Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[C:11](/NC=O)\[C:12]([O:14][CH2:15]C)=[O:13])\[CH2:2][CH2:3][CH2:4][C:5]2[C:10]\1=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-:20].[Na+].I[CH3:23]>>[CH3:23][C:1]1([C:11](=[O:20])[C:12]([O:14][CH3:15])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: [OH-]
Reactant: CCOC(=O)/C(NC=O)=C1\CCCc2ccccc21
Agent: [Na+]
Product: COC(=O)C(=O)C1(C)CCCc2ccccc21
Temperature: 70 °C

Procedure:
Ethyl (2Z)-3,4-dihydro-1(2H)-naphthalenylidene(formylamino)ethanoate (1.31 g, 5.05 mmol, from Reference Example 9) is refluxed with 6N HCL (10 mL) for 1 hour. The mixture is evaporated, dried and the residue taken up in tetrahydrofuran (8 mL) and water (1.7 mL). To this is added 5 N sodium hydroxide solution (3.6 mL, 18.0 mmol) and iodomethane (0.9 mL, 14.5 mmol). While stirring under a nitrogen atmosphere, the reaction mixture is heated in a 70° C. oil bath for 5½ hours. Additional volumes of 5 N sodium hydroxide solution (2.0 mL) and iodomethane (0.3 mL, 4.8 mmol) are added. The reaction mixture is allowed to stir for 2 days at room temperature, then evaporated in vacuo to remove most of the tetrahydrofuran. This is extracted with ethyl acetate and the organic layer then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a clear oil, 0.49 g, MS: m/z 233.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[CH3:12][C:13]1[C:18]([CH3:19])=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N+:14]=1[O-:23]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:16]=[CH:15][N+:14]([O-:23])=[C:13]([CH3:12])[C:18]=2[CH3:19])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(Br)c(F)c2)cc[n+]([O-])c1C
Temperature: 180 °C
Yield: 175.5 %

Procedure:
To a room temperature solution of 4-bromo-3-fluorophenol (15 g, 78.53 mmol) in DMF (50 ml) was added sodium hydride (3.32 g, 85.67 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 2,3-dimethyl-4-nitro-pyridine 1-oxide (1.05 g, 6.28 mmol) was added The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was filtered through a diatomaceous earth pad and the filtrate was then diluted with EtOAc and washed with water. The solution was then extracted with additional EtOAc (2×150 ml). The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 21 (3.44 g, 19%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].C(N(C(C)C)C(C)C)C.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[CH:22]=1>C(Cl)Cl.CCOC(C)=O>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)=[O:27]
Reactant: Nc1cc(C=O)ccc1Cl
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cc(C=O)ccc2Cl)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of 3-amino-4-chlorobenzaldehyde 2 (0.267 g, 1.72 mmol) in DCM (5 mL) at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (0.600 mL, 3.44 mmol) and 5-methylisoxazole-3-carbonyl chloride (0.292 g, 2.01 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature, stirred for 1 h, and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 15% to 50% EtOAc in hexanes) gave N-(2-chloro-5-formylphenyl)-5-methylisoxazole-3-carboxamide 3 (0.117 g, 25.8% yield) as a white solid. Mass spectrum: calculated for C12H9ClN2O3 264.0. found 265.0 (M++1).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[N+:16]([O-])([O-:18])=[O:17].[K+]>OS(O)(=O)=O>[N+:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
A solution of 724 mg (3.51 retool) of 3-nitro-4-hydroxy-1,2-dihydroquinolin-2-one and 401 mg (3.97 retool) of KNO3 in 4 mL of 96% H2SO4 was stirred in an ice-bath for 30 min, then 25° C. for 20 h. The solution was added into 25 mL of ice-water to give a yellow precipitate and the mixture was stirred for 1 h, filtered and washed with water, and dried to leave 602 mg (68%) of title compound as a yellow solid, mp 197°-198° C. (decomposed, lit (Buckle et al., supra) 199° -200° C.). 1H NMR (CDCl3 +DMSO-d6), 7.114 (d, 1, J=9.12), 7.980 (dd, 1, J=2.27, 9.13), 8.628 (d, 1, J=2.28), 12.13 (mb, 1).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15].[CH3:18][O:19][C:20](=[O:23])[C:21]#[CH:22]>CO>[CH3:18][O:19][C:20](=[O:23])[CH:21]=[CH:22][C:13](=[C:14]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:15])[C:12]([O:11][CH3:10])=[O:17]
Reactant: NCCc1ccccc1
Reactant: C#CC(=O)OC
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)NCCc1ccccc1
Yield: 75.9 %

