Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:51][CH:50]=1>CN(C=O)C.C(OCC)C>[F:68][C:65]1[CH:64]=[CH:63][C:62]([CH:55]([C:52]2[CH:53]=[CH:54][C:49]([F:48])=[CH:50][CH:51]=2)[N:56]2[CH2:57][CH2:58][N:59]([C:5](=[O:7])[C@@H:4]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:60][CH2:61]2)=[CH:67][CH:66]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)CC(C(=O)O)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
4-Methyl-2-morpholin-4-yl-pentanoic acid (0.200 g, 0.994 mmol, Example 23, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.346 mL, 1.99 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.379 g, 0.994 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.287 g, 0.994 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) to provide 0.284 g (60%) of the pure titled compound as a white foam; mp 55-63° C. APCI-MS m/z 472.3.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:4]=2[N:3]=1.CN(C)C=O.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:4]=2[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-amino-1-(trans-4-hydroxycyclohexyl)-1H-benzimidazole-5-carboxylate (0.97 g, 0.0032 mol) was dissolved in N,N-dimethylformamide (10 mL, 0.2 mol) at room temperature. 1H-Imidazole (0.50 g, 0.0074 mol) and tert-butyldimethylsilyl chloride (0.53 g, 0.0035 mol) were added and the mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated bicarbonate then brine. The organics were collected and dried over sodium sulfate and concentrated. The crude solid was purified by combiflash chromatography using methylene chloride and methanol as eluent. Product fractions were concentrated to give an off white solid (1.099 g). MS (ESI (+)m/z) 418.04 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[C:7]([CH3:19])=[CH:6][C:5]=1[O:20][CH3:21].FC(F)(F)S(O[C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:34]([C:44](=[O:47])[NH:45][CH3:46])[C:33]=2[CH:48]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.O.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>[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:35]2[O:36][C:32]3[CH:31]=[CH:30][C:29]([C:8]4[C:7]([CH3:19])=[CH:6][C:5]([O:20][CH3:21])=[C:4]([CH:9]=4)[C:3]([O:2][CH3:1])=[O:22])=[CH:48][C:33]=3[C:34]=2[C:44](=[O:47])[NH:45][CH3:46])=[CH:42][CH:41]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Methyl-2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.2 g, 3.92 mmol, 1 eq), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.6 g, 3.92 mmol, 1 eq), Cesium carbonate (3.8 g, 11.7 mmol, 3 eq) and Tetrakis triphenylphosphinepalladium (0.13 g, 0.11 mmol, 0.03 eq) were dissolved in 1,4-dioxane/water and the above solution was stirred at 90° C. for 10 h. Then the reaction mixture was diluted with water and product was extracted with ethyl acetate and purified by combiflash chromatography using 40% ethyl acetate/hexane as eluent. Yield: 0.95 g (55%). 1H NMR (400 MHz, DMSO-d6): δ 2.3 (s, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 7.15 (s, 1H), 7.51 (s, 1H), 7.64 (m, 2H), 7.65 (m, 2H), 7.74 (d, 1H, J=8.48 Hz), 8.00-8.01 (m, 2H), 8.48 (d, 1H). LCMS: (ES+) m/z=448 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[CH2:12][CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[Ca+2]>O>[OH:15][CH2:14][CH2:13][CH2:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CNc1cccc(C#N)c1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CN(CCCO)c1cccc(C#N)c1
Yield: 125.7 %

Procedure:
3-methylaminobenzonitrile (17.34 g, 0.13 mol, 1.0 eq), 3-chloropropanol (49.70 g, 0.53 mol, 4.0 eq) and CaCO3 (52.50 g, 0.53 mol, 4.0 eq) are added into water (230 ml) at room temperature, the mixture is refluxed at elevated temperature for 40 h, and cooled, filtered and extracted with ethyl acetate (200 ml*3). The organic phases are combined, washed with water (100 ml*2), washed with saturated brine twice, dried over anhydrous sodium sulfate and concentrated to give a light yellow oily crude product (31.08 g). The residue could be used directly in next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[OH-:14].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:14][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(O)c1cc(C(=O)O)c(Br)cn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(C(=O)O)c(O)cn1
Temperature: 165 °C
Reaction time: 20 h

