Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=C([C:8]2[N:9]=[C:10]3[C:16]([CH:17]=[O:18])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)C=N1)C.S(=O)(=O)([OH:29])N.[O-]Cl=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O>[N:9]1[CH:8]=[CH:13][N:12]=[C:11]2[NH:14][CH:15]=[C:16]([C:17]([OH:18])=[O:29])[C:10]=12
Reactant: NS(=O)(=O)O
Reactant: CCn1cc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)cn1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.12 g, 3.01 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) at 0° C. was added sulfamic acid (1.76 g, 18.1 mmol). Then added a solution of NaClO2 (0.44 g, 3.92 mmol) and KH2PO4 (4.92 g, 36.2 mmol) in H2O (30 mL) via dropping funnel over 15 min. The ice bath was removed and the yellow cloudy reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated to an oily yellow solid which was triturated with 5% EtOAc/hexanes to afford 1.05 g (90%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid as a light yellow solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:24])[CH:14]=2)[N:9]=1.O>CN(C=O)C>[Cl:24][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([S:1][CH2:2][CH2:3][OH:4])[N:17]=[C:16]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCS
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCSc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 86 mg of 2-mercaptoethanol in DMF (7.5 ml) was added 44 mg of sodium hydride (60%), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), followed by stirring at room temperature for 2 hours. The reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The resultant extract was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 266 mg of the titled compound. Mp.124.4° C. 1H NMR (CDCl3): 3.50 (2H, t, J=5.5 Hz), 3.64 (1H, br. t), 4.07 (2H, q-like, J=5.5 Hz), 7.57-7.61 (3H, m), 7.71-7.74 (2H, m), 7.77 (1H, dd, J=8.9, 2.3 Hz), 7.85 (1H, d, J=8.9 Hz), 7.97 (1H, d, J=2.3 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])[CH3:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1sccc1N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 65 °C
Yield: 83.6 %

Procedure:
To a solution of 55 (0.15 g; 0.42 mmol) in N,N-dimethylformamide (2 mL) at room temperature was added potassium carbonate (0.282 g; 2.12 mmol) followed by iodomethane (0.053 mL; 0.85 mmol). The reaction mixture was heated at 65° C. for 12 hours, cooled to room temperature, diluted with aqueous hydrochloric acid (50 mL; 2M) and extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude residue that was purified by chromatography on silica gel eluting with a 0 to 10% ethyl acetate/hexanes gradient to give the title product (0.129 g).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][O:9][CH2:10][C:11](O)=[O:12].B.C1COCC1>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(O)COCCc1cccc(Br)c1
Agent: B
Agent: N#N
Solvent: C1CCOC1
Product: OCCOCCc1cccc(Br)c1
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A 100 mL three-necked flask was fitted with a dropping funnel, septa and a N2 balloon. The flask was charged with a solution of 2-(3-bromophenethoxy)acetic acid (2.20 g, 8.49 mmol) in anhydrous THF (20 mL) and cooled in an ice bath. Borane-THF complex (1.0 M in THF, 17 mL, 2 equiv.) was added dropwise to the solution of the starting material in 15 min. After 3 h, the reaction was quenched by addition (cautiously at first until H2 evolution has abated) of THF/H2O (1:1, 30 mL). The resulting mixture was an amber solution together with a colorless precipitate. THF was removed from the solution by partial evaporation, and the product was extracted into ether (200 mL). The organic phase was washed sequentially with water (20 mL) and brine (20 mL), evaporated, and dried over Na2SO4 to afford the title product (2.00 g, 96%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.40 (s, 1H), 7.35-7.39 (m, 1H), 7.17-7.22 (m, 2H), 3.70-3.75 (m, 4H), 3.58 (t, 2H, J=6.9 Hz), 2.90 (t, 2H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].[CH2:12](I)[CH3:13].ClCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:12][CH3:13])=[C:2]([F:1])[CH:7]=1
Reactant: CCI
