Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=3[F:21])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cc(F)ccc1F

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2,5-difluoro-benzamide was prepared starting from intermediate D and 2,5-difluoro-benzoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (br. s., 1H) 8.28 (d, J=8.66 Hz, 1H) 8.00 (s, 1H) 7.53-7.79 (m, 5 H) 7.21-7.52 (m, 4H) 6.92 (d, J=1.81 Hz, 1H) 4.39 (d, J=5.64 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:12][C:6]1[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:8]([OH:10])=[O:9])[CH3:18]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(OC)cc1C(=O)O
Yield: 58 %

Procedure:
5-Methoxysalicylic acid (2.00 g) was suspended in ethanol (28 ml), and thionyl chloride (2.11 g) was gradually added dropwise to the suspension. Thereafter, the mixture was heated under reflux for 2 hr. The solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with a 20% aqueous sodium hydroxide solution and was then extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-methoxysalicylic acid (1.37 g, yield 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C@H:16]2[CH2:18][C@H:17]2[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[OH:21][CH2:20][CH2:19][C@@H:17]1[CH2:18][C@@H:16]1[CH:13]1[CH2:12][CH2:11][N:10]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 ml RBF the 6-chloropyridine-3-carbaldehyde (1.907 g, 13.47 mmol) and 2-[(1S,2R)-2-(piperidin-4-yl)cyclopropyl]ethanol (2.28 g, 13.47 mmol) were dissolved in DMF (13.47 ml). Cesium carbonate (13.17 g, 40.4 mmol) was added and the mixture stirred at RT overnight. The mixture was poured into 4:1 water:brine (200 ml), extracted with EtOAc (3×100 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 275 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH:12](Br)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:9]>[Na].CN(C=O)C>[CH2:8]([O:10][C:11](=[O:20])[CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: Oc1ccncc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccncc1)c1cccnc1
Yield: 8 %

Procedure:
The product was formed in a manner similar to preparation 396 using the in situ-generated sodium salt of the 4-hydroxypyridine (2.13 g; 18.2 mmol; 1.2 equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). Column chromatographic purification over SiO2 (1% methanol/chloroform) produced a yellow/orange oil (320 mg; approx. 8% yield). MS(ES) calc'd: [M+H]+=259.2 m/z. Pound: 259.1 m/z.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[OH-].[K+].[BH4-].[Na+].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:2]([CH3:1])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH3:20]
Reactant: COC(=O)CC=C(C)CCC=C(C)C
Reactant: CCO
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(C)(C)CCCC(C)=CCC(=O)OC
Reaction time: 2 h

Procedure:
To a solution of 1.7 g. of methyl 4,8-dimethylnona-3,7-dienoate in 20 ml. of ethanol, cooled to about 0°, is added a suspension of 2.3 g. of mercuric acetate in 50 ml. of ethanol, over about 15 minutes. The reaction mixture is stirred for two hours and then, with cooling, 1.2 g. of potassium hydroxide in 20 ml. of ethanol is added. Then 0.26 g. of sodium borohydride is added in small portions and stirring continued 30 minutes. The solution is decanted, concentrated to half volume, diluted with water and extracted with ether. The ethereal phase is washed with water, dried over magnesium sulfate and the product chromatographed to yield methyl 8-ethoxy-4,8-dimethylnon-3-enoate.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[O:17]1[C:21]2=[CH:22][C:23]3[CH2:24][CH2:25][CH2:26][NH:27][C:28]=3[CH:29]=[C:20]2[O:19][CH2:18]1>CN1C(=O)CCC1>[O:17]1[C:21]2=[CH:22][C:23]3[CH2:24][CH2:25][CH2:26][N:27]([C:2]4[C:3](=[O:16])[NH:4][C:5]5[C:10]([N:11]=4)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=5)[C:28]=3[CH:29]=[C:20]2[O:19][CH2:18]1
Reactant: c1c2c(cc3c1OCO3)NCCC2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (161 mg, 0.67 mmol) in NMP (5 ml) was added the 2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinoline (180 mg, 1.02 mmol) and the reaction was stirred for 1 h at 140° C. The reaction mixture was cooled to room temperature, and the product was precipitated by the addition of water and filtered off to afford methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a brown solid (140 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:29]=[C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[N:28]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3)n2)s1
Yield: 89.6 %

