Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1.C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:37][C:5]1[C:4](=[O:22])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)O)c1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(N)c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (6.00 g, 19.1 mmol), DPPA (6.16 mL, 28.6 mmol) and Et3N (3.99 mL, 28.6 mmol) in toluene (60 mL) was heated to 100° C. for 2 h. To the mixture was added 8 M NaOH aqueous solution (23.8 mL) at 0° C. The mixture was stirred at room temperature for 3 h, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc/i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (3.57 g, 66% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.83 (3H, s), 6.31 (2H, s), 7.64-7.79 (2H, m), 8.13 (2H, s), 8.64 (1H, s).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][O:23][C:24]1[CH:53]=[CH:52][C:27]2[N:28]=[C:29]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)[O:30][C:26]=2[CH:25]=1>CO>[ClH:1].[CH3:22][O:23][C:24]1[CH:53]=[CH:52][C:27]2[N:28]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)[O:30][C:26]=2[CH:25]=1
Reactant: COc1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)oc2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(N3CCNCC3COc3cccnc3)oc2c1
Reaction time: 2 h
Yield: 44 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-methoxybenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (150.6 mg, 0.225 mmol) in MeOH (1 mL). After 2 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH, and brine (20 mL) was added. This was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.031 mL) was added. The mixture was concentrated under reduced pressure to give 37.4 mg (44%) of the desired product as the hydrochloride salt. LC-MS: RT=4.00 min, [M+H]+=341.1.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].NC1C=C2C(=CC=1)C(=O)OC2.[I:38]C1C=C(C(C)(C)CC(=O)C(O)=O)C=CC=1>>[I:38][C:20]1[CH:19]=[C:18]([C:16]([CH3:24])([CH3:17])[CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]2[CH:2]=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:6](=[O:7])[O:5][CH2:4]3)=[O:26])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reactant: CC(C)(CC(=O)C(=O)O)c1cccc(I)c1
Agent: Nc1ccc2c(c1)COC2=O
Product: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1)COC2=O)c1cccc(I)c1

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(3-iodophenyl)-4-methyl-2-oxo-valeric acid, melting point 160-161° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[N:7]=[C:8]([NH:12][C:13](=[O:31])[CH:14]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[S:9][C:10]=1[CH3:11])C.[OH-].[Na+].Cl>O1CCOCC1>[CH:16]1([CH2:15][CH:14]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:13]([NH:12][C:8]2[S:9][C:10]([CH3:11])=[C:6]([CH2:5][C:4]([OH:32])=[O:3])[N:7]=2)=[O:31])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)Cc1nc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1sc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1CC(=O)O
Yield: 93 %

Procedure:
{2-[3-Cyclopentyl-2-(4-methanesulfonylphenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic acid ethyl ester (49 mg, 0.1 mmol), dioxan (0.5 mL), and 1 N sodium hydroxide were stirred at room temperature for 20 h. The pH was adjusted to approx. 3 with 1 N hydrochloric acid (0.5 mL), the reaction mixture was concentrated in vacuo, and the precipitate was isolated by filtration. Yellow crystals of the title compound were washed with water and dried to give 43 mg (yield: 93%). 1H-NMR (CDCl3): δ 7.85 (d, 2H), 7.58 (d, 2H), 3.78 (t, 1H), 3.62 (s, 2H), 3.01 (s, 3H), 2.42 (s, 3H), 2.22-2.15 (m, 1H), 1.93-1.86 (m, 1H), 1.75-1.49 (m, 7H), 1.15-1.02 (m, 2H); HPLC-MS: m/z=451 (M+1).
Reaction SMILES: [CH:1](S(O)(=O)=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CC(C)=O>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC=CS(=O)(=O)O
Solvent: CC(C)=O
Product: C=CCCCCCCCCCCCCCC

Procedure:
The aqueous-acetone layer which contained the sulfonic acid fraction of the product was stripped of solvents at 40°-45°C. under a vacuum to give 2.85 g. of viscous acid identified as hexadecene sulfonic acid on the basis of an IR spectrum which showed the presence of trans olefinic double bond (965 cm-1) and the absence of sultones (no 830 and 530 cm-1 bands).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:24](=[O:25])[O:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1oc2c(ccc3[nH]c(=O)oc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 7-amino-3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-chromen-4-one (0.0532 g, 0.16 mmol) in anhydrous methylene chloride (2 ml) is treated at room temperature with a 20% phosgene in toluene solution (0.08 ml). After 30 min, triethylamine (0.032 g, 0.045 ml, 0.32 mmol, 2 eq.) is added, and the reaction mixture is stirred at room temperature for 1 h, transferred to the head of an aminoalkylated silica gel column (Sepra NH2, 50 micrometer, Phenomenex) and purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 1% acetic acid in ethyl acetate) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:23][C:24]=1[CH3:25].FC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[Cl:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1F
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester (example 15 d]) was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{2-chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16])[NH2:11].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]([NH:11][C:22]([C:19]2([CH3:18])[CH2:21][CH2:20]2)=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(N)cc1Cl
Reactant: CC1(C(=O)Cl)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)C2(C)CC2)cc1Cl
Reaction time: 1 h
Yield: 0 %

