.7, 5.9 Hz, 2H), 4.32-4.47 (m, 3H), 4.52 (tt, J=8.1, 3.8 Hz, 1H), 6.05 (d, J=7.8 Hz, 0.4H), 6.08 (d, J=8.3 Hz, 0.6H 6.96-7.07 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 458.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.COC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)=CC=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 56 h
Yield: 95 %

Procedure:
Ethyl (1RS,2RS,3SR)-1-(4Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activated carbon (1 g). The resulting suspension was stirred under an atmosphere of H2 for 56 h and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.70 g, 95%), which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: NCc1ccccc1F
Product: Fc1ccccc1CNc1cccn2nc(Cl)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-fluoro-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 2-fluorobenzylamine (1.11 mL, 9.72 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid, (1.45 g. 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.11 (d, J=6.9 Hz, 1H), 7.39-7.26 (m, 2H), 7.23-7.10 (m, 3H), 6.98 (t, J=14.0, 7.3 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 4.53 (d, J=6.1 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.CN1CCOCC1.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl.C1COCC1.C(Cl)Cl>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)O
Reactant: CNOC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a flask charged with compound (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The solution was cooled to 0° C. and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4 mL, 257 mmol) was added dropwise sequentially. After addition, the mixture was stirred at 0° C. under nitrogen for 1 h. To the other flask charged with N,O-dimethylhydroxylamine HCl (25.0 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0° C. and TEA (38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction flask. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was then quenched with water (500 mL) and the two phases were separated. The organic phase was washed with water (500 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-tert-butyl (3-cyclopentyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate as colorless oil (60 g, 93% yield), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([OH:14])=O)=[N:9]2)=[CH:4][N:3]=1.[CH2:15]([N:17](CC)[CH2:18]C)C.ClC(OCC)=O.CNC>CC(C)=O.C1(C)C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([N:17]([CH3:18])[CH3:15])=[O:14])=[N:9]2)=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2cnc(Br)cc2n1
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)C(=O)c1ccc2cnc(Br)cc2n1
Temperature: 2.5 °C
Reaction time: 0.42 h
Yield: 41.1 %

Procedure:
7-Bromo-1,6-naphthyridine-2-carboxylic acid (Preparation 64, 232 mg 0.92 mmole) was azeotroped with ethanol (10 mL) and then with toluene (2×12 mL). The residue was dissolved in acetone (3 mL) with triethylamine (260 uL, 1.85 mmole) and cooled in ice. Ethyl chloroformate (195 uL, 2.03 mmole) was added and the reaction stirred at 0-5° C. for 25 minutes. Dimethylamine (2M in THF, 2.2 mL, 4.4 mmole) was added and the reaction stirred at 0-5° C. for 10 minutes followed by room temperature for 50 minutes. The acetone was evaporated and the residue partitioned between ethyl acetate (25 mL) and water (8 mL). The organic layer was washed with water (8 mL), brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 9:1 ethyl acetate:acetone to afford the title compound (106 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-])[C:6]=2[CH:20]=1.[C:24](O)(=O)C>[C].[Pd]>[CH3:11][C:9]1([CH3:12])[CH2:8][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]2[CH:20]=[C:2]3[NH:1][CH:24]=[N:21][C:3]3=[CH:4][C:5]=2[O:10]1
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)c([N+](=O)[O-])cc2O1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC1(C)CN(c2ccccn2)c2cc3[nH]cnc3cc2O1

