Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42]#[N:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42]3[NH:48][N:47]=[N:46][N:43]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC#N)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=Cc3nnn[nH]3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A mixture of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanovinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (385 mg), sodium azide (99 mg), ammonium chloride (81 mg) and N,N-dimethylformamide (5 ml) is stirred at 100°C. overnight. The mixture is partitioned by adding ethyl acetate and a saturated brine. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform to chloroform:methanol=5:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[2-(tetrazole-5-yl)vinyl]pyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (155 mg). MS (m/z): 678 [M+H]+
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>CCOCC>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:5][CH2:1][CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C#CCCOC1CCCCO1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
3-Butyn-1-ol (3) (7.0 g, 100 mmol) was dissolved in 50 mL dry ether, and the solution was cooled to 0°. A few crystals of p-toluenesulphonic acid were added, followed by dropwise addition of 9.24 g (110 mmol) of dihydropyran. The resulting solution was warmed to 20°, stirred for 16 hr, and extracted with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The solution was dried (MgSO4), concentrated in vacuo, and distilled to give 7 (14.78 g, 96% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]=1.[C:20]1([CH2:26]CO)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S([O-])(O)(=O)=O.[K+].CO>C1(C)C=CC=CC=1>[C:4]1([CH2:3][CH2:19][O:18][CH:3]([O:2][CH2:1][CH2:26][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1
Reactant: OCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Oc1cccc(C(OCCc2ccccc2)OCCc2ccccc2)c1
Reaction time: 2 h

Procedure:
One g (3.73 mmol) of 3-tert.-butoxycarbonyloxy-benzaldehyde dimethylacetal was dissolved in 40 ml of dried toluene. After addition of 0.91 g (7.46 mmol) of 2-phenylethanol and 18 mg of potassium hydrogen sulfate, the resulting mixture was stirred for 2 hours under reflux. The methanol formed was then distilled off slowly, while more toluene was added to the mixture. After complete removal of the methanol, the mixture was cooled down and the potassium hydrogen sulfate was filtered off. The filtrate was concentrated in a rotary evaporator. This gave a yellowish, viscous oil, which was dried in an oil pump vacuum.
Reaction SMILES: C(=O)(OC(C)(C)C)[NH2:2].Br[C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1(C)C=CC=CC=1>[NH2:2][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc(Br)c1F
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(N)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
In a 500 mL flask was placed 1,1-dimethylethyl carbamate (6.03 g, 51.5 mmol), methyl 3-bromo-2-fluorobenzoate (10 g, 42.9 mmol), Pd2(dba)3.CHCl3 (0.89 g, 0.86 mmol), xantphos (1.49 g, 2.57 mmol) and cesium carbonate (16.8 g, 51.5 mmol). The flask was sealed with a rubber septum, placed under high vacuum, and toluene (200 mL) was added. Three cycles of high vacuum/N2 were performed and the reaction mixture was stirred at 90° C. overnight. The reaction was filtered through a pad of celite with EtOAc washing and concentrated. To the residue was added DCM (200 mL) followed by TFA (50 mL, 649 mmol), and the mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over NaSO4, stripped onto silica and column chromatographed on silica with 5% to 50% EtOAc:Hexane to give 5.53 g (76%) of the title compound of Step B. 1H-NMR (400 MHz, DMSO-d6) δ 6.92-7.01 (m, 3H), 5.37 (s, 2H), and 3.81 (s, 3H). MS (ESI): 170 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH2:5]([O:7][C:8]([C:10]1([C:13]2[O:14][CH:15]([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=2)[CH2:12][CH2:11]1)=[O:9])[CH3:6].Cl>O.C1COCC1.C(O)C>[CH2:5]([O:7][C:8]([C:10]1([CH:13]2[NH:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH:15]([CH3:21])[O:14]2)[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)C1(C2=NC(C)(C)CC(C)O2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C2NC(C)(C)CC(C)O2)CC1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
NaBH4 (3.18 g, 13.3 mmol) was dissolved in H2O (10 mL) and a drop of 10 M NaOH was added. To a solution of 1-(4,4,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-cyclopropanecarboxylic acid ethyl ester (10 g, 0.04 mol) in THF (33 mL) and ethanol (33 mL) was added the above alkaline solution of NaBH4 dropwise at −40° C. followed by 12M HCl (about 0.1 mL, the pH of the reaction mixture was adjusted to 6˜8). The resulting mixture was stirred at −40° C. for 1.5 hour. The reaction mixture was poured into water (100 mL) and basified with 10M NaOH to pH=10. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to give crude 1-(4,4,6-trimethyl-[1,3]oxazinan-2-yl)-cyclopropanecarboxylic acid ethyl ester (9.0 g), which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]([CH3:40])[C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:28]4[CH:27]=[N:26][C:25]([N:24]([CH3:40])[CH3:23])=[N:30][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cnc(N(C)C)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (140 mg, 0.561 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.8 (s, 2H), 7.6-7.77 (m, 3H), 7.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.77 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (s, 6H), 3.1 (m, 4H), 3.0 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:17]1[N:16]=[N:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:18]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2nnc(C3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 438 mg (1.7 mmol) of 1-(t-butoxycarbonyl)-4-(1H-tetrazol-5-yl)piperidine (from Step B) in 2 mL of DMF at 0° C. was treated with 83 mg (0.50 mmol) of NaH (60% in mineral oil) and 0.41 mL (3.4 mmol) of benzyl bromide. The resulting mixture was warmed to rt and stirred for 2.5 h. The mixture was partitioned between 50 mL of ether and 50 mL of water and the layers were separated. The organic layer was washed with 50 mL sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography using 2:1 v/v CH2Cl2/ether, then 1:2 v/v CH2Cl2/ether afforded 85 mg (15%) of 1-butoxycarbonyl)-4-((2-benzyl)tetrazol-5-yl)piperidine. Elution with 2:1 v/v EtOAc/CH2Cl2 afforded 95 mg (17%) of 1-butoxycarbonyl)-4-((1-benzyl)tetrazol-5-yl)piperidine. For 1-(butoxycarbonyl)-4-((2-benzyl)tetrazol-5-yl)piperidine: 1H NMR (500 MHz) δ1.47 (s, 9H), 1.76-1.84 (2H), 2.02-2.05 (2H), 2.91-2.95 (2H), 3.07-3.12 (m, 1H), 4.00-4.20 (2H), 5.71 (s, 2H), 7.35-7.40 (5H). For 1-(butoxycarbonyl)-4-((1-benzyl)tetrazol-5-yl)piperidine: 1H NMR (500 MHz) δ1.45 (s, 9H), 1.59-1.61 (2H), 1.76-1.84 (2H), 2.70-2.80 (2H), 2.85-2.89 (m, 1H), 4.00-4.20 (2H), 5.55 (s, 2H), 7.17-7.19 (2H), 7.36-7.39 (3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1>C(O)(=O)CCC>[CH2:2]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)[CH2:3][CH2:15][CH3:14]
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Solvent: CCCC(=O)O
Product: CCCCOCc1cc2c3ccccc3[nH]c(=O)n2n1
Yield: 148.5 %