Procedure:
To 90 ml of benzene were added 1.0 g (5.9/1000 mole) of 3-chloro-4-isopropylaniline, 0.7 g of triethylamine, and 0.8 g (6.8/1000 mole) of 1-methylcyclopropanecarboxylic acid chloride. The mixture was stirred for 1 hour at 5° to 10° C. The precipitated crystals were separated by filtration, and the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The resulting dried filtrate was concentrated by an evaporator. The resulting oily product was isolated and purified by silica gel column chromatography [eluent: benzene/ethyl acetate=40/1 (v/v)] to give 1.3 g of N-(3-chloro-4-isopropylphenyl)-1-methylcyclopropanecarboxamide as an oil in a yield of 87.6 % based on 3-chloro-4-isopropylaniline. On standing for a long period of time, the oil crystallized.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11](=[O:16])(=[O:15])[NH:12][CH2:13][CH3:14])[CH:6]=1.O[Li].O>C1COCC1.O.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:13]([NH:12][S:11]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:17])=[O:2])[CH:10]=[CH:9][CH:8]=1)(=[O:16])=[O:15])[CH3:14]
Reactant: CCNS(=O)(=O)c1cccc(CC(=O)OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
(3-Ethylsulfamoyl-phenyl)-acetic acid methyl ester (0.28 g, 1.1 mmol) was dissolved in THF and LiOH hydrate (63 mg, 1.5 mmol) in water was added. The reaction mixture was stirred at room temperature for 4 hours and then diluted with ethyl acetate and 10% citric acid. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to afford (3-ethylsulfamoyl-phenyl)-acetic acid as a solid (0.25 g, 1.1 mmol 99% yield). 1H NMR (DMSO-d6) 7.71 ppm, 1H, s; 7.70 ppm, 1H, m; 7.50 ppm, 3H, m; 4.11 ppm, 1H, br s; 3.70 ppm, 2H, s; 2.81 ppm, 2H, m; 0.99 ppm, 3H, t.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]C)=O.[CH3:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:28][C:26]1[S:27][C:23]([CH3:22])=[CH:24][N:25]=1)=[O:20]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)s1
Yield: 46 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5-methyl-2-thiazolamine with a yield of 46% of theory.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Cl[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[N:27]=1>CCO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[N:27]=3)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1C=O
Reactant: OB(O)c1cc2cc(Cc3ccccc3)ccc2o1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(-c2cc3cc(Cc4ccccc4)ccc3o2)ccc1C=O
Temperature: 80 °C

Procedure:
In a sealed flask, a mixture of 5-benzylbenzofuran-2-ylboronic acid (525 mg, 2.1 mmol) and potassium acetate (0.41 g, 4.2 mmol) was set under argon, treated with bis{di(tbutyl)phenyl}palladium(II) dichloride (0.078 g, 0.12 mmol), followed by a solution of 6-chloro-2-methylnicotinaldehyde (0.29 g, 1.9 mmol) in EtOH (10 mL). The resulting suspension was degassed again and heated to 80° C. for 2 h. The mixture was cooled to 24° C., treated with EtOAc and washed with saturated aqueous NaHCO3 and brine (each 1×). The combined organic layers were dried over MgSO4 and evaporated. Purification by flash chromatography (hexanes to hexanes/EtOAc=9:1) gave 6-(5-Benzylbenzofuran-2-yl)-2-methylnicotinaldehyde as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.33 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.97-7.95 (m, 2H), 7.51-7.49 (m, 2H), 7.31-7.29 (m, 2H), 7.24-7.21 (m, 3H), 4.10 (s, 2H), 3.07 (s, 3H). MS (ESI) m/z: Calculated: 327.4; Observed: 328.1 (M++1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:28])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]4=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.[CH2:29]1[O:32][C@H:30]1[CH3:31]>CN1C(=O)CCC1.CO>[Cl:28][C:6]1[C:5]([CH:3]2[CH2:2][N:1]([CH2:29][C@@H:30]([OH:32])[CH3:31])[CH2:4]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:16]2[N:15]=1
Reactant: C[C@H]1CO1
Reactant: CCNc1nc(Nc2cc(C#N)cc(C3CNC3)c2Cl)nn2c(C#N)cnc12
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCNc1nc(Nc2cc(C#N)cc(C3CN(C[C@H](C)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 32.9 %

