Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCCl)cc1)c1ccccc1
Solvent: C1CCOC1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1x and piperidine (15 eq) in tetrahydrofuran at reflux. 1z was then precipitated from a mixture of ethyl acetate and 1N HCl as the HCl salt. Yield (60%); 1H NMR (d6-DMSO) δ 11.90 (br s, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.40–7.09 (m, 12H), 6.87 (d, J=7.7 Hz, 2H), 6.53 (d, J=15.7 Hz, 1H), 3.08 (br, 2H), 2.95 (br, 1H), 2.81 (br, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.08 (br, 2H), 1.71 (br, 6H), 1.62 (br, 1H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 541 (M−H−).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([OH:32])[C@@H:22]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:21]2)[CH2:18][CH2:17]3>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:13]3[CH2:30][C@@:29]4([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]5[C@@H:28]4[CH2:27][CH2:26][C@@:24]4([CH3:25])[C@H:20]5[CH2:21][C@H:22]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C@@H:23]4[OH:32])[CH2:15][C@@H:14]3[OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: O
Solvent: CC#N
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
After adding 63 g of 1,4-dioxa-8-azaspiro[4.5]decane and 13 ml of water to 17 g of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17β-ol, the reaction mixture is maintained at 100° to 105° C. for 80 hours while introducing nitrogen. After completion of the reaction, the solution containing a precipitate is diluted with 200 ml of acetonitrile and after filtering, the precipitate is thoroughly washed with water and then with acetonitrile, dried and recrystallized from methanol to give the title product in a yield of 18.2 g (76.5%), m.p.: 184°-187° C.
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][C:2]1[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:20][C:3]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C(=O)NC(C)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(C)c(-c2ccccc2)s1
Reaction time: 12 h
Yield: 97.6 %

Procedure:
The product from Step 89b (2.58 g, 10.4 mmol, 1 eq) and P2S5 (4.83 g, 10.9 mmol, 1.05 eq) are suspended in 30 mL CHCl3. The mixture is heated under reflux. After 12 h, water and solid K2CO3 are carefully added until all material dissolves. The aqueous layer is made sufficiently basic with 1N NaOH (pH more than 10) and extracted with EtOAc. The combined organic layers are washed with 1N NaOH and brine, dried over MgSO4, filtered and concentrated to give ethyl 4-methyl-5-phenyl-1,3-thiazole-2-carboxylate as a yellow oil (2.51 g, 98%). MS (ESI) for C13H13NO2S m/z 248.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH3:14])[N:11]([CH3:15])[C:10]2=N)[CH:6]=[CH:7][CH:8]=1.Cl.N([O-])=[O:25].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH3:14])[N:11]([CH3:15])[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=O)c1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
Product from Step 4 (20 g) was added to 5N hydrochloric acid and the reaction mixture was refluxed under argon purging. To this mixture was added in portions 160 g of sodium nitrite dissolved in water (200 mL). The reaction mixture was refluxed for 30 min further and cooled to 25° C. and extracted with chloroform (2000 mL). The organic layer was dried on anhydrous sodium sulfate, was filtered and then was concentrated under vacuum to obtain dark brown colored crude product of Step 5 (12 g). The crude product was purified on the BIOTAGE® AB ISOLERA™ flash chromatography system as follows: The crude product was dissolved in chloroform (10 mL) and was loaded on a SNAP cartridge containing 340 g silica gel. The column was eluted with a gradient of ethyl acetate and hexane. Fractions containing product were pooled and evaporated under vacuum to obtain viscous yellow oil (21 g). 1H NMR (CDCl3): 1.2 δ (3H, —CH—CH3 of isopropyl), 2.8 δ (3H, —N—(CH3)), 2.2, 3.1, 3.5 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 3.8 δ (3H, —OCH3), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=296 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH3:14].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:22](=[O:24])[CH3:23])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH3:14]
Reactant: Cc1cc(=O)oc2cc(O)c(Br)cc12
Reactant: CC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc2oc(=O)cc(C)c2cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.7 %