Reactant: Oc1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred virgorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were dired over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[OH-].[K+]>COCCOCCOC.Cl>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cc(Sc2ccc3ccccc3c2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: N#Cc1cc(Sc2ccc3ccccc3c2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A stirred solution of 13.0 grams (0.042 mole) of 2-nitro-5-(naphth-2-ylthio)benzonitrile in 200 mL of 2-methoxyethyl ether was cooled to 0° C., and a solution of 30.3 grams (0.134 mole) of stannous chloride dihydrate in 91 mL of concentrated hydrochloric acid was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred during a 2 hour period. After this time, the reaction mixture was poured, with stirring, into a mixture of 260 grams of aqueous 50% potassium hydroxide in 300 grams of ice. An oily material, which dropped out of the solution, ultimately solidified. The solid was collected by filtration and was washed with water. The solid was dissolved in methylene chloride and was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 12.0 grams of 2-amino-5-(naphth-2-ylthio)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][C:3]=1[O:16][CH3:17].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH:24]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[O:23][CH:24]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: COc1cc(CCCn2ccnc2)ccc1O
Reactant: ClCc1coc(-c2cccs2)n1
Product: COc1cc(CCCn2ccnc2)ccc1OCc1coc(-c2cccs2)n1
Yield: 80 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(2-thienyl)oxazole to obtain 4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-(2-thienyl)oxazole. The yield was 80%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 94-95° C.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][OH:7])[O:3][C@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1.CC#N.C([O-])(=O)CCC.C[O-].[Na+]>CO>[CH2:1]1[S:5][C@H:4]([CH2:6][OH:7])[O:3][C@@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1
Reactant: Nc1nc(=O)n([C@H]2CS[C@@H](CO)O2)cc1F
Agent: CCCC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2CS[C@H](CO)O2)cc1F
Reaction time: 20 h
Yield: 82 %

Procedure:
The 5'-O-butyrate of (+)-FTC (0.47 mmol, 149 mg) was dissolved in 16 mL of a solution of 4:1 pH 8 buffer:CH3CN. The clear solution was stirred and treated with 26 mg of pig liver esterase (PLE-A). The progress of the reaction was monitored by HPLC (FIG. 4). After 20 hours (52% conversion), the reaction mixture was extracted with 2×80 mL of CHCl3 and 80 mL of ethyl acetate. The organic layer extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The resulting residue was eluted on 2×1000 m pTLC plates using ethyl acetate as eluant (double elution) to give, after isolation, 53 mg (36% based on starting material) of FTC butyrate which was determined to have 98% enantiomeric excess (e.e.) by HPLC analysis. The enantiomerically-enriched butyrate was then treated with 1.6 mL of methanol followed by 0.38 mmol (20 mg) of sodium methoxide. The resulting mixture was stirred at room temperature, and the progress of the reaction was monitored by HPLC. The reaction was completed within 30 minutes. The solvent was removed by rotary evaporation to give a crude white solid (76 mg) that was eluted on a 1000 m pTLC using 5:1 ethyl acetate:ethanol. (-)-FTC was isolated as a white solid (33 mg; 82% yield). HPLC analysis of the FTC as its 5'-O-acetate derivative showed 97% e.e.; [α](20,D) -120.5° (c=0.88; abs. ethanol).
Reaction SMILES: [OH:1][CH:2]([C:7]([O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:3]([OH:5])=[O:4]
Reactant: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
9.2 g (19.3 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionate were dissolved in 26 ml of dioxane, and 13 ml of 3 N NaOH solution were added. The mixture was stirred at 60° C. for 3 hours. Water was added to the mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was distilled off. 6.5 g (71%) of a yellowish oil were isolated and were immediately reacted further.