Procedure:
2-(Hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (3.0 g, 0.0139 mole) is suspended in 250 ml of n-butyric acid and refluxed overnight under nitrogen. The resultant solution is stripped to a solid which is crystallized from a mixture of ethyl acetate-absolute ethanol to give 2.8 g of product (71% yield), m.p. 170°-172°. An analytical sample is prepared by recrystallizing the above material from ethyl acetate-absolute ethanol (1:4) to give 2.5 g of pure title compound, m.p. 170°-172°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[CH:16]=2)[CH2:11]1)=[O:9].[ClH:30]>CO>[ClH:30].[OH:23][NH:22][C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:8](=[O:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:19][CH2:18]2)=[O:21]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1ccccn1)C2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)Cc1ccccn1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 75 mg of 2-(pyridin-2-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 6 ml methanol and 6 ml of an aqueous, 0.1 N hydrochloric acid is stirred overnight at ambient temperature. The reaction mixture is evaporated and the residue is dissolved in a mixture of 2 ml water and 2 ml acetonitrile and lyophilized. 75 mg of the title compound are obtained as colorless solid. MH+=312.1
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH2:9][CH2:8]1)#[CH:2].FC(F)(F)C(O)=[O:32]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)(=[O:32])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: C#Cc1cccc(CC2CCc3c2cc(C(=O)OC)n3C(=O)OC(C)(C)C)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C(C)=O)c1
Reaction time: 2 h

Procedure:
The title compound was synthesized from 1-tert-butyl 2-methyl 4-(3-ethynylbenzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate (see Example 2.51). 1-tert-Butyl 2-methyl 4-(3-ethynylbenzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate (0.016 g, 0.042 mmol) was dissolved in trifluoroacetic acid (1 mL) and stirred for 2 h. The reaction was then quenched with bicarbonate solution and extracted three times with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane to afford the title compound. 0.006 g. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.07-2.16 (m, 1H) 2.49-2.55 (m, 1H) 2.57 (s, 3H) 2.61-2.68 (m, 2H) 2.88 (d, J=7.40 Hz, 2H) 3.29-3.37 (m, 1H) 3.70 (s, 3H) 6.28 (d, J=1.59 Hz, 1H) 7.41-7.50 (m, 2H) 7.82-7.87 (m, 2H) 10.48 (br. s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[C:28]4[C:23](=[C:24]([N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].Cl.[NH2:33][OH:34].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:34][NH:33][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[C:28]4[C:23](=[C:24]([N:29]([CH3:30])[CH3:31])[CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3cccc4c(N(C)C)cccc34)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCN(c4ncc(C(=O)NO)s4)CC3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of compound (12k) (125 mg, 0.270 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (187 mg, 2.70 mmol) and a freshly prepared solution of sodium methoxide in methanol (92 mg, 4.00 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h (progress of the reaction was monitored by TLC analysis). The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13k (10 mg, yield 8.0%). HPLC: 90.69% (Rt=12.77 min).
Reaction SMILES: CC([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][CH3:19])CO.C(C(CCCCCCCCCCCCCC)[CH2:23][OH:24])C>>[CH2:12]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:23][OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCC(CC)CO
Reactant: CCCCCCCCCCCCCCCC(C)CO
Product: CCCCCCCCC(CO)CCCCCC