Procedure:
A mixture of 500 mg of 5-bromo-2,4-pyridinedicarboxylic acid from Example 2, 20 ml of 10 N aqueous sodium hydroxide solution and 250 mg of copper sulfate is heated at 165° C. in an autoclave for 4 hours. After cooling, the copper salt is filtered off with suction, the pH is brought to 1 with concentrated hydrochloric acid and the solution is evaporated. The solid is heated in a little methanol, the salts are filtered off and the solution is left to stand at 0° C. for 20 hours. The solid which has precipitated out is separated off and dried.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1([C:14](O)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[NH2:7][C:8]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1(C(=O)O)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NC1(CO)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 108.4 %

Procedure:
LiAlH4 powder (2.28 g, 60.0 mmol) was placed in a 200 mL round-bottom flask equipped with a magnetic stir bar. The flask was evacuated and backflushed with Ar, cooled to 0° C., and charged with dry THF (10 mL) via cannula. 1-Amino-cyclohexylcarboxylic acid (2.86 g, 20.0 mmol) was added in small portions as a solid. Upon completion of the addition, the mixture was heated to reflux for 12 h. The mixture was cooled to 0° C., treated slowly with satd aq Na2 CO3 (50 mL), warmed to rt, and stirred for 2 h. A white precipitate formed, which was separated by filtration, washed with THF (75 mL), and washed twice with EtOAc (100 mL). The filtrate was concentrated in vacuo. The residue was dissolved in DCM (50 mL), dried over Na2 SO4, and concentrated in vacuo to afford 2.80 g (97%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 3.33 (s, 2H), 1.45-1.56 (m, 6H), 1.31-1.45 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([OH:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCC(C)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of the product of Example 7A (505 mg, 2.447 mmol) in THF (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum hydride (12.2 mL, 12.237 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. Then, in succession, was added water (183 μL), 15% NaOH solution (183 μL), and water (548 μL). The reaction stirred for an additional 15 minutes before it was filtered and washed with THF. The filtrate was then concentrated under reduced pressure to obtain 4-(4-hydroxymethyl-phenyl)butan-2-ol as a brown oil (314 mg, 71% yield). Then to a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (234 mg, 1.155 mmol) in THF (45 mL) was added 4-(4-hydroxymethylphenyl)butan-2-ol (312 mg, 1.732 mmol), triphenylphosphine (454 mg, 1.732 mmol), and then diisopropyl azodicarboxylate (DIAD, 335 μL, 1.732 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography (100% ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated. The crude material was purified by flash column chromatography (4:1 hexane:ethyl acetate to 100% ethyl acetate) to obtain a clear oil (200 mg, 48% yield). 1H NMR (600 MHz, CDCl3): δ 7.73 (s, 1H), 7.32 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 5.30 (s, 1H), 5.27 (s, 2H), 3.83 (m, 1H), 2.80-2.76 (m, 1H), 2.71-2.66 (m, 1H), 1.63 (s, 9H), 1.23 (d, 3H, J=6.2); 13C (CDCl3 159.3, 153.9, 143.2, 132.5, 129.2, 127.6, 125.4, 150 MHz): δ HRMS calcd for C118.5, 73.4, 67.6, 66.6, 40.9, 32.0, 28.1, 23.9.19H25ClN2O3: 365.162647, found 365.1624.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:19]=[C:18](Cl)[S:17][N:16]=1.C(N(CC)CC)C>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:18]1[S:17][N:16]=[C:15]([Cl:14])[N:19]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nsc(Cl)n1
Reactant: CNCCCNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCCNC(=O)OC(C)(C)C)c1nc(Cl)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
(3-Methylamino-propyl)-carbamic acid tert-butyl ester (7.00 g, 36.8 mmol) and 3,5-dichloro-[1,2,4]thiadiazole (4.75 g, 30.7 mmol) were dissolved in DMSO (150 mL). Finally, triethylamine (3 mL) was added and the reaction mixture was stirred at room temperature for 24 h. After this period, brine (100 mL) was poured into the reaction vessel and the mixture was transferred to a separatory funnel. The resulting layer was extracted with DCM (3×300 mL). The DCM layer was then dried over anhydrous Na2SO4. The crude product was purified using flash silica chromatography (DCM to 9:1 DCM/MeOH) to afford 6.5 g (69%) of {3-[(3-chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 307.40.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([S:14]C(=O)N(C)C)=[CH:6][C:5]=1C.[CH3:22]C(C[AlH]CC(C)C)C.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:10]([C:8]1([CH3:22])[CH:9]=[C:4]([CH2:3][OH:21])[CH:5]=[CH:6][CH:7]1[SH:14])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1cc(C(C)(C)C)c(SC(=O)N(C)C)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(C)C=C(CO)C=CC1S
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 12.2 g (39.4 mmol) of 5-tert-butyl-4-dimethylcarbamoylsulfanyl-2-methyl-benzoic acid methyl ester (prepared in Example DDD) in toluene (140 mL) cooled to -78° C. under nitrogen was added 1.0M DIBAL/CH2Cl2 (236.6 mL), dropwise over a 2.5 hour period. The reaction mixture was stirred an additional 30 minutes at -78° C. following addition, then at 0° C. for 1 hour. Saturated aqueous citric acid solution (approximately 600 mL) was added very slowly and carefully. The mixture was then extracted twice with EtOAc; the organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.47 (s, 9 H), 2.27 (s, 3 H), 3.57 (s, 1 H), 4.63 (s, 2 H), 7.06 (s, 1 H), 7.32 (s, 1 H).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([S:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]2[CH2:37][O:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[ClH:1].[C:15]1([S:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[CH2:37][O:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:22])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 91 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(phenylsulfonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (122 mg, 0.223 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 82.4 mg (91%) of the desired product as a yellow solid. LC-MS: RT=3.71 min, [M+H]+=334.1.
Reaction SMILES: [NH2:1][C:2]1[N:20]=[C:5]2[C:6]([O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:1][C:2]3[N:20]=[C:5]4[C:6]([O:10][CH2:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: N#Cc1ccccc1COc1cccn2nc(N)nc12
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)cc2)CC1