Reaction SMILES: C(O)(=O)C.[CH:5]1([NH:8][NH2:9])[CH2:7][CH2:6]1.Cl.[CH:11](=O)[C:12]([CH3:14])=[O:13]>O>[CH:5]1([NH:8][N:9]=[CH:11][C:12](=[O:13])[CH3:14])[CH2:7][CH2:6]1
Reactant: CC(=O)C=O
Reactant: NNC1CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C=NNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Acetic acid (1.71 mL, 29.9 mmol) was slowly added to a solution of cyclopropylhydrazine.HCl (2.5 g, 18.1 mmol) in H2O (30 mL), and was then quickly added dropwise to a solution of pyruvaldehyde (40%, 2.36 mL, 14.5 mmol) in H2O (240 mL). This solution was stirred overnight at room temperature. The aqueous layer was salted and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 1.04 g of crude product as a reddish oil. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of ethyl acetate/hexanes (25:75 to 50:50) to afford 637 mg (35%) of 2-oxopropanal cyclopropylhydrazone as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:18][N:17]=2)[N:3]=1.[OH-].[K+].[F:30][C:31]([F:35])([F:34])[CH2:32]I>CS(C)=O.C(OCC)(=O)C>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[C:26]([O:27][CH2:32][C:31]([F:35])([F:34])[F:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3O)n2)n1
Reactant: FC(F)(F)CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3OCC(F)(F)F)n2)n1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 2-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridin-3-ol (prepared in an analogous manner to Intermediate 58, 85 mg, 0.23 mmol) in DMSO (5 mL) was added potassium hydroxide (77 mg, 138 μmol) and 1,1,1-trifluoro-2-iodo-ethane (159 mg, 760 μmol). The resultant solution was heated at 120 C for 12 h, allowed to cool to room temperature, diluted with ethyl acetate (10 mL) and washed with brine (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep HPLC (Method A) to give the title compound as a cream solid (58 mg, 57%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1ccccn1
Reactant: COc1ccc(B(O)O)cc1C=O
Product: COc1ccc(-c2ccccn2)cc1C=O

Procedure:
The title compound was prepared by employing the method described in Example 111, Step A with (3-formyl-4-methoxyphenyl)boronic acid and the commercially available 2-bromopyridine.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([C:31](=[O:33])[NH2:32])([NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl>CC(O)(C)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2([N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[NH:32][C:31]2=[O:33])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(Cl)c2F)(C(N)=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1cccc(Cl)c1F)NC2=O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Potassium t-butoxide (1.01 g, 8.97 mmol) was added to a solution of 4-carbamoyl-4-(3-chloro-2-fluoro-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 2.99 mmol) in tBuOH (30.0 ml) at room temperature, and the mixture was stirred at 40° C. for six hours. The reaction mixture was adjusted to pH 6 by adding 2 N HCl and then extracted with AcOEt three times. The organic layers were sequentially washed with H2O (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/AcOEt=90:10→50:50) to give 2-(3-chloro-2-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester as a colorless form (1.13 g, 99%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[CH:19][N:18](C(OC(C)(C)C)=O)[N:17]=4)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:28]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:20]=[CH:19][NH:18][N:17]=4)=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(-c3nc4cc(I)ccc4o3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Ic1ccc2oc(-c3ccc(-c4cc[nH]n4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Subsequently, tert-butyl 3-[4-(5-iodo-1,3-benzoxazol-2-yl)phenyl]-1H-1-pyrazolecarboxylate (14.6 mg) was dissolved in chloroform (500 μL), and trifluoroacetic acid (231 μL) was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by drying. The thus-obtained white solid was dissolved in chloroform, and the solution was washed sequentially with 1N aqueous sodium hydroxide, water, and saturated saline, followed by drying over magnesium sulfate. The solvent was evaporated under reduce pressure, and the solid was recovered through filtration by use of isopropyl ether, followed by drying under reduced pressure, to thereby yield the title compound (9.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH2:39]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:39][CH2:38][CH2:37][CH2:36][O:35][CH3:34])=[O:8])=[CH:4][N:3]=1