Procedure:
Phenethylamine (5.0 mL, 39.7 mmol) was dissolved in MeOH (130 mL). 3-Oxo-butyric acid methyl ester (5.1 mL, 47.6 mmol) was added, and the mixture was refluxed for 3 h. To the reaction mixture was added propynoic acid methyl ester (5.3 mL, 59.5 mmol), and the resulting mixture was then refluxed for 2 days. The solvent was evaporated, and the crude solid was recrystallized from MeOH to give 9.14 g of the title compound as a light orange solid. MS: (+) m/z 326.23 (M+Na).
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl[CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>C(O)(C)C>[CH2:3]([S:11][CH2:13][CH2:14][CH2:15][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:16][CH2:15][CH:14]([OH:17])[CH3:13]
Reactant: CCCCCCCCS
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(O)CO
Product: CCCCCCCCSCCCCCCCC
Temperature: 80 °C

Procedure:
Approximately 40 g of 50% aqueous sodium hydroxide solution was added dropwise over a period of 1 hour to a solution of n-octyl mercaptan (72.3 g) and 1-chloropropane-2,3-diol (55 g) in isopropanol solvent (400 cc) at ambient temperature. The reaction temperature rose from 23° to 55° C. during addition. The reaction was refluxed for 3 hours at 80° C. and then filtered hot through paper to remove the precipitated salts. The isopropanol solvent was removed by distillation. The product residue was dissolved in 700 cc of toluene and washed with water several times. The toluene solution was dried over magnesium sulfate and filtered through diatomaceous earth. Toluene was removed by high speed rotary evaporation under reduced pressure to yield a colorless, opaque fluid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[NH:26][C:27]([I:31])=[C:28](I)[N:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].C1(C)C=CC=CC=1.CCOCC>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([O-:38])=[O:33].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[NH:26][C:27]([I:31])=[CH:28][NH+:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1nc(I)c(I)[nH]1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1[nH]c(I)c[nH+]1
Product: O=C([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of D4 in DCM (0.19 M) cooled to 0° C. was slowly added TFA (35 eq.). The reaction mixture was stirred at 0° C. for 30 min then allowed to warm up to room temperature and stirred for another 2 h. Solvent was evaporated under reduced pressure affording an oily residue was co-evaporated first with toluene then with Et2O to give the title compound as a pale brown solid which was used as such in the next step. MS (ES+) C18H22IN3O4: 472 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]1[N:7](Cl)[CH:6]=[CH:5][N:4]=[CH:3]1.CN(C=O)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC1C=NC=CN1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3,4-Dichloro-pyrazine (3 g, 20.1 mmol, 1.0 eq.), dry DMF (20 mL) and piperazine-1-carboxylic acid tert-butyl ester (7.3 g, 40 mmol, 2 eq). The reaction mixture was heated to 90° C. and allowed to stir for 4 hours. After allowing the reaction to return to room temperature water (100 mL) was added and the product extracted with DCM (2×200 mL). The organic layer was washed 1 N HCl (2×) and brine (2×) and dried over NaSO4. After removing the solvent the product was isolated as an orange oil (6 g, 80%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C#CCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCCCO)cc1

Procedure:
A mixture of 2.55 g of methyl 4-(4-hydrox-but-1-yn-1-yl)benzoate in 200 mL of ethanol is hydrogenated at 50 psi of hydrogen for 12 hours in the presence of 0.26 g (10% weight equivalent) of 5% palladium on charcoal. The reaction mixture is filtered through a silica gel pad, which is washed with ethanol, and concentrated to yield methyl 4-(4-hydroxybutyl)benzoate as an oil. IR (film) νmax 3390, 2965, 2920, 2850, 1705, 1605, 1568, 1520, 1500, 1410, 1387, 1362, 1308, 1286, 1250, 1160, 1055, 1013, 843, 755, and 695 cm-1 ; 1H NMR (CDCl3) delta 7.95 (d, J=8.1 Hz, 2H, Ar), 7.25 (d, J=8.1 Hz, 2H, Ar), 3.89 (s, 3H, --CH3), 3.65 (t, J=6.3 Hz, 2H, --CH2OH), 2.69 (t, J=7.5 Hz, 2H, benzyl), 1.66 (m, 4H, 2° aliphatic).
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+].O.C(O)C>C(O)(=O)C>[CH3:32][Si:2]([CH3:1])([CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C=CC(=O)O)cc1