Procedure:
262 b) 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}benzonitrile was prepared from 2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-benzonitrile (115.0 mg, 0.434 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (128 mg, 0.500 mmol) in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.101 g, 53%). MP=156-157° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.32 (s, 1H), 8.40 (d, J=6.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.80 (d, J=4.5 Hz, 2H), 7.62-7.60 (m, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 6.98-6.88 (m, 3H), 5.49 (s, 2H), 3.04-3.02 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H). MS=440 (MH)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:22]O>>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: CO
Reactant: CN1CCN(c2cc(CC(=O)O)ccn2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 85 °C
Yield: 78 %

Procedure:
Thionyl chloride (0.9 ml) was added to a solution of 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetic acid (900 mg, 3.82 mmol) in MeOH (15 ml) at 0° C. The reaction mixture was heated for 4 h at 85° C. and concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 750 mg (78%) of methyl 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetate as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[H-].[Na+].[C:17]([CH2:19]P(=O)(OCC)OCC)#[N:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:19][C:17]#[N:18]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1C=CC#N

Procedure:
Starting from 5 g (26.85 mmol) of 2-methoxynaphthaldehyde in 30 ml of anhydrous THF in the presence of 1.3 g (1.2 eq) of NaH (60% in oil) in 15 ml of anhydrous THF and 6.5 ml (1.2 eq) of diethyl cyanomethylphosphonate, the title product is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[F:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 12 h
Yield: 42.8 %

Procedure:
1.0 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 2.85 g of N-methylpiperazine were added to 15 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100° to 110° C. (bath temperature) for 12 hours and the reaction mixture was concentrated to dryness in vacuo and 40 ml of water was added to the residue. Then the product was extracted with chloroform. The extract was dried and concentrated to dryness in vacuo. The residue was recrystallized from ethanol to provide 550 mg of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as colorless needles with m.p. 250°-257° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][CH:3]=1.C1C(O)=CC=C(C)C=1.Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(O)cc1
Product: COC(=O)c1cnc(Oc2ccc(C)cc2)cn1