Procedure:
To a solution of 453.1 mg (1.776 mmol) of compound 17 and 545 mL (3.9 mmol) of triethylamine in dry acetonitrile (5 mL) was added 255 mL (3.59 mmol) of acetyl chloride. The reaction mixture was stirred for 15 hours at room temperature, quenched with 1N HCl, diluted with chloroform and separated. The organic layer was washed with saturated aqueous NaHCO3 and saturated aqueous brine, dried (MgSO4) and evaporated to dryness to yield 404.9 mg (1.363 mmol, 76.7% yield) of the crude compound 18. This compound was used for the next reaction without a further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A mixture of methyl 2-amino-5-bromobenzoate (23.34 g, 101 mmol) in pyridine (100 mL) was treated with a solution of benzenesulfonyl chloride (14 mL, 110 mmol), stirred for 16 hours at ambient temperature, and concentrated. The concentrate was dissolved in dichloromethane, washed twice with 1N NaHSO4, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from 3:1 ethanol/water (200 mL) to provide the desired product (33.4 g). MS (DCI) m/e 387, 389 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 7.77 (s, 1H), 7.75 (dd, 1H), 7.66 (d, 1H), 7.61-7.53 (m, 2H), 7.39 (d, 1H), 3.79 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]1([NH:31][CH2:32][CH2:33]O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:33][CH2:32][NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OCCNc1ccccc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CCNc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a THF solution (2 ml) of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, 2-(phenylamino)ethanol (19 mg, 0.13 mmol), triphenylphosphine (55 mg, 0.21 mmol) was added diethyl azodicarboxylate (0.09 ml, 42% wt in toluene, 0.21 mmol). After 1 h, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-(phenylamino)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (14.4 mg, 23%) as a yellow solid. MS M+H=476; 1H NMR (CDCl3) δ 8.20 (1H), 7.41-7.20 (11H), 7.10 (2H), 4.51 (2H), 3.91 (2H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:12]=[CH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:19](OC)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:20][CH:19]=[C:14]([N:13]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10][CH:11]=[N:12]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC=O
Reactant: COC(=O)Cn1ncnc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)n1ncnc1-c1ccccc1
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
Sodium hydride (0.88 g, 0.018 mol, 50% dispersion in oil) was washed with dry petrol 40°-60° and suspended in DMF (15 ml). A mixture of methyl [5-phenyl-1,2,4-triazol1-yl]-acetate (2.0 Og, 0.009 mol) and methyl formate (11.4 ml, 0.18 mol) in DMF (15 ml) was added at room temperature with stirring over 10 minutes. After 2 hours aqueous potassium carbonate (200 ml, 10%) was added and the aqueous layer extracted with diethyl ether (2×100 ml), then the aqueous layer was neutralised with concentrated hydrochloric acid and then extracted with ethyl acetate (3×150 ml). The ethyl acetate extract was washed with brine and dried then evaporated under reduced pressure to give methyl 3-hydroxy-2-[5-phenyl-1,2,4-triazol-1-yl]acrylate (2.2 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:5]([NH:7][C:8]1([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:5]([NH:7][C:8]1([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6]
Reactant: CCCCCN1C(=O)C(CCC(=O)OC)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN1C(=O)C(CCC(=O)O)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A mixture of 3.89 g of methyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]propionate, 16 ml of a 2N sodium hydroxide aqueous solution and 100 ml of methanol was refluxed for 40 minutes. After the reaction mixture was cooled to room temperature, the solvent was removed by evaporation under reduced pressure. The residue was diluted with water, adjusted to pH 4 with 10% hydrochloric acid and then extracted with chloroform. After the extract was washed with water and dried, the solvent was removed by evaporation. The resulting crude crystals were recrystallized from ethyl acetate-hexane to afford 3.34 g of 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]propionic acid as colorless crystals. Melting point: 202° to 204° C., IR (Nujol) (cm-1): 3260, 1730, 1675, 1660, FAB-MS (m/z): 463 (MH+), 173 (base).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH2:17].C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:1][C:2]1[CH:14]=[CH:13][C:12]([CH:17]=[CH:16][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)COC(=O)c1cc(I)ccc1O
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1

Procedure:
Isobutyl 2-hydroxy-5-iodobenzoate (70.2 g, 0.22 mol) and 4-ethenyl-N-(3-methyl-2pyridinyl)benzensulfonamide (54.8 g, 0.20 mol) were suspended in a solution of tributylamine (55.5 g, 0.3 mol) and palladium(II) acetate (0.44 g 0.0022 mol) in dimethylacetamide (200 ml)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]([NH:17][C:18]([C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:22]=3[CH:23]=[N:24][CH:25]=2)=[O:19])[CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]([NH:17][C:18]([C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[C:22]=3[CH:23]=[N:24][CH:25]=2)=[O:19])[CH2:15][CH3:16])[CH2:9]1
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.3 mmol) was added a 10% solution of trifluoroacetic acid in dichloromethane (10 mL). The mixture was stirred at room temperature overnight and the reaction was monitored by HPLC-MS indicating incomplete conversion. Additional trifluoroacetic acid (1 mL) was added. The mixture stirred until HPLC-MS indicated starting material was consumed. The mixture was concentrated in vacuo and the residue was diluted with EtOAc (100 mL), made basic with saturated aqueous sodium bicarbonate (pH=10), washed with brine, and dried over sodium sulfate, filtered and concentrated. A portion of the crude material was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 mM 30×150 mm column) eluting with a gradient of 15-85% acetonitrile in water (0.1% TFA). The fractions from the column were concentrated to remove acetonitrile made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layers were dried and concentrated to afford the title compound as a white foam.
Reaction SMILES: C([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])C.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH2:23]CC#N>>[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH2:23][CH2:14][C:13]1[NH:3][C:4](=[O:12])[C:5]2[C:6]([CH:11]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: N#CCCN1CCCCC1CO
Reactant: CCN(CC)C(=O)c1ccccc1C
Product: O=c1[nH]c(CCN2CCCCC2CO)cc2ccccc12
Yield: 15.3 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2-methylbenzamide (3.42 g) and 3-(2-hydroxymethylpiperidin-1-yl)propionitrile (1.51 g), 3-[2-(2-hydroxymethylpiperidin-1-yl)ethyl]-2H-isoquinolin-1-one (392 mg) was obtained.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)([O:3]C)=[O:2].[OH-].[K+].C(O)C.Cl>O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1