Procedure:
A mixture of 5.0 g. ethyl 4-aminocinnamate, 9.14 g. of 14-(trimethylsilyl)tetradecyl bromide and 3.6 g. of powdered anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate. The ester is hydrolyzed with.sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the title product as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:14]([C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)=[CH:5][CH:4]=1.O[Li].O>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:14]([C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)=[O:16])[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 78.3 %

Procedure:
The title compound (E21) (19 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (D139) (25 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 108.2 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (50 g, 0.2 mol), triethylamine (50.5 g, 0.5 mol) in DCM was added methanesulfonyl chloride (28 g, 0.25 mol) in portions and the reaction mixture was stirred at 0° C. for 20 min and at RT for 1.5 h, and washed with citric acid solution and water. The organic layer was dried over sodium sulfate and concentrated to give the title intermediate (70 g, 97% yield). 1H NMR (CDCl3, 400 MHz) δ (ppm) 5.23 (m, 1H), 4.44 (m, 1H), 3.75 (m, 5H), 3.04 (s, 3H), 2.64 (m, 1H), 2.26 (m, 1H), 1.43 (m, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC=CC=1.[C:34]1(=O)[O:39][C:37](=[O:38])[CH2:36][CH2:35]1.C(N(CC)CC)C>C(OCC)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:1]5[C:37](=[O:38])[CH2:36][CH2:35][C:34]5=[O:39])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)O1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1Cc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 80 °C

Procedure:
A mixture of 200 mg (0.537 mmol) of 3(3-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5) and 10 ml of toluene is concentrated by evaporation in vacuo for the purpose of removing water and, after repetition of that operation, the residue is taken up in 10 ml of toluene. After the addition of 59 mg (0.59 mmol) of succinic anhydride and 0.082 ml (0.59 mmol) of triethylamine, the reaction mixture is heated for 1 hour at 80° C. and for 18 hours under reflux. A further 21 mg (0.21 mmol) of succinic anhydride and 0.041 ml (0.2949 mmol) of triethylamine are added to the reaction mixture which is heated for a further 6 hours under reflux, then cooled to room temperature and 10 ml of diethyl ether are added. Filtration, purification of the filter residue by flash chromatography (silica gel having a particle size of 0.04-0.06 mm; eluant: ethyl acetate), concentration of the product-containing fractions by evaporation in vacuo and recrystallization of the residue from methanol yield 4-(3-chloro-phenylamino)-3-(3-[succinimido-methyl]-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 7.72%; m.p. 140-142° C.; ESI-MS: (M−H)−=446.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[H][H].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[S:25][CH:26]=1)(=O)=O>O1CCCC1>[C:3]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[S:25][CH:26]=1)#[N:4]
Reactant: [H][H]
Reactant: CCOC(=O)CC#N
Reactant: COC(=O)c1cc(CCCCOS(C)(=O)=O)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCCCc1csc(C(=O)OC)c1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A 250 Ml three-neck round bottom flask, equipped with a magnetic stirrer, reflux condenser, addition funnel, and gas inlet, was charged with 0.59 g (1.1 eq) of 60% sodium hydride and flame dried under a nitrogen atmosphere. After cooling to room temperature, mineral oil was removed by washing twice with anhydrous tetrahydrofuran and 100 mL of anhydrous tetrahydrofuran were then added. This mixture was brought to 0° C. on an ice bath and an anhydrous tetrahydrofuran solution of 1.52 g (1.0 eq) of ethyl cyanoacetate was added dropwise under a nitrogen atmosphere with moderation of evolution of hydrogen gas. The mixture was stirred vigorously while warming to room temperature until gas evolution was no longer observed. To this mixture, an anhydrous tetrahydrofuran solution of 3.92 g (1.0 eq) of methyl 4-(4-methylsulfonyloxybutyl)thien-2-ylcarboxylate was added dropwise. The resulting mixture was refluxed with stirring under a nitrogen atmosphere for 24 hours. After cooling to room temperature, solvent was removed under reduced pressure and diethyl ether was added to the residue. The organic extract was washed with water, brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 1:1 ethyl acetate:hexanes. Fractions homogeneous by thin layer chromatography for the major component were combined and concentrated under reduced pressure to give 1.98 g (47.7%) of pure methyl 4-(5-cyano-5-carbethoxypentyl)thien-2-carboxylate as a clear oil; IR (KBr, cm-1): 1746, 1711, 1444, 1260, 1225, 1220, 1207; UV (Ethanol): μmax =280 nm (epsilon=5940), 248 nm (epsilon=9290); 1H NMR (CDCl3, 300 MHz) delta 7.60 (s, 1H), 7.15 (s, 1H), 4.23, (q, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.47 (t, J=6.9 Hz, 1H), 2.62 (t, J=7.5 Hz, 2H), 1.95 (q, J=7.3 Hz, 2H), 1.62-1.69 (m, 2H), 1.48-1.47 (m, 2H), 1.27-1.33 (m, 3H); MASS: M+ =309 (FD).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:43][CH2:44][O:45][CH2:46][CH2:47]Br>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][N:1]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: BrCCOCCBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN3CCOCC3)cc2c(=O)n1C
Temperature: 90 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
A solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in toluene (750 μl) was treated with DIEA (13.60 μl, 0.078 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (5.87 μl, 0.047 mmol). The mixture was stirred at 90° C. for 6 hours. Additional DIEA (13.60 μl, 0.078 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (5.87 μl, 0.047 mmol) were added, the reaction was stirred at 90° C. overnight. The reaction was cooled to rt, diluted with EtOAc, washed with water, brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(morpholinomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (15.6 mg, 0.031 mmol, 79% yield). The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethyl phenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (14 mg, 0.027 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.71-7.61 (m, 1 H), 7.24-7.33 (m, 1 H), 7.26-7.17 (m, 2 H), 7.07-6.96 (m, 1 H), 5.35 (s, 1 H), 4.40-4.22 (m, 2 H), 4.03-3.81 (m, 4 H), 3.71 (s, 3 H), 3.59-3.37 (m, 2 H), 2.92 (br. s., 2 H), 2.37 (s, 3 H), 2.32 (s, 1.5 H), 2.29 (s, 1.5 H). 1.06 (s, 4.5 H), 1.05 (s, 4.5 H); LCMS (m/z) ES+=493 (M+1).
Reaction SMILES: C=O.O.[Cl:4][C:5]1[C:6]([CH3:31])=[C:7]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8]([O:23][CH3:24])=[C:9]([CH:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:10]=1.[CH3:32]CN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:4][C:5]1[C:6]([CH3:31])=[C:7]([CH:25]2[CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)[C:8]([O:23][CH3:24])=[C:9]([CH:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:10]=1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCN(C)CC1
Reaction time: 0.17 h