Procedure:
Instead of 4-hydroxybenzotrifluoride and 6-bromo-3-pyridinecarboxyaldehyde, p-cresol (833 mg) and methyl 5-chloro-2-pyrazinecarboxylate (1.33 g) were respectively used and treated by the same technique as in Reference Example 13-1 to give methyl 5-(4-methylphenoxyl)pyrazine-2-carboxylate as a colorless solid (1.36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[NH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].N1C=CC=CC=1.C(Cl)Cl>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cn[nH]c1-2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)n1cc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 0.33 g of 8-chloro-6-(2-chlorophenyl)-1H,4H-pyrazolo[4,3-d](2)benzazepine, 0.141 g of ethyl chloroformate, 0.16 g of pyridine and 10 ml of methylene chloride is stirred at room temperature for 2 hours. It is diluted with chloroform, washed with aqueous sodium bicarbonate, the organic phase separated, dried and evaporated. The residue is taken up in the minimum amount of acetone and the solution neutralized with ethereal hydrogen chloride, to yield the 8-chloro-6-(2-chlorophenyl)-2-ethoxycarbonyl-2H,4H-pyrazolo[4,3-d](2)benzazepine hydrochloride melting at 151°-152°.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C@H:6]([CH3:18])[CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])C.[OH-].[Na+]>CO>[CH3:18][C@H:6]([CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CC(=O)O
Yield: 82.3 %

Procedure:
145 mg of 3(R),7(R),11-trimethyl-dodecanoic acid ethyl ester and 0.5 ml of 6 N aqueous NaOH were refluxed in 3 ml of methanol for 2.0 hr. The methanol was removed at reduced pressure and water (100 ml) was added. The aqueous alkaline solution was extracted with diethyl ether (2 × 30 ml), cooled in an ice-bath, and acidified with concentrated hydrochloric acid. The acidic aqueous solution was extracted with diethyl ether (3 × 20 ml). The combined ether extract was washed with water (3 × 20 ml) and dried (MgSO4). Evaporation of ether to dryness at reduced pressure gave 107 mg of light yellow oil, which was distilled (Kugelrohr 135°-139°/0.2 mm) to yield 101 mg of 3(R),7,(R),11-trimethyl-dodecanoic acid as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:38]1[C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]2[C:34]1=[O:44]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCCCCCCCCCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Yield: 93 %

Procedure:
Following general procedure A, 70.0 mmol (18.6 g) of 12-Bromododecan-1-ol, 77.0 mmol (20.2 g) of triphenylphosphine, 77.0 mmol (11.3 g) of phthalimide and 77.0 mmol (16.1 mL) of diisopropyl azo dicarboxylate were reacted in 350 mL of tetrahydrofuran for 2.5 h and the mixture was processed accordingly. The crude product was purified by column chromatography (cyclohexane/ethyl acetate 9:1). Yield 93%.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[Cl:9][CH:10]([C:15](=O)[CH3:16])[C:11](OC)=[O:12].Cl>CO.CCOCC>[Cl:9][C:10]1[C:11]([OH:12])=[N:7][C:5]([CH3:6])=[N:8][C:15]=1[CH3:16]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1nc(C)c(Cl)c(O)n1
Temperature: 80 °C

Procedure:
Sodium methoxide (328 mg, 6.08 mmol, 30% solution in MeOH) was added to a stirring suspension of acetamidine hydrochloride (191 mg, 2.03 mmol) and methyl 2-chloro-3-oxobutanoate (500 mg, 3.04 mmol) in MeOH (10.1 mL). The reaction mixture was heated to 80° C. for 3 hours and then cooled to room temperature. With stirring, the reaction was treated with 2N HCl in Et2O (50 mL), and then concentrated in vacuo. The resulting solid was suspended in 1:1 acetone/CH2Cl2, stirred vigorously for 10 mins, and the solids collected by filtration to afford the title compound as a light yellow solid. The isolated product was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 159.2 found, 159.0 required.