Procedure:
To a solution of 500 mg 2-(6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine 1-oxide in 25 ml acetic acid, was added a catalytic amount of 10% palladium-carbon to perform catalytic hydrogenation. The catalyst was filtered off from the reaction mixture, the solvent was distilled off from the filtrate under reduced pressure, the residue was dissolved in 10 ml formic acid, and the solution was heated under reflux for 18 hours with stirring. After distilling off the solvent from the reaction mixture, water was added to the residue, and the resulting mixture was neutralized by addition of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off from the dried solution, the residue was subjected to column chromatography on silica gel, elution was conducted by the use of a 20:1 mixture of chloroform and methanol, and the crude product thus obtained was recrystallized from ethanol, thus giving 119 mg of 1,6,7,8-tetrahydro-6,6-dimethyl-8-(2-pyridyl)imidazo[4,5-g][1,4]benzoxazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC1CCNCC1
Product: CC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 4-methylpiperidine according to conditions described in general procedure C. Mp: 117-118° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.84-0.94 (m, 5 H), 1.49-1.52 (m, 3 H), 2.67 (t, J=12.0 Hz, 2 H), 3.25 (m, 4 H), 3.73 (m, 4 H), 4.30 (s, 2 H), 6.19-6.20 (m, 1 H), 7.03-7.06 (m, 1 H), 7.27 (d, J=8.4 Hz, 1 H), 7.41-7.63 (m, 5 H), 7.83-7.85 (m, 1 H), 7.98-8.01 (m, 1 H), 8.25-8.27 (m, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[C:21](N)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.O>CO>[CH2:1]([C:8]1[NH:9][C:21]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[CH:13][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: Nc1cc2ccccc2cc1N
Agent: Cl
Solvent: O
Solvent: CO
Product: c1ccc(Cc2nc3cc4ccccc4cc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1M solution of benzyl cyanide in anhydrous methanol is treated with hydrogen chloride gas at 0° C. for about thirty minutes. The mixture is stirred for two hours at 0° C. and then a 1M solution of 2,3-diaminonaphthalene is added and the resulting solution is stirred at 0° C. The progress of the reaction is monitored by thin layer chromatography. The reaction mixture is then poured into water. The unreacted nitrile is extracted with ethyl acetate. The aqueous layer is neutralized with 1N sodium hydroxide. The organic fraction is extracted with ethyl acetate and condensed. The desired title product is recrystallized from methanol/water.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=O)=[CH:25][CH:24]=1.CO[C:34](OC)([N:36](C)C)[CH3:35].C(O)(=O)C.O.[NH2:46]N>O1CCOCC1>[CH3:35][C:34]1[NH:29][C:27]([C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:14][O:13][C:12]5[CH:15]=[C:16]6[C:20](=[CH:21][C:11]4=5)[CH2:19][CH2:18][O:17]6)[C:2]3=[O:1])=[CH:24][CH:25]=2)=[N:46][N:36]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Reactant: NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccc(CN3C(=O)C4(COc5cc6c(cc54)CCO6)c4ccccc43)cc2)[nH]1
Temperature: 90 °C
Reaction time: 6 h
Yield: 16.2 %

Procedure:
To a solution of 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.40 g, 0.96 mmol) in 1,4-dioxane (15 mL) was added N,N-dimethylacetamide dimethyl acetal (1.42 mL, 9.71 mmol). The reaction was heated to reflux for 18 h, concentrated in vacuo. To the above residue were added acetic acid (15 mL) and hydrazine monohydrate (0.15 mL, 3.17 mmol). The reaction was stirred at 90° C. for 6 h, cooled to ambient temperature, quenched with saturated sodium bicarbonate (15 mL), and extracted with chloroform. The combined organic solution was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography with 5% methanol in ethyl acetate, and recrystallized from dichloromethane and hexanes to afford 1′-[4-(5-methyl-4H-1,2,4-triazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1'H)-one (0.07 g, 16%) as a colorless solid: mp 169-180° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ10.72 (s, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.15 (d, J=7.5 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.45 (s, 1H), 6.40 (s, 1H), 5.19-4.09 (m, 4H), 4.53-4.47 (m, 2H), 2.95-2.90 (m, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.3, 161.9, 161.4, 141.9, 136.9, 132.7, 128.8, 127.8, 126.9, 123.9, 123.6, 120.0, 119.9, 118.8, 109.4, 93.2, 80.6, 72.4, 57.8, 44.0, 28.9, 11.7; MS (ES+) m/z 450.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:25])=[O:23])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(Nc2ccc(F)cc2)CCNCC1