Procedure:
A suspension of 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 367)(16 mg, 0.041 mmol) and (S)-(−)-propylene oxide (0.085 mL, 1.22 mmol) in a mixture of NMP (0.8 mL) and MeOH (0.2 mL) was stirred at 50° C. for 4.5 hr. The solvent was removed and the product was purified by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound (6.1 mg). This was converted to the mono HCl salt.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:7][CH2:8][CH2:9][N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][OH:13]
Reactant: OCCNCCO
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OCCN(CCO)Cc1ccccc1

Procedure:
The improvements in the above process aspects of the invention which afford a substantially quantitative yield of N,N-bis(2-chloroethyl)benzylamine, are based in part on modifications which eliminate formation of by-products and in part on a reverse in the order of addition of reactants. One improvement is based on the use of a molar equivalent quantity of sodium carbonate in the reaction of bis(2-hydroxyethyl)amine with benzyl chloride to produce N,N-bis(2-hydroxyethyl)benzyl amine, thereby completely inhibiting formation of the by-products N,N-dibenzyl-N-(2-hydroxyethyl)amine and N-benzyl-N-(2-benzyloxyethyl)-N-(2-hydroxyethyl)amine, which are produced in relatively large quantities (about 16% and 20% respectively) in the absence of said sodium carbonate. Another improvement is based on the addition of N,N-bis(2-hydroxyethyl)benzylamine in toluene solution to slightly more than a two molar excess of thionyl chloride rather than the heretofore reverse addition of thionyl chloride to N,N-bis(2-hydroxyethyl)benzylamine, thereby completely eliminating the formation of N-benzylmorpholine. Another improvement is the azeotropic distillation of the toluene solution of N,N-bis(2-hydroxyethyl)benzylamine to remove the water formed by the reaction, thereby avoiding the use of excess thionyl chloride to ensure completion of reaction in the chlorination step.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].O.C(OCC)(=O)C>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCc1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-octylaniline (5 ml) in a mixture of pyridine (12.5 ml) and chloroform (40 ml) was added phenyl chloroformate (2.95 ml) and stirred for 1.5 hours at ambient temperature. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-Octyl-N-phenoxycarbonylaniline (4.51 g)
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[I:1])=[CH:7][CH:8]=1)([CH3:20])[CH3:19]
Reactant: Oc1ccc2cccc(I)c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2cccc(I)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-iodo-2-naphthol, as described in Step A of Example 103 (2.75 g, 10.2 mmol) in dry DMF (25 mL), under argon, were added imidazole (1.39 g, 20.4 mmol) and triisopropylsilyl chloride (2.55 g, 13.2 mmol). The resulting mixture was stirred at ambient temperature for 4 hrs, then quenched with 10% aqueous citric acid (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2—50% hexane to yield the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1F)=[O:5])[CH3:2].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=2[O:15]1>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][O:18][C:17]=3[CH:19]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[F:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(F)cccc1F
Reactant: Oc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of ethyl-2,6-difluorobenzene-carboxylate (EXAMPLE 1C; 373 mg, 2.0 mmol) in DMSO (0.5 ml) was added to a solution of the solid prepared above in DMSO (1.0 ml). The brownish solution was heated at 80° C. for 2 hours. The solvent was evaporated, the solid filtered, washed with water several times and dried. The crude product was purified by flash column chromatography on silica gel using 3-15% ethyl acetate in hexane to give 371 mg of the product (61% yield) as a light yellow oil and unreacted sesamol.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C([C:57](OC)=[O:58])#N>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:57][OH:58])[CH2:18][CH2:19][N:20]([C:23]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:21][CH2:22]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:3][CH2:2]1
Reactant: COC(=O)C#N
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-neopentyl-5-(1-tritylpiperidin-4-ylsulfonyl)-1H-benzo[d]imidazole (STEP E, 2.05 g, 3.24 mmol) in tetrahydrofuran (60 mL) at −60° C. was added lithium diisopropylamide (1.8 mol/L heptane/tetrahydrofuran/ethylbenzene solution, 2.34 mL, 4.22 mmol). After the mixture was warmed up to −40° C. over a period of 20 min and then stirred for 40 min at the same temperature, methyl cyanoformate (828 mg, 9.73 mmol) in tetrahydrofuran (3 mL) was added to the mixture. The mixture was stirred at 0° C. for 1.5 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate, gradient) to give 4:1 mixture of the title compound and the starting material (2.15 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:15]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][N+:12]([O-:15])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: OO
Reactant: N#Cc1cccc(-c2ccncc2)c1
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2cc[n+]([O-])cc2)c1

Procedure:
Starting from 4-(3-cyanophenyl)-pyridine, the title compound is prepared by oxidation with H2O2 in glacial acetic acid [J. Heterocycl. Chem. 11, 299 (1974)].