Procedure:
To a mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(4-fluoro-phenyl)-guanidine nitrate (2.0 mmol, 0.44 g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixture was refluxed under N2 for 24 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as brown crystals (269 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.03 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, I H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1>CC#N.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CN(Cc1cc(Br)ccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CN(Cc1cc(Br)ccc1OCc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of (5-bromo-2-hydroxy-benzyl)-methyl-carbamic acid tert-butyl ester (1.0 g, 3.2 mmol), K2CO3 (655 mg, 4.74 mmol), and 4-bromomethyl-1,2-dichloro-benzene (1.14 g, 4.74 mmol) in CH3CN (6.3 mL) was heated at 90° C. overnight. The mixture was then cooled to rt, diluted with EtOAc and water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification by FCC (EtOAc/hexanes) gave the desired product (1.49 g, 99%). 1H NMR (CDCl3, mixture of rotamers): 7.49 (d, J=1.9, 1H), 7.46 (d, J=7.8, 1H), 7.31 (dd, J=8.7, 2.0, 1H), 7.28-7.22 (m, 2H), 6.73 (d, J=8.6, 1H), 5.00 (s, 2H), 4.52-4.38 (m, 2H), 2.90-2.80 (m, 3H), 1.52-1.39 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[CH3:34][N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[N:16]=[C:15]([C:4]4[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=5)[N:5]=4)[O:19][N:18]=3)=[CH:21][CH:22]=2)[CH2:27]1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CNCC5=O)cc4)no3)cc2C)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CN(C)CC5=O)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
A mixture of 3-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-phenyl)imidazolidin-4-one (Example 141, 50 mg, 0.12 mmol) and aqueous formaldehyde solution (37%, 0.09 mL, 1.21 mmol) in acetic acid (0.5 mL) was stirred at rt for 15 min and then cooled to 0° C. Sodium triacetoxyborohydride (384 mg, 1.81 mmol) was added, and the mixture was stirred for 1 h at 0° C. and then at rt over night. Dichloromethane was added, and the mixture was extracted twice with saturated aqueous sodium bicarbonate solution, whereupon it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to preparative HPLC (RP-18 column; acetonitrile/water gradient containing 0.1% trifluoroacetic acid). The product-containing fractions were combined, and the solvent was partly removed which resulted in precipitation of a solid. A neutral pH was established by adding saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 30 min whereupon the solid was filtered off and dried under reduced pressure to yield the title compound (30 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 2H), 7.69 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.80 (s, 1H), 5.41 (s, 2H), 4.61 (s, 2H), 3.48 (s, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ES-MS m/z 429 (MH)+, HPLC RT (Method D) 2.31 min.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: C/C=C/CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (71 mg, 70%), MS (ISP) m/z=409.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25].Cl.[Al]>C(=S)=S>[CH3:25][CH:24]([C:23]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([OH:9])=[CH:5][C:6]=1[OH:8])=[O:27])[CH3:26]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Al]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: S=C=S
Product: CC(C)C(=O)c1c(O)cc(O)cc1O
Reaction time: 5 h
Yield: 87.2 %