Reactant: COCCCN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCCNC(=O)c1ccc(Cl)nc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 75.8 %

Procedure:
Combined 6-chloronicotinic acid (6.0 g, 38.1 mmol), HOBT (2.57 g, 19.04 mmol) and EDC (10.95 g, 57.1 mmol) in CH2Cl2 (100 mL) the Hunig's base (9.98 mL, 57.1 mmol) and 3-methoxypropan-1-amine (5.85 mL, 57.1 mmol) were added and stirred at 20° C. for 22 h. The reaction mixture was concentrated in vacuo to give a residue which was taken up in EtOAc (250 mL) and washed with saturated aqueous ammonium chloride (250 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 330 g silica gel column eluted with 10 to 80% EtOAc in hexanes to give the title compound (6.6 g, 76% yield) as a white solid. MS m/z 229, 231 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76 (quin, J=6.7 Hz, 2 H) 3.24 (s, 3 H) 3.27-3.35 (m, 2 H) 3.38 (t, J=6.3 Hz, 2 H) 7.65 (dd, J=8.3, 0.8 Hz, 1 H) 8.23 (dd, J=8.3, 2.5 Hz, 1 H) 8.73 (t, J=5.3 Hz, 1 H) 8.82 (dd, J=2.5, 0.8 Hz, 1 H).
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=4[F:42])=[O:30])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1.ClCCCl.[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>O1CCCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=4[F:42])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:50]([N:49]([CH3:53])[CH3:48])=[O:51])[CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: CN(C)C(=O)Cl
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Agent: N#N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCN(C(=O)N(C)C)CC1
Temperature: 0 °C
Yield: 17.8 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL). Tetrahydrofuran was added dropwise until the reaction mixture was a complete solution. The solution was cooled to 0° C. and dimethylcarbamoyl chloride (4.7 μl, 1 eq) was added. The reaction mixture was allowed to gradually warm to rt over 17 hours. The reaction was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and purified via flash column chromatography (6:4 tetrahydrofuran/hexanes). The purified fractions were collected, concentrated, stirred in hexanes and filtered. The filtrate was placed under vacuum overnight to yield the title compound (6 mg, 17.8% yield). 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=6.5 Hz, 1H), 8.29 (t, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m, 1H), 7.29 (dd, J=12.3, 1.7 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 4.23 (s, 2H), 3.68 (m, 2H), 3.44 (m, 1H), 3.16 (s, 3H), 2.75 (s, 6H), 2.26 (m, 2H), 1.64 (m, 2H); MS [M+H]+=647; LCMS RT=3.03 min.
Reaction SMILES: C(C1[C:10](=O)[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]C1)CC.S1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2N=C1.[C:25]([OH:32])(=[O:31])C=CCCC>>[S:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N:9]=[CH:10]1.[C:19]1([C:25]([OH:32])=[O:31])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: CCCC=CC(=O)O
Reactant: CCCC1CSc2ccccc2NC1=O
Agent: c1ccc2scnc2c1
Product: O=C(O)C1=CCCCC1

Procedure:
In an analogous manner to the previous examples, 2,3-dihydro-3-propyl-1,5-benzothiazepin-4(5H)-one (melting point: 120°-122° C.) was obtained from benzothiazole and 2-hexenic acid, 2,3-dihydro-2,3-tetramethylene-1,5-benzothiazepin-4(5H)-one (melting point: 225°-227° C.) was obtained from benzothiazole and cyclohexene-1-carboxylic acid and 2,3-dihydro-7,8-dimethyl-1,5-benzothiazepin-(5H)one (melting point: 241°-244° C.) was obtained from 5,6-dimethylbenzothiazole and acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:20](Cl)=[O:21]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])=[CH:7][C:3]=1[C:4]([N:6]=[C:20]=[O:21])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Yield: 91.3 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzamide (0.700 g, 2.5 mmol), oxalyl chloride (0.3 mL, 3.0 mmol) and EDC (30 mL) to afford 0.700 g of the desired product.