Procedure:
A mixture of 53 parts of methyl 4-[(4-fluorophenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 15% of methanol, previously saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on scratching in hexane. The product is filtered off and dried, yielding methyl 4-[(4-fluorophenyl)amino]-4-piperidinecarboxylate; mp. 83.7° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (13.4 g: 50 mmole) in dichloromethane (50 ml), p-chlorobenzenesulfonyl chloride (12.66 g: 60 mmole) is added in a nitrogen atmosphere at room temperature and a solution of triethylamine (8.69 ml: 62.5 mmole) in dichloromethane (10 ml) is further added dropwise. The mixture is stirred at room temperature overnight. The reaction mixture is successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxy methyl-4-methanesulfonyloxypyrrolidine (23.73 g) as oil. Yield: 105%. NMR δ(CDCl3) ppm: 2.2 to 2.6(m, 2H), 3.04(s, 3H), 3.58(dd, J=5.0 Hz, J=11.4 Hz, 1H), 3.8 to 4.0(m, 1H), 4.1 to 4.3(m, 3H), 4.5(m, 3H), 5.1 to 5.4(m, 3H), 5.7 to 6.0(m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([NH2:18])=[N:16][CH:17]=1.C(OCC)(=O)C>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([NH:18][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][CH:17]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.257 g, 1.51 mmol) and 5-bromo-3-phenoxypyridin-2-amine (0.400 g, 1.51 mmol) in DMF (4 mL) at 80° C. for 3 hours. Heated at 120° C. overnight. Cooled, partitioned between 2N NaOH and ethyl acetate. Washed the organic layer twice with water, brine, dried, and concentrated. Subjected the residue to Biotage, eluting with 3:1 hexane:ethyl acetate to afford the title compound (0.465 g, 77.2% yield) as a white powder. 1H NMR (d6-DMSO) δ 7.15 (d, 2H), 7.23 (t, 1H), 7.40-7.50 (m, 4H), 7.92 (s, 1H), 8.34 (s, 1H), 8.37 (d, 1H), 11.63 (bs, 1H).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CO>[CH3:1][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5]
Reactant: CC(=O)Cl
Reactant: O=C(O)CCCCCBr
Solvent: CO
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Yield: 351.9 %

Procedure:
To a solution of acetyl chloride (1.0 mL, 14 mmol) in methanol (150 mL) at 0° C. was added a solution of 6-bromohexanoic acid (10.0 g, 51 mmol) in methanol (50 mL). The mixture was heated at reflux for 2 hours, then allowed to cool down to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and washed consecutively with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound (10.3 g, 96%) as a colourless oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.[N:33]([CH:36]([CH3:38])[CH3:37])=[C:34]=[O:35]>>[NH2:32][C:11]1[N:12]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([NH:33][CH:36]([CH3:38])[CH3:37])=[O:35])[CH2:30][CH2:31]4)=[CH:20][CH:21]=3)[CH2:16]2)[CH:14]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)[N:10]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC(C)N=C=O
Agent: Cl
Product: CC(C)NC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and 2— isocyanatopropane. LCMS (M+H)+: m/z=507.3.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:11])[C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[N:6]=1.CN(C=O)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Na]>C1COCC1>[C:2]([NH:6][C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[C:4]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:11])(=[O:3])[CH3:1]
Reactant: CC1=NC(C)(C(C)C)C(=O)O1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2,4-Dimethyl-4-isopropyl-2-oxazolin-5-one (2.0 g) is mixed with DMF (50 mL), THF (70 mL) and sodium p-toluene sulfonamide (5.0 g), and the resulting mixture is heated at reflux for 16 hours. At the end of this time the mixture is cooled, and the solvents are removed under vacuum. The residue is mixed with water and the pH adjusted to 8 with NaHCO3. The aqueous mixture is extracted with ethyl acetate and the organic layers are discarded. The aqueous mixture is acidified to pH-4 with HCl and saturated with NaCl and extracted with ethyl acetate. The organic extracts are combined, dried over MgSO4, filtered and evaporated to give 0.66 of the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([OH:12])=[C:6]([CH2:13][CH3:14])[CH:5]=1.[OH-].[Na+].O.S(OC)(O[CH3:23])(=O)=O>CCOCC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([O:12][CH3:23])=[C:6]([CH2:13][CH3:14])[CH:5]=1
Reactant: CCc1cc(C(=O)OC)cc(CC)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCc1cc(C(=O)OC)cc(CC)c1OC

Procedure:
To a cooled solution of 16.2 (0.078 mol.) of 3,5-diethyl-4-hydroxybenzoic acid methyl ester and 4.0 g. (0.1 mol.) of sodium hydroxide in 100 ml. of water is added 9.8 g. (7.3 ml., 0.079 mol.) of dimethyl sulfate. The reaction mixture is refluxed for two hours. After cooling, ether is added and the layers are separated. The organic phase is washed with water, dilute sulfuric acid and water, dried (Na2SO4) and concentrated to give 3,5-diethyl-4-methoxybenzoic acid methyl ester.