Procedure:
In a vessel fitted with a calcium chloride tube, 12.61 g (100.0 mmol) of 1,3,5-trihydroxybenzene (1) was suspended on a mixture of 35 ml of nitrobenzene and 45 ml of carbon disulfide and they were stirred. To the mixture, 40.0 g (300 mmol, 3.00 equivalents) of granular aluminum chloride was added piecemeal at room temperature. They were stirred for one hour and a nitrobenzene (10.0 ml) solution of 10.66 g (100.0 mmol, 1.000 equivalent) of isobutyryl chloride was slowly added dropwise to the mixture. After about 5 hours, the reaction mixture was poured into a cold 2 M hydrochloric acid (500 ml) solution to induce decomposition of aluminum salt and then was extracted from ether. The organic layer was washed with water and distilled off ether under a reduced pressure. To this was added a large amount of water and water was distilled under reduced pressure to remove nitrobenzene solvent by steam distillation method. The residue was dissolved in ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain 21.7 g of a crude reaction product. By recrystallization of the crude product from petroleum ether-methylene chloride (1:1), 17.1 g (yield 87.2%) of the product (4) was obtained in the form of light yellow powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+]>ClCCl.C1COCC1.O>[C:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)([CH3:27])([CH3:25])[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-3-methylbenzoic acid (3.5 g, 16.27 mmol) was suspended in anhydrous dichloromethane (25 mL) under argon. DMF (0.5 mL) was added and followed by addition of oxalyl chloride (1.7 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 min. and oxalyl chloride (0.5 mL) was added dropwise. The mixture was then stirred at room temperature for further 2 h. Solvent was evaporated. The residue was dissolved in anhydrous THF (25 mL) and cooled in an ice-bath. A solution of potassium tert-butoxide (3.65 g, 32.52 mmol) in anhydrous THF (20 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The mixture was extracted with EtOAc and organic phase was washed with brine and water, and dried over anhydrous MgSO4. After evaporation of solvent, brown oil was obtained (3.78 g, 86%). MS (ESI) 272.76 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5](C(O)=O)[CH:4]=[C:3]1[C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=1>Cl.C(O)(=O)C>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:3]2[C:2](=[O:1])[N:11]3[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]3)=[CH:5][CH:4]=2)[CH:16]=1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c(=O)n2ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(-c2cccc(C(F)(F)F)c2)ccc2ccccn12

Procedure:
0.83 g of 4-oxo-3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizine-1-carboxylic acid was heated to reflux in a mixture of 13 ml of concentrated hydrochloric acid and 6.5 ml of acetic acid until the reaction was completed. The solution was evaporated, whereupon 10 ml of water are added. The crystals were removed by filtration and dried. After chromatography on silica gel and recrystallization, there was obtained 3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizin-4-one as yellow crystals of m.p. 110°-111° (n-hexane/toluene).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38][CH3:39])=[O:37])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][CH2:27][C:28](=O)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CSC>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38][CH3:39])=[O:37])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCNCC1)COc1ccccc1-3
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCCN1CCNCC1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
A solution of methyl 14-cyclohexyl-7-(3-oxo-3-piperazin-1-ylpropyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.08 M) in THF was treated dropwise with BH3 DMS complex (2M in THF; 10 eq). The resulting solution was stirred at RT for 2.5 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution refluxed for 2 h. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product as a yellow foam (100%) that was used without further purification. (ES+) m/z 516 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:21]([F:22])=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]([O:37]C)=[O:36])[CH:30]=1.CCN=C=NCCCN(C)C.Cl.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:21]([F:22])=[CH:20][C:16]([C:17]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=3)=[O:18])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1cc(CN)ccn1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cc2F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3ccnc(C(=O)O)c3)cc2F)C1