Procedure:
A solution of 5 g. of ethyl 4-(15-carbomethoxypentadecylamino)benzoate and 0.8 g. of potassium hydroxide in 50 ml. of 95% ethanol is stirred at 50° C. for 10 hours, diluted with 100 ml. of water and acidified with concentrated hydrochloric acid. The solid is collected by filtration, dried, and recrystallized from toluene to yield ethyl 4-(15-carboxypentadecylamino)benzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH3:19].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1cnn(C)c1-c1cc(C(=O)O)sc1C

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg, 0.78 mmol) in 6N sodium hydroxide (2.60 ml, 15.59 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (242 mg, 0.78 mmol, 100° A yield) as a white foam: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:42])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)=[CH:8][C:9]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)=[N:10]2)=[CH:5][CH:4]=1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:42])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)=[CH:8][C:9]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3cscn3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3cscn3)nc2c1

Procedure:
The title compound was prepared from 18-[7-methoxy-2-(thiazol-4-yl)quinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (35) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=694 (M+H)+. 1H NMR (CDCl3): 0.80-1.55 (m, 13H), 1.80-1.98 (m, 3H), 2.19-2.28 (m, 1H), 2.30-2.40 (m, 1H), 2.47-2.62 (m, 2H), 2.63-2.75 (m, 2H), 2.88-2.96 (m, 1H), 3.97 (9s, 3H), 4.02 (d, J=11.5 Hz, 1H), 4.11 (dd, J=11.4 Hz, J=3.8 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 5.00 (t, J=9.5 Hz, 1H), 5.49 (br s, 1H), 5.70-5.77 (m, 1H), 6.68 (s, 1H), 7.12 (dd, J=2.5 Hz, J=9.1 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.96 (d, J=9.1 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.94 (d, J=2.1 Hz, 1H), 9.2 (br s, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C.CN(C)C=O>[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]4)[CH2:19][CH2:20]2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCC(Oc3ccc4c(=O)[nH]ccc4c3)CC2)cc1
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (100 mg, 3.9 mol eq) was added to a solution of 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol), acetic acid (2 drops) and 4-methylbenzaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (700 μl) and shaken for 17 hours. The reaction was quenched with water and methanol and the product semi-purified using an SCX cartridge. The product was further purified by prep-HPLC to afford 6-[1-(4-Methylbenzyl)piperidin4-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=349.4 [M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.C(=O)=O.CC(C)=O.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1.CI>O1CCCC1.O>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:1])[N:22]=1
Reactant: Cc1cccc(Br)n1
Reactant: [Li]CCCC
Agent: O=C=O
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: CCc1cccc(Br)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
Add under nitrogen a solution of 2.5; M n-butyllithium in hexanes (186.74; mL, 0.467; mol) over 41; min to a solution of diisopropylamine (68.7; mL, 0.488; mol) in tetrahydrofuran (745; mL, 9.16; mol) at −78° C. (dry-ice/acetone bath). Stir for 15; min and add 2-bromo-6-methylpyridine (49.3; mL, 0.424; mol) dropwise over 22; min. Stir 15; min, add methyl iodide (52.87; mL, 0.848; mol) dropwise over 1; hour and then warm to room temperature over 1.5; hour. Add water (250; mL) while cooling with a dry-ice/acetone bath and separate the layers. Extract the aqueous phase twice with ethyl acetate (300 mL). Combine the organic phases, concentrate and purify by silica gel chromatography, gradient eluting from 100:0; to 80:20; using hexanes:ethyl acetate, to give the title compound as a yellow oil (59.74; g, 75%). 1H NMR (CDCl3) δ 1.28; (t, 3H), 2.80; (q, 2H), 7.11; (d, 1H), 7.27; (d, 1H), 7.45; (t, 1H).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])/[CH:7]=[C:8](\[NH2:13])/[C:9]([F:12])([F:11])[F:10])C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:6](=[O:14])[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:13][C:23]2=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.5 g) in anhydrous N,N-dimethylformamide (100 ml) was added dropwise a solution of ethyl-3-amino-4,4,4-trifluorocrotonate in toluene (50 ml) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred for 20 min at same temperature, then cooled to −30° C. A solution of (4-chloro-2-nitrophenyl)isocyanate in toluene (50 ml) was added dropwise. After stirring for 20 min, the cold bath was removed and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate and 1N-hydrochloric acid. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluted with ethyl acetate and hexane (1:1) to afford 3-(4-chloro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (10.2 g) as a yellow solid.