Procedure:
2-methyl-1-heptadecanol; 2-ethyl-1-hexadecanol;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3cnccn3)n2)c1
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A mixture of ethyl 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (370 mg), 1N aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred overnight under reflux conditions, and then 1N hydrochloric acid (6 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (210 mg, yield: 60%). This was recrystallized from ethanol. Melting point: 97–98° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[CH:4]=[C:3]([CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: COc1cc2ccc(CCl)cc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2ccc(CN3CCN(Cc4ccc5cc(OC)c(OC)c(OC)c5c4)CC3)cc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxynaphthalene (226 mg) and piperazine (37 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:7]=[C:6]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]S(=O)(=O)N)=[C:22]([F:31])[CH:21]=2)(=[O:19])=[O:18])[CH:5]=1.S(Cl)(=O)(=O)N.C1(C)C=CC=CC=1.CCOC(C)=O>CC(N(C)C)=O.O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:7]=[C:6]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:31])[CH:21]=2)(=[O:18])=[O:19])[CH:5]=1
Reactant: COC(=O)c1cc(Cn2cncn2)cc(NS(=O)(=O)c2ccc(OS(N)(=O)=O)c(F)c2)c1
Agent: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(Cn2cncn2)cc(NS(=O)(=O)c2ccc(O)c(F)c2)c1
Reaction time: 18 h

Procedure:
3-(3-Fluoro-4-sulfamoyloxy-benzenesulfonylamino)-5-[1,2,4]triazol-1-ylmethyl-benzoic acid methyl ester (CAB04128, STX1528): Sulphamoyl chloride solution in toluene (3 ml, 0.7 M, 2.1 mmol) was concentrated under reduced pressure. The residue was dissolved In DMA (5 ml) at 0° C. and CAB04122 (120 mg, 0.295 mmol) was added to the solution. Stirring was continued for 18 hours, EtOAc (50 ml) and water 30 ml were added, the organic layer was separated, washed with water (3×30 ml) and brine (20 ml), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (chloroform/acetone 1:1) to give the title compound as a light yellow solid. Yield 86 mg (60%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=C[C:52]2[N:53](C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.NCC1C=CC(B(O)O)=CC=1>>[NH2:53][CH2:52][C:43]1[CH:2]=[CH:3][C:4]([C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:21]5[N:25]([CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]6)[C:24]6[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=6[N:22]=5)[CH:17]=4)[N:12]=3)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: NCc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(CN)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 46 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-aminomethylphenylboronic acid (49 mg, 0.2625 mmol) to produce the title compound (48 mg, 46% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][C:42](O)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:33]([F:51])[CH:32]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=[CH:10]4)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:33]([F:51])[CH:32]=1
Reactant: O=c1ccn(CCCO)cc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1ccc(=O)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
1-(3-Hydroxypropyl)-1,4-dihydro-4-pyridone (220 mg, 1.44 mmol) in methylene chloride (4 ml) followed by 1,1'-(Azodicarbonyl)dipiperidine (720 mg, 2.86 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), and tributylphosphine (0.69 ml, 2.8 mmol) in methylene chloride (20 ml) under nitrogen at 5° C. The mixture was stirred at 5° C. for 3 hours, allowed to warm to ambient temperature and stirred for a further 18 hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), and solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine mixtures (100/010 increasing to 70/30/0.5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[3-(4-oxo-1,4-dihydro-1-pyridyl)propoxy]quinazoline (48 mg, 11%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)CC2CCCN2C)c1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCCC1CC(=O)c1cccc(O)c1

Procedure:
40.5 of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)ethanone are boiled under reflux for 6 hours with 180 ml of acetic acid and 180 ml of 47% hydrobromic acid. After concentration of the solution, the oily residue is brought to crystallization through treatment with 150 ml of hot ethanol. Cooling is allowed to take place, and 39.8 g (76% of theory) of the hydrobromide of the title compound is filtered off as greenish crystals: m.p. 165° to 168°.