Procedure:
(R)-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)methyl)picolinic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid and methyl 4-(aminomethyl)picolinate using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (500 MHz, CDCl3) δ 8.57 (d, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.67 (dd, 1H), 7.57 (d, 1H), 7.03 (dd, 1H), 6.95 (m, 1H), 6.88 (m, 2H), 6.78 (br s, 1H), 4.74 (d, 2H), 4.34 (m, 1H), 4.29 (m, 1H), 4.03 (m, 2H), 3.93 (m, 1H), 3.49 (m, 1H), 3.43 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H), 1.89 (m, 1H), 1.64 (m, 1H), 1.40 (t, 3H). MS (ES+) 495.2 (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([F:26])[CH:16]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:13]2=[O:27])=[CH:10][CH:9]=[CH:8][C:7]=1[C:28]1[CH:29]=[C:30]([NH:36][C:37]2[N:42]=[CH:41][C:40]([N:43]3[CH2:56][C:45]4([CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]4)[CH2:44]3)=[CH:39][CH:38]=2)[C:31](=[O:35])[N:32]([CH3:34])[N:33]=1)(=O)C.[Li+].[OH-]>O1CCOCC1>[C:52]([O:51][C:49]([N:47]1[CH2:46][C:45]2([CH2:56][N:43]([C:40]3[CH:41]=[N:42][C:37]([NH:36][C:30]4[C:31](=[O:35])[N:32]([CH3:34])[N:33]=[C:28]([C:7]5[CH:8]=[CH:9][CH:10]=[C:11]([N:12]6[N:21]=[CH:20][C:19]7[C:14](=[C:15]([F:26])[CH:16]=[C:17]([C:22]([CH3:23])([CH3:24])[CH3:25])[CH:18]=7)[C:13]6=[O:27])[C:6]=5[CH2:5][OH:4])[CH:29]=4)=[CH:38][CH:39]=3)[CH2:44]2)[CH2:48]1)=[O:50])([CH3:53])([CH3:54])[CH3:55]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (530 mg, 693 μmol) was combined with dioxane (15 ml) and 1M LiOH (3 ml) to give a dark brown solution. The reaction mixture was stirred at 25° C. for 4 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 4% MeOH in DCM) to afford 0.169 g (34%) of the title compound as a light yellow powder. (M+H)+=723 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.36 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.19 (s, 1H), 7.37-7.69 (m, 6H), 6.84-6.94 (m, 1H), 6.80 (d, J=3.0 Hz, 1H), 4.39 (d, J=6.8 Hz, 2H), 4.08 (s, 4H), 3.96 (s, 4H), 3.85 (s, 3H), 1.42 (s, 9H), 1.39 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:30])[C:7](=[N:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Br:28])[CH:21]=2)=[C:14]([CH3:29])[CH:13]=1)[C:8]#[N:9])C.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[O:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([N:11]2[C:4](=[O:3])[NH:5][C:6](=[O:30])[C:7]([C:8]#[N:9])=[N:10]2)=[CH:13][C:14]=1[CH3:29]
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(C)c(Oc2ccc(OC)c(Br)c2)c(C)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(C)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2C)cc1Br
Temperature: 120 °C
Yield: 98.8 %

Procedure:
A solution of ({[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-hydrazono}-cyano-acetyl)-carbamic acid ethyl ester (1.0 g) of PREPARATION 3, potassium acetate (200 mg) and acetic acid (11 ml) were heated to 120° C. for 5 h. The reaction was concentrated, water was added, and the resulting solids were collected and dried to afford the title compound as a yellow solid (895 mg). Calc.: 442.0; Found: 441.0 (M−1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][C:9]=1[CH2:14][O:15][Si](C(C)(C)C)(C)C)(=O)=O.[NH:23]1[CH2:26][CH2:25][CH2:24]1>C1COCC1>[N:23]1([CH2:6][CH2:7][C:8]2[N:12]([CH3:13])[N:11]=[N:10][C:9]=2[CH2:14][OH:15])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1nnc(CO[Si](C)(C)C(C)(C)C)c1CCOS(C)(=O)=O
Reactant: C1CNC1
Solvent: C1CCOC1
Product: Cn1nnc(CO)c1CCN1CCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 28.5 %

Procedure:
A solution of 2-[4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-methyl-1H-1,2,3-triazol-5-yl]ethyl methanesulphonate (642 mg, 1.84 mmol) and azetidine (2.48 ml, 18.4 mmol) in THF (10 ml) was heated at reflux for 4 h and then concentrated under reduced pressure while dry loading onto silica. The mixture was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 solution as eluent. After concentrating under reduced pressure, THF (3 ml), H2O (3ml) and AcOH (9 ml) were added and the mixture stirred at RT for 60 h. The solvents were removed under reduced pressure while azeotroping with toluene (2×25 ml). The residue was dissolved in CH2Cl2, dry loaded onto silica and purified by column chromatography on silica using 15% MeOH/CH2Cl2 containing 1% NH3 solution as eluent to yield the desired hydroxymethyltriazole (103 mg, 29%). 1H NMR (360 MHz, CDCl3) δ 4.65 (2H, s), 3.94 (3H, s), 3.25 (4H, t, J=7.2 Hz), 2.76-2.62 (4H, m), 2.11 (2H, quintet, 7.2 Hz). m/z (ES+) 196 (M+H+).