Procedure:
12.0 M Formaldehyde in water (0.4 mL, 5 mmol) was added to a mixture of N-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-9H-purin-6-amine (200 mg, 0.5 mmol) and DIPEA (0.35 mL, 2.0 mmol) in methylene chloride (5 mL) at 0° C. The reaction was stirred for 10 minutes, and after this time sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added. The reaction was stirred at 0° C. for 1 hour. The mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H28ClN6O (M+H)+: m/z=415.2. found: 415.3. 1H NMR (DMSO-d6, 500 MHz) δ 9.67 (1H, br s), 8.72 (1H, br s), 8.35 (2H, s), 7.51 (1H, s), 5.75 (1H, m), 3.88 (3H, s), 3.49 (2H, m), 3.34 (1H, m), 3.12 (2H, m), 2.81 (1.5H, s), 2.80 (1.5H, s), 2.44-2.31 (2H, m), 2.36 (3H, s), 1.79 (2H, m), 1.49 (3H, d, J=6.5 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:15](O)CC>[Ti]>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCO
Agent: [Ti]
Product: CCCOC(=O)CP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Titanium IV propoxide (12.1 g) was added to a stirred mixture of ethyl diethylphosphonoacetate (100.4 g) and n-propanol (610 cm3) under a nitrogen atmosphere. The mixture was stirred at the ambient temperature for a total of 18 hours, after which time analysis of the mixture showed that the reaction was complete. The volatile components were removed by distillation firstly at atmospheric pressure and then under reduced pressure on a rotary evaporator. 1.5 M aqueous hydrochloric acid (350cm3) was added to the crude product and the mixture extracted with diethyl ether. The organic layer was separated and washed with further 1.5 M aqueous hydrochloric acid solution. The aqueous phases were combined and extracted with more diethyl ether (2×100cm3). All of the organic layers were combined, washed with water and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure qave a yellow oil (85.4 g) which